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Jeong H, Kim SH, Kim J, Jeon D, Uhm C, Oh H, Cho K, Park IH, Oh J, Kim JJ, Jeong SH, Park JH, Park JW, Yun JW, Seo JY, Shin JS, Goldenring JR, Seong JK, Nam KT. Post-COVID-19 Effects on Chronic Gastritis and Gastric Cellular and Molecular Characteristics in Male Mice. Cell Mol Gastroenterol Hepatol 2025; 19:101511. [PMID: 40157534 DOI: 10.1016/j.jcmgh.2025.101511] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Revised: 03/20/2025] [Accepted: 03/21/2025] [Indexed: 04/01/2025]
Abstract
BACKGROUNDS & AIMS Since the Omicron variant emerged as a major severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant, COVID-19-associated mortality has decreased remarkably. Nevertheless, patients with a history of SARS-CoV-2 infection have been suffering from an aftereffect commonly known as 'long COVID,' affecting diverse organs. However, the effect of SARS-CoV-2 on gastric cells and disease progression was not previously known. We aimed to investigate whether SARS-CoV-2 infection affects stomach cells and if post-COVID-19 conditions can lead to severe gastric disease. METHODS Stomach specimens obtained from male K18-hACE2 mice 7 days after SARS-CoV-2 infection were subjected to a transcriptomic analysis for molecular profiling. To investigate the putative role of SARS-CoV-2 in gastric carcinogenesis, K18-hACE2 mice affected by nonlethal COVID-19 were also inoculated with Helicobacter pylori SS1. RESULTS Despite the lack of viral dissemination and pathologic traits in the stomach, SARS-CoV-2 infection caused dramatic changes to the molecular profile and some immune subsets in this organ. Notably, the gene sets related to metaplasia and gastric cancer were significantly enriched after viral infection. As a result, chronic inflammatory responses and preneoplastic transitions were promoted in these mice. CONCLUSION SARS-CoV-2 infection indirectly leads to profound and post-acute COVID-19 alterations in the stomach at the cellular and molecular levels, resulting in adverse outcomes following co-infection with SARS-CoV-2 and Hpylori. Our results show that 2 prevalent pathogens of humans elicit a negative synergistic effect and provide evidence of the risk of severe chronic gastritis in the post-COVID-19 era.
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Affiliation(s)
- Haengdueng Jeong
- Department of Biomedical Sciences, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea; Epithelial Biology Center and Department of Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Sung-Hee Kim
- Department of Biomedical Sciences, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea
| | - Jiseon Kim
- Department of Biomedical Sciences, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea
| | - Donghun Jeon
- Department of Biomedical Sciences, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea
| | - Chanyang Uhm
- Department of Biomedical Sciences, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea
| | - Heeju Oh
- Department of Biomedical Sciences, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea
| | - Kyungrae Cho
- Department of Biomedical Sciences, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea
| | - In Ho Park
- Department of Biomedical Sciences, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea; Institute of Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, South Korea
| | - Jooyeon Oh
- Department of Microbiology, Yonsei University College of Medicine, Seoul, South Korea
| | - Jeong Jin Kim
- Department of Biomedical Sciences, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea
| | - Sang-Ho Jeong
- Department of Surgery, Gyongsang National University Hospital, Jinju, Korea
| | - Ji-Ho Park
- Department of Surgery, Gyongsang National University Hospital, Jinju, Korea
| | - Jun Won Park
- Laboratory Animal Medicine, College of Veterinary Medicine, Seoul National University, Seoul, South Korea
| | - Jun-Won Yun
- Laboratory of Veterinary Toxicology, College of Veterinary Medicine, Seoul National University, Seoul, South Korea
| | - Jun-Young Seo
- Department of Biomedical Sciences, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea
| | - Jeon-Soo Shin
- Department of Biomedical Sciences, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea; Institute of Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, South Korea; Department of Microbiology, Yonsei University College of Medicine, Seoul, South Korea
| | - James R Goldenring
- Epithelial Biology Center and Department of Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Je Kyung Seong
- Korea Mouse Phenotyping Center, Seoul National University, Seoul, South Korea; Laboratory of Developmental Biology and Genomics, Research Institute for Veterinary Science, Brain Korea 21 PLUS Program for Creative Veterinary Science Research, College of Veterinary Medicine, Seoul National University, Seoul, South Korea; BIO-MAX Institute, Seoul National University, Seoul, South Korea; Interdisciplinary Program for Bioinformatics, Seoul National University, Seoul, South Korea.
| | - Ki Taek Nam
- Department of Biomedical Sciences, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea.
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Hdoufane I, Oubahmane M, Habibi Y, Delaite C, Alanazi MM, Cherqaoui D. Identification of potent TMPRSS4 inhibitors through structural modeling and molecular dynamics simulations. Sci Rep 2025; 15:2748. [PMID: 39838126 PMCID: PMC11750979 DOI: 10.1038/s41598-025-86961-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Accepted: 01/15/2025] [Indexed: 01/23/2025] Open
Abstract
TMPRSS4, a transmembrane serine protease type II, is associated with various pathological illnesses. It has been found to activate SARS-CoV-2, enhance viral infection of human small-intestinal enterocytes and is overexpressed in different types of cancers. Therefore, this study aims to disover potential TMPRSS4 inhibitors that have better binding affinity than the approved inhibitors: 2-hydroxydiarylamide and tyroserleutide. Since no 3D-structure is known for TMPRSS4, structural models for the TMPRSS4 serine protease domain were developed. The modeled structures were validated and subjected to molecular dynamics simulations. FDA-approved, clinical/preclinical drugs and natural products were docked to the pocket of TMPRSS4. Moreover, through a systematic analysis, MD simulations and MM-GBSA binding free energy calculations revealed that the best candidates Ergotamine, S55746, NPC478048, Lifirafenib, and NPC77101 are highly stable drug candidates in complex with TMPRSS4, displaying low RMSD and RMSF values with strong binding stability. Among these compounds, Ergotamine showed the most favorable binding energy (-33.73 kcal/mol). Overall, our in silico results revealed that these compounds could act as potent TMPRSS4 inhibitors and need to be validated by future experimental studies.
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Affiliation(s)
- Ismail Hdoufane
- Laboratory of Molecular Chemistry, Department of Chemistry, Faculty of Sciences Semlalia, Cadi Ayyad University, BP 2390, 40000, Marrakech, Morocco.
| | - Mehdi Oubahmane
- Laboratory of Molecular Chemistry, Department of Chemistry, Faculty of Sciences Semlalia, Cadi Ayyad University, BP 2390, 40000, Marrakech, Morocco
| | - Youssef Habibi
- Sustainable Materials Research Center (SUSMAT-RC), University Mohamed VI Polytechnic (UM6P), Hay Moulay Rachid, Benguerir, Morocco
| | - Christelle Delaite
- Laboratoire de Photochimie et d'Ingénierie Macromoléculaires (LPIM EA 4567), Université de Haute-Alsace, 68100, Mulhouse, France
| | - Mohammed M Alanazi
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia
| | - Driss Cherqaoui
- Laboratory of Molecular Chemistry, Department of Chemistry, Faculty of Sciences Semlalia, Cadi Ayyad University, BP 2390, 40000, Marrakech, Morocco
- Sustainable Materials Research Center (SUSMAT-RC), University Mohamed VI Polytechnic (UM6P), Hay Moulay Rachid, Benguerir, Morocco
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D'Arpino MC, Sineli PE, Goroso G, Watanabe W, Saavedra ML, Hebert EM, Martínez MA, Migliavacca J, Gerstenfeld S, Chahla RE, Bellomio A, Albarracín VH. Wastewater monitoring of SARS-CoV-2 gene for COVID-19 epidemiological surveillance in Tucumán, Argentina. J Basic Microbiol 2024; 64:e2300773. [PMID: 38712352 DOI: 10.1002/jobm.202300773] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 03/12/2024] [Accepted: 04/08/2024] [Indexed: 05/08/2024]
Abstract
Wastewater-based epidemiology provides temporal and spatial information about the health status of a population. The objective of this study was to analyze and report the epidemiological dynamics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the province of Tucumán, Argentina during the second and third waves of coronavirus disease 2019 (COVID-19) between April 2021 and March 2022. The study aimed to quantify SARS-CoV-2 RNA in wastewater, correlating it with clinically reported COVID-19 cases. Wastewater samples (n = 72) were collected from 16 sampling points located in three cities of Tucumán (San Miguel de Tucumán, Yerba Buena y Banda del Río Salí). Detection of viral nucleocapsid markers (N1 gene) was carried out using one-step reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Viral loads were determined for each positive sample using a standard curve. A positive correlation (p < 0.05) was observed between viral load (copies/mL) and the clinically confirmed COVID-19 cases reported at specific sampling points in San Miguel de Tucumán (SP4, SP7, and SP8) in both months, May and June. Indeed, the high viral load concurred with the peaks of COVID-19 cases. This method allowed us to follow the behavior of SARS-CoV-2 infection during epidemic outbreaks. Thus, wastewater monitoring is a valuable epidemiological indicator that enables the anticipation of increases in COVID-19 cases and tracking the progress of the pandemic. SARS-CoV-2 genome-based surveillance should be implemented as a routine practice to prepare for any future surge in infections.
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Affiliation(s)
- María Cecilia D'Arpino
- Laboratory of Molecular and Ultraestructural Microbiology, Centro Integral de Microscopía Electrónica, (CIME-UNT-CONICET), Facultad de Agronomía, Zootecnia y Veterinaria, Universidad Nacional de Tucumán, Tucumán, Argentina
| | - Pedro Eugenio Sineli
- Planta Piloto de Procesos Industriales Microbiológicos (PROIMI-CONICET), Tucumán, Argentina
| | - Gustavo Goroso
- Laboratorio de Processamento de Sinais e Modelagem de Sistemas Biológicos. Núcleo de Pesquisas Tecnológicas, Universidade Mogi das Cruzes, Sao Paulo, Brasil
| | - William Watanabe
- Laboratorio de Processamento de Sinais e Modelagem de Sistemas Biológicos. Núcleo de Pesquisas Tecnológicas, Universidade Mogi das Cruzes, Sao Paulo, Brasil
| | | | | | | | | | | | | | - Augusto Bellomio
- Instituto Superior de Investigaciones Biológicas (INSIBIO, CONICET-Universidad Nacional de Tucumán), Tucumán, Argentina
| | - Virginia Helena Albarracín
- Laboratory of Molecular and Ultraestructural Microbiology, Centro Integral de Microscopía Electrónica, (CIME-UNT-CONICET), Facultad de Agronomía, Zootecnia y Veterinaria, Universidad Nacional de Tucumán, Tucumán, Argentina
- Facultad de Ciencias Naturales e Instituto Miguel Lillo, Universidad Nacional Tucumán, Tucumán, Argentina
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McCoy R, Oldroyd S, Yang W, Wang K, Hoven D, Bulmer D, Zilbauer M, Owens RM. In Vitro Models for Investigating Intestinal Host-Pathogen Interactions. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2306727. [PMID: 38155358 PMCID: PMC10885678 DOI: 10.1002/advs.202306727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 12/01/2023] [Indexed: 12/30/2023]
Abstract
Infectious diseases are increasingly recognized as a major threat worldwide due to the rise of antimicrobial resistance and the emergence of novel pathogens. In vitro models that can adequately mimic in vivo gastrointestinal physiology are in high demand to elucidate mechanisms behind pathogen infectivity, and to aid the design of effective preventive and therapeutic interventions. There exists a trade-off between simple and high throughput models and those that are more complex and physiologically relevant. The complexity of the model used shall be guided by the biological question to be addressed. This review provides an overview of the structure and function of the intestine and the models that are developed to emulate this. Conventional models are discussed in addition to emerging models which employ engineering principles to equip them with necessary advanced monitoring capabilities for intestinal host-pathogen interrogation. Limitations of current models and future perspectives on the field are presented.
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Affiliation(s)
- Reece McCoy
- Department of Chemical Engineering and BiotechnologyUniversity of CambridgeCambridgeCB3 0ASUK
| | - Sophie Oldroyd
- Department of Chemical Engineering and BiotechnologyUniversity of CambridgeCambridgeCB3 0ASUK
| | - Woojin Yang
- Department of Chemical Engineering and BiotechnologyUniversity of CambridgeCambridgeCB3 0ASUK
- Wellcome‐MRC Cambridge Stem Cell InstituteUniversity of CambridgeCambridgeCB2 0AWUK
| | - Kaixin Wang
- Department of Chemical Engineering and BiotechnologyUniversity of CambridgeCambridgeCB3 0ASUK
| | - Darius Hoven
- Department of Chemical Engineering and BiotechnologyUniversity of CambridgeCambridgeCB3 0ASUK
| | - David Bulmer
- Department of PharmacologyUniversity of CambridgeCambridgeCB2 1PDUK
| | - Matthias Zilbauer
- Wellcome‐MRC Cambridge Stem Cell InstituteUniversity of CambridgeCambridgeCB2 0AWUK
| | - Róisín M. Owens
- Department of Chemical Engineering and BiotechnologyUniversity of CambridgeCambridgeCB3 0ASUK
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Arienzo A, Gallo V, Tomassetti F, Pitaro N, Pitaro M, Antonini G. A narrative review of alternative transmission routes of COVID 19: what we know so far. Pathog Glob Health 2023; 117:681-695. [PMID: 37350182 PMCID: PMC10614718 DOI: 10.1080/20477724.2023.2228048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/24/2023] Open
Abstract
The Coronavirus disease 19 (COVID-19) pandemics, caused by severe acute respiratory syndrome coronaviruses, SARS-CoV-2, represent an unprecedented public health challenge. Beside person-to-person contagion via airborne droplets and aerosol, which is the main SARS-CoV-2's route of transmission, alternative modes, including transmission via fomites, food and food packaging, have been investigated for their potential impact on SARS-CoV-2 diffusion. In this context, several studies have demonstrated the persistence of SARS-CoV-2 RNA and, in some cases, of infectious particles on exposed fomites, food and water samples, confirming their possible role as sources of contamination and transmission. Indeed, fomite-to-human transmission has been demonstrated in a few cases where person-to-person transmission had been excluded. In addition, recent studies supported the possibility of acquiring COVID-19 through the fecal-oro route; the occurrence of COVID-19 gastrointestinal infections, in the absence of respiratory symptoms, also opens the intriguing possibility that these cases could be directly related to the ingestion of contaminated food and water. Overall, most of the studies considered these alternative routes of transmission of low epidemiological relevance; however, it should be considered that they could play an important role, or even be prevalent, in settings characterized by different environmental and socio-economic conditions. In this review, we discuss the most recent findings regarding SARS-CoV-2 alternative transmission routes, with the aim to disclose what is known about their impact on COVID-19 spread and to stimulate research in this field, which could potentially have a great impact, especially in low-resource contexts.
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Affiliation(s)
| | | | | | | | - Michele Pitaro
- National Institute of Biostructures and Biosystems (INBB), Rome, Italy
| | - Giovanni Antonini
- National Institute of Biostructures and Biosystems (INBB), Rome, Italy
- Department of Science, Roma Tre University, Rome, Italy
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6
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Hirani D, Salem V, Khunti K, Misra S. Newly detected diabetes during the COVID-19 pandemic: What have we learnt? Best Pract Res Clin Endocrinol Metab 2023; 37:101793. [PMID: 37468405 PMCID: PMC10303323 DOI: 10.1016/j.beem.2023.101793] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/21/2023]
Abstract
The SARS-CoV-2 pandemic has had an unprecedented effect on global health, mortality and healthcare provision. Diabetes has emerged as a key disease entity over the pandemic period, influencing outcomes from COVID-19 but also a tantalising hypothesis that the virus itself may be inducing diabetes. An uptick in diabetes cases over the pandemic has been noted for both type 1 diabetes (in children) and type 2 diabetes but understanding how this increase in incidence relates to the pandemic is challenging. It remains unclear whether indirect effects of the pandemic on behaviour, lifestyle and health have contributed to the increase; whether the virus itself has somehow mediated new-onset diabetes or whether other factors such as stress hyperglycaemic of steroid treatment during COVID-19 infection have played a roll. Within the myriad possibilities are some real challenges in interpreting epidemiological data, assigning diabetes type and understanding what in vitro data are telling us. In this review article we address the issue of newly-diagnosed diabetes during the pandemic, reviewing both epidemiological and basic science data and bringing together both strands of this emerging story.
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Affiliation(s)
- Dhruti Hirani
- Diabetes, Endocrinology And Metabolism, Imperial College Healthcare NHS Trust, UK
| | - Victoria Salem
- Diabetes, Endocrinology And Metabolism, Imperial College Healthcare NHS Trust, UK; Department of Bioengineering, Faculty of Engineering, Imperial College London, London, UK
| | - Kamlesh Khunti
- Diabetes Research Centre, University of Leicester, Leicester General Hospital, Leicester, UK
| | - Shivani Misra
- Diabetes, Endocrinology And Metabolism, Imperial College Healthcare NHS Trust, UK; Division of Metabolism, Digestion & Reproduction, Faculty of Medicine, Imperial College London, London, UK.
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Oh S, Seo H. Dietary intervention with functional foods modulating gut microbiota for improving the efficacy of COVID-19 vaccines. Heliyon 2023; 9:e15668. [PMID: 37124341 PMCID: PMC10121067 DOI: 10.1016/j.heliyon.2023.e15668] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Revised: 04/17/2023] [Accepted: 04/18/2023] [Indexed: 05/02/2023] Open
Abstract
Dysbiosis of the gut microbiota with aging contributes to a reduction in important cross-feeding bacterial reactions in the gut and immunosenescence, which could contribute to a decrease in vaccine efficacy. Fever, cough, and fatigue are the main signs of coronavirus disease 2019 (COVID-19); however, some patients with COVID-19 present with gastrointestinal symptoms. COVID-19 vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is one of the best measures to reduce SARS-CoV-2 infection rates and the severity of COVID-19. The immunogenicity of COVID-19 vaccines is influenced by the composition of the gut microbiota, and the immune response to COVID-19 vaccines decreases with age. In this review, we discuss gut microbiota dysbiosis and immunosenescence in the older adults, the role of gut microbiota in improving the efficacy of COVID-19 vaccines, and dietary interventions to improve the efficacy of COVID-19 vaccines in the older adults.
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Affiliation(s)
- Soyoung Oh
- Infectious Disease Research Center, Citizen's Health Bureau, Seoul Metropolitan Government, 110, Sejong-daero, Jung-gu, Seoul, 04524, Republic of Korea
| | - Haesook Seo
- Infectious Disease Research Center, Citizen's Health Bureau, Seoul Metropolitan Government, 110, Sejong-daero, Jung-gu, Seoul, 04524, Republic of Korea
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Moon Y. Gut distress and intervention via communications of SARS-CoV-2 with mucosal exposome. Front Public Health 2023; 11:1098774. [PMID: 37139365 PMCID: PMC10150023 DOI: 10.3389/fpubh.2023.1098774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 03/27/2023] [Indexed: 05/05/2023] Open
Abstract
Acute coronavirus disease 2019 (COVID-19) has been associated with prevalent gastrointestinal distress, characterized by fecal shedding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA or persistent antigen presence in the gut. Using a meta-analysis, the present review addressed gastrointestinal symptoms, such as nausea, vomiting, abdominal pain, and diarrhea. Despite limited data on the gut-lung axis, viral transmission to the gut and its influence on gut mucosa and microbial community were found to be associated by means of various biochemical mechanisms. Notably, the prolonged presence of viral antigens and disrupted mucosal immunity may increase gut microbial and inflammatory risks, leading to acute pathological outcomes or post-acute COVID-19 symptoms. Patients with COVID-19 exhibit lower bacterial diversity and a higher relative abundance of opportunistic pathogens in their gut microbiota than healthy controls. Considering the dysbiotic changes during infection, remodeling or supplementation with beneficial microbial communities may counteract adverse outcomes in the gut and other organs in patients with COVID-19. Moreover, nutritional status, such as vitamin D deficiency, has been associated with disease severity in patients with COVID-19 via the regulation of the gut microbial community and host immunity. The nutritional and microbiological interventions improve the gut exposome including the host immunity, gut microbiota, and nutritional status, contributing to defense against acute or post-acute COVID-19 in the gut-lung axis.
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Affiliation(s)
- Yuseok Moon
- Laboratory of Mucosal Exposome and Biomodulation, Department of Integrative Biomedical Sciences, Pusan National University, Yangsan-si, Republic of Korea
- Biomedical Research Institute, Pusan National University, Busan, Republic of Korea
- Graduate Program of Genomic Data Sciences, Pusan National University, Yangsan-si, Republic of Korea
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Zheng L, Zhang L, Zheng Y, An J, Wen G, Jin H, Tuo B. Digestive system infection by SARS‑CoV‑2: Entry mechanism, clinical symptoms and expression of major receptors (Review). Int J Mol Med 2023; 51:19. [PMID: 36660939 PMCID: PMC9911086 DOI: 10.3892/ijmm.2023.5222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Accepted: 01/05/2022] [Indexed: 01/21/2023] Open
Abstract
Besides causing severe acute respiratory syndrome (SARS), SARS‑coronavirus 2 (SARS‑CoV‑2) also harms the digestive system. Given the appearance of numerous cases of SARS‑CoV‑2, it has been demonstrated that SARS‑CoV‑2 is able to harm target organs such as the gastrointestinal tract, liver and pancreas, and either worsen the condition of patients with basic digestive illnesses or make their prognosis poor. According to several previously published studies, angiotensin‑converting enzyme II (ACE2) and transmembrane serine protease II (TMPRSS2) are expressed either singly or in combination in the digestive system and in other regions of the human body. In order to change the viral conformation, create a fusion hole and release viral RNA into the host cell for replication and transcription, SARS‑CoV‑2 is capable of binding to these two proteins through the spike protein on its surface. As a result, the body experiences an immune reaction and an inflammatory reaction, which may lead to nausea, diarrhea, abdominal pain and even gastrointestinal bleeding, elevated levels of liver enzymes, acute liver injury, pancreatitis and other serious lesions. In order to provide possible strategies for the clinical diagnosis and treatment of digestive system diseases during the COVID‑19 pandemic, the molecular structure of SARS‑CoV‑2 and the mechanism via which SARS‑CoV‑2 enters the human body through ACE2 and TMPRSS2 were discussed in the present review, and the clinical manifestations of SARS‑CoV‑2 infection in the digestive system were also summarized. Finally, the expression characteristics of ACE2 and TMPRSS2 in the main target organs of the digestive system were described.
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Affiliation(s)
- Liming Zheng
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Li Zhang
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Yi Zheng
- Department of Gastroenterology, The Fifth People's Hospital of Zunyi, Zunyi, Guizhou 563000, P.R. China
| | - Jiaxing An
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Guorong Wen
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Hai Jin
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Biguang Tuo
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
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Valyaeva AA, Zharikova AA, Sheval EV. SARS-CoV-2 cellular tropism and direct multiorgan failure in COVID-19 patients: Bioinformatic predictions, experimental observations, and open questions. Cell Biol Int 2023; 47:308-326. [PMID: 36229927 PMCID: PMC9874490 DOI: 10.1002/cbin.11928] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 08/24/2022] [Accepted: 09/25/2022] [Indexed: 02/06/2023]
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19), has led to an unprecedented public health emergency worldwide. While common cold symptoms are observed in mild cases, COVID-19 is accompanied by multiorgan failure in severe patients. Organ damage in COVID-19 patients is partially associated with the indirect effects of SARS-CoV-2 infection (e.g., systemic inflammation, hypoxic-ischemic damage, coagulopathy), but early processes in COVID-19 patients that trigger a chain of indirect effects are connected with the direct infection of cells by the virus. To understand the virus transmission routes and the reasons for the wide-spectrum of complications and severe outcomes of COVID-19, it is important to identify the cells targeted by SARS-CoV-2. This review summarizes the major steps of investigation and the most recent findings regarding SARS-CoV-2 cellular tropism and the possible connection between the early stages of infection and multiorgan failure in COVID-19. The SARS-CoV-2 pandemic is the first epidemic in which data extracted from single-cell RNA-seq (scRNA-seq) gene expression data sets have been widely used to predict cellular tropism. The analysis presented here indicates that the SARS-CoV-2 cellular tropism predictions are accurate enough for estimating the potential susceptibility of different cells to SARS-CoV-2 infection; however, it appears that not all susceptible cells may be infected in patients with COVID-19.
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Affiliation(s)
- Anna A. Valyaeva
- School of Bioengineering and BioinformaticsLomonosov Moscow State UniversityMoscowRussia
- Belozersky Institute of Physico‐Chemical BiologyLomonosov Moscow State UniversityMoscowRussia
| | - Anastasia A. Zharikova
- School of Bioengineering and BioinformaticsLomonosov Moscow State UniversityMoscowRussia
- Belozersky Institute of Physico‐Chemical BiologyLomonosov Moscow State UniversityMoscowRussia
| | - Eugene V. Sheval
- School of Bioengineering and BioinformaticsLomonosov Moscow State UniversityMoscowRussia
- Belozersky Institute of Physico‐Chemical BiologyLomonosov Moscow State UniversityMoscowRussia
- Department of Cell Biology and Histology, School of BiologyLomonosov Moscow State UniversityMoscowRussia
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Nobre JG, Delgadinho M, Silva C, Mendes J, Mateus V, Ribeiro E, Costa DA, Lopes M, Pedroso AI, Trigueiros F, Rodrigues MI, de Sousa CL, Brito M. Gut microbiota profile of COVID-19 patients: Prognosis and risk stratification (MicroCOVID-19 study). Front Microbiol 2022; 13:1035422. [PMID: 36483197 PMCID: PMC9723140 DOI: 10.3389/fmicb.2022.1035422] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 09/27/2022] [Indexed: 03/10/2024] Open
Abstract
Background Gut microbiota is intrinsically associated with the immune system and can promote or suppress infectious diseases, especially viral infections. This study aims to characterize and compare the microbiota profile of infected patients with SARS-CoV-2 (milder or severe symptoms), non-infected people, and recovered patients. This is a national, transversal, observational, multicenter, and case-control study that analyzed the microbiota of COVID-19 patients with mild or severe symptoms at home, at the hospital, or in the intensive care unit, patients already recovered, and healthy volunteers cohabiting with COVID-19 patients. DNA was isolated from stool samples and sequenced in a NGS platform. A demographic questionnaire was also applied. Statistical analysis was performed in SPSS. Results Firmicutes/Bacteroidetes ratios were found to be significantly lower in infected patients (1.61 and 2.57) compared to healthy volunteers (3.23) and recovered patients (3.89). Furthermore, the microbiota composition differed significantly between healthy volunteers, mild and severe COVID-19 patients, and recovered patients. Furthermore, Escherichia coli, Actinomyces naeslundii, and Dorea longicatena were shown to be more frequent in severe cases. The most common COVID-19 symptoms were linked to certain microbiome groups. Conclusion We can conclude that microbiota composition is significantly affected by SARS-CoV-2 infection and may be used to predict COVID-19 clinical evolution. Therefore, it will be possible to better allocate healthcare resources and better tackle future pandemics.
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Affiliation(s)
- José Guilherme Nobre
- Faculty of Medicine, Lisbon University, Lisbon, Portugal
- Faculdade de Medicina, Instituto de Saúde Ambiental, Universidade de Lisboa, Lisboa, Portugal
- PTSurg – Portuguese Surgical Research Collaborative, Lisbon, Portugal
| | - Mariana Delgadinho
- H&TRC- Health and Technology Research Center, ESTeSL- Escola Superior de Tecnologia da Saúde de Lisboa, Instituto Politécnico de Lisboa, Lisbon, Portugal
| | - Carina Silva
- H&TRC- Health and Technology Research Center, ESTeSL- Escola Superior de Tecnologia da Saúde de Lisboa, Instituto Politécnico de Lisboa, Lisbon, Portugal
- Centro de Estatística e Aplicações, Universidade de Lisboa, Lisbon, Portugal
| | - Joana Mendes
- H&TRC- Health and Technology Research Center, ESTeSL- Escola Superior de Tecnologia da Saúde de Lisboa, Instituto Politécnico de Lisboa, Lisbon, Portugal
| | - Vanessa Mateus
- H&TRC- Health and Technology Research Center, ESTeSL- Escola Superior de Tecnologia da Saúde de Lisboa, Instituto Politécnico de Lisboa, Lisbon, Portugal
| | - Edna Ribeiro
- H&TRC- Health and Technology Research Center, ESTeSL- Escola Superior de Tecnologia da Saúde de Lisboa, Instituto Politécnico de Lisboa, Lisbon, Portugal
| | - Diogo Alpuim Costa
- Breast Cancer Unit, CUF Oncologia, Lisbon, Portugal
- Faculdade de Ciências Médicas, NOVA Medical School, Lisbon, Portugal
| | - Miguel Lopes
- Departamento de Pneumologia, Hospital Garcia de Orta, Almada, Portugal
| | - Ana Isabel Pedroso
- Serviço de Medicina Intensiva, Hospital de Cascais Dr. José de Almeida, Cascais, Portugal
| | - Frederico Trigueiros
- Departamento de Medicina Interna I, Centro Hospitalar Lisboa Norte – Hospital de Santa Maria, Lisbon, Portugal
| | - Maria Inês Rodrigues
- Departamento de Medicina Interna I, Centro Hospitalar Lisboa Norte – Hospital de Santa Maria, Lisbon, Portugal
| | | | - Miguel Brito
- H&TRC- Health and Technology Research Center, ESTeSL- Escola Superior de Tecnologia da Saúde de Lisboa, Instituto Politécnico de Lisboa, Lisbon, Portugal
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12
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Clerbaux LA, Mayasich SA, Muñoz A, Soares H, Petrillo M, Albertini MC, Lanthier N, Grenga L, Amorim MJ. Gut as an Alternative Entry Route for SARS-CoV-2: Current Evidence and Uncertainties of Productive Enteric Infection in COVID-19. J Clin Med 2022; 11:5691. [PMID: 36233559 PMCID: PMC9573230 DOI: 10.3390/jcm11195691] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 08/17/2022] [Accepted: 09/20/2022] [Indexed: 12/15/2022] Open
Abstract
The gut has been proposed as a potential alternative entry route for SARS-CoV-2. This was mainly based on the high levels of SARS-CoV-2 receptor expressed in the gastrointestinal (GI) tract, the observations of GI disorders (such as diarrhea) in some COVID-19 patients and the detection of SARS-CoV-2 RNA in feces. However, the underlying mechanisms remain poorly understood. It has been proposed that SARS-CoV-2 can productively infect enterocytes, damaging the intestinal barrier and contributing to inflammatory response, which might lead to GI manifestations, including diarrhea. Here, we report a methodological approach to assess the evidence supporting the sequence of events driving SARS-CoV-2 enteric infection up to gut adverse outcomes. Exploring evidence permits to highlight knowledge gaps and current inconsistencies in the literature and to guide further research. Based on the current insights on SARS-CoV-2 intestinal infection and transmission, we then discuss the potential implication on clinical practice, including on long COVID. A better understanding of the GI implication in COVID-19 is still needed to improve disease management and could help identify innovative therapies or preventive actions targeting the GI tract.
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Affiliation(s)
| | - Sally A. Mayasich
- University of Wisconsin-Madison Aquatic Sciences Center at US EPA, Duluth, MN 55804, USA
| | - Amalia Muñoz
- European Commission, Joint Research Centre (JRC), 2440 Geel, Belgium
| | - Helena Soares
- Laboratory of Human Immunobiology and Pathogenesis, iNOVA4Health, Faculdade de Ciências Médicas—Nova Medical School, Universidade Nova de Lisboa, 1099-085 Lisbon, Portugal
| | | | | | - Nicolas Lanthier
- Laboratory of Hepatogastroenterology, Service d’Hépato-Gastroentérologie, Cliniques Universitaires Saint-Luc, UCLouvain, 1200 Brussels, Belgium
| | - Lucia Grenga
- Département Médicaments et Technologies pour la Santé, Commissariat à l’Énergie Atomique et aux Énergies Alternatives (CEA), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université Paris-Saclay, 91190 Paris, France
| | - Maria-Joao Amorim
- Instituto Gulbenkian de Ciência, 2780-156 Lisbon, Portugal
- Católica Biomedical Research Centre, Católica Medical School, Universidade Católica Portuguesa, 1649-023 Lisbon, Portugal
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13
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Clerbaux LA, Fillipovska J, Muñoz A, Petrillo M, Coecke S, Amorim MJ, Grenga L. Mechanisms Leading to Gut Dysbiosis in COVID-19: Current Evidence and Uncertainties Based on Adverse Outcome Pathways. J Clin Med 2022; 11:5400. [PMID: 36143044 PMCID: PMC9505288 DOI: 10.3390/jcm11185400] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 08/24/2022] [Accepted: 09/09/2022] [Indexed: 02/06/2023] Open
Abstract
Alteration in gut microbiota has been associated with COVID-19. However, the underlying mechanisms remain poorly understood. Here, we outlined three potential interconnected mechanistic pathways leading to gut dysbiosis as an adverse outcome following SARS-CoV-2 presence in the gastrointestinal tract. Evidence from the literature and current uncertainties are reported for each step of the different pathways. One pathway investigates evidence that intestinal infection by SARS-CoV-2 inducing intestinal inflammation alters the gut microbiota. Another pathway links the binding of viral S protein to angiotensin-converting enzyme 2 (ACE2) to the dysregulation of this receptor, essential in intestinal homeostasis-notably for amino acid metabolism-leading to gut dysbiosis. Additionally, SARS-CoV-2 could induce gut dysbiosis by infecting intestinal bacteria. Assessing current evidence within the Adverse Outcome Pathway framework justifies confidence in the proposed mechanisms to support disease management and permits the identification of inconsistencies and knowledge gaps to orient further research.
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Affiliation(s)
| | | | - Amalia Muñoz
- European Commission, Joint Research Centre (JRC), 2440 Geel, Belgium
| | | | - Sandra Coecke
- European Commission, Joint Research Centre (JRC), 21027 Ispra, Italy
| | - Maria-Joao Amorim
- Instituto Gulbenkian de Ciência, 2780-156 Oerias, Portugal
- Católica Medical School, Católica Biomedical Research Centre, Universidade Católica Portuguesa, 1649-023 Lisbon, Portugal
| | - Lucia Grenga
- Département Médicaments et Technologies pour la Santé, Commissariat à l’Énergie Atomique et Aux Énergies Alternatives (CEA), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université Paris-Saclay, 30200 Bagnols-sur-Cèze, France
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14
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Clerbaux LA, Albertini MC, Amigó N, Beronius A, Bezemer GFG, Coecke S, Daskalopoulos EP, del Giudice G, Greco D, Grenga L, Mantovani A, Muñoz A, Omeragic E, Parissis N, Petrillo M, Saarimäki LA, Soares H, Sullivan K, Landesmann B. Factors Modulating COVID-19: A Mechanistic Understanding Based on the Adverse Outcome Pathway Framework. J Clin Med 2022; 11:4464. [PMID: 35956081 PMCID: PMC9369763 DOI: 10.3390/jcm11154464] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 07/05/2022] [Accepted: 07/06/2022] [Indexed: 12/10/2022] Open
Abstract
Addressing factors modulating COVID-19 is crucial since abundant clinical evidence shows that outcomes are markedly heterogeneous between patients. This requires identifying the factors and understanding how they mechanistically influence COVID-19. Here, we describe how eleven selected factors (age, sex, genetic factors, lipid disorders, heart failure, gut dysbiosis, diet, vitamin D deficiency, air pollution and exposure to chemicals) influence COVID-19 by applying the Adverse Outcome Pathway (AOP), which is well-established in regulatory toxicology. This framework aims to model the sequence of events leading to an adverse health outcome. Several linear AOPs depicting pathways from the binding of the virus to ACE2 up to clinical outcomes observed in COVID-19 have been developed and integrated into a network offering a unique overview of the mechanisms underlying the disease. As SARS-CoV-2 infectibility and ACE2 activity are the major starting points and inflammatory response is central in the development of COVID-19, we evaluated how those eleven intrinsic and extrinsic factors modulate those processes impacting clinical outcomes. Applying this AOP-aligned approach enables the identification of current knowledge gaps orientating for further research and allows to propose biomarkers to identify of high-risk patients. This approach also facilitates expertise synergy from different disciplines to address public health issues.
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Affiliation(s)
- Laure-Alix Clerbaux
- European Commission, Joint Research Centre (JRC), 21027 Ispra, Italy; (S.C.); (E.P.D.); (N.P.); (M.P.); (B.L.)
| | | | - Núria Amigó
- Biosfer Teslab SL., 43204 Reus, Spain;
- Department of Basic Medical Sciences, Universitat Rovira i Virgili (URV), 23204 Reus, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
| | - Anna Beronius
- Institute of Environmental Medicine, Karolinska Institutet, 17177 Stockholm, Sweden;
| | - Gillina F. G. Bezemer
- Impact Station, 1223 JR Hilversum, The Netherlands;
- Department of Pharmaceutical Sciences, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands
| | - Sandra Coecke
- European Commission, Joint Research Centre (JRC), 21027 Ispra, Italy; (S.C.); (E.P.D.); (N.P.); (M.P.); (B.L.)
| | - Evangelos P. Daskalopoulos
- European Commission, Joint Research Centre (JRC), 21027 Ispra, Italy; (S.C.); (E.P.D.); (N.P.); (M.P.); (B.L.)
| | - Giusy del Giudice
- Finnish Hub for Development and Validation of Integrated Approaches (FHAIVE), Faculty of Medicine and Health Technology, Tampere University, 33100 Tampere, Finland; (G.d.G.); (D.G.); (L.A.S.)
| | - Dario Greco
- Finnish Hub for Development and Validation of Integrated Approaches (FHAIVE), Faculty of Medicine and Health Technology, Tampere University, 33100 Tampere, Finland; (G.d.G.); (D.G.); (L.A.S.)
| | - Lucia Grenga
- Département Médicaments et Technologies pour la Santé (DMTS), Université Paris-Saclay, CEA, INRAE, SPI, F-30200 Bagnols-sur-Ceze, France;
| | - Alberto Mantovani
- Department of Food Safety, Nutrition and Veterinary Public Health, Istituto Superiore di Sanità, 00161 Rome, Italy;
| | - Amalia Muñoz
- European Commission, Joint Research Centre (JRC), 2440 Geel, Belgium;
| | - Elma Omeragic
- Faculty of Pharmacy, University of Sarajevo, 71000 Sarajevo, Bosnia and Herzegovina;
| | - Nikolaos Parissis
- European Commission, Joint Research Centre (JRC), 21027 Ispra, Italy; (S.C.); (E.P.D.); (N.P.); (M.P.); (B.L.)
| | - Mauro Petrillo
- European Commission, Joint Research Centre (JRC), 21027 Ispra, Italy; (S.C.); (E.P.D.); (N.P.); (M.P.); (B.L.)
| | - Laura A. Saarimäki
- Finnish Hub for Development and Validation of Integrated Approaches (FHAIVE), Faculty of Medicine and Health Technology, Tampere University, 33100 Tampere, Finland; (G.d.G.); (D.G.); (L.A.S.)
| | - Helena Soares
- Laboratory of Immunobiology and Pathogenesis, Chronic Diseases Research Centre, Faculdade de Ciências Médicas Medical School, University of Lisbon, 1649-004 Lisbon, Portugal;
| | - Kristie Sullivan
- Physicians Committee for Responsible Medicine, Washington, DC 20016, USA;
| | - Brigitte Landesmann
- European Commission, Joint Research Centre (JRC), 21027 Ispra, Italy; (S.C.); (E.P.D.); (N.P.); (M.P.); (B.L.)
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15
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Arnaboldi S, Mangeri L, Galuppini E, Righi F, Tilola M, Scarazzato A, Bertasi B, Finazzi G, Varisco G, Filipello V, Losio MN. Is SARS-CoV-2 a Concern for Food Safety? A Very Low Prevalence from a Food Survey during the COVID-19 Pandemic in Northern Italy. Foods 2022; 11:2096. [PMID: 35885339 PMCID: PMC9324013 DOI: 10.3390/foods11142096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 07/08/2022] [Accepted: 07/13/2022] [Indexed: 02/04/2023] Open
Abstract
In 2019, SARS-CoV-2 was identified as the cause of an easily transmissible disease that was declared as a world pandemic. Foodborne transmission was never reported. However, early studies suggested that food could be involved in SARS-CoV-2 entry in the human gastrointestinal tract leading to possible infection, and highlighting the importance of further studies to inspect possible issues linked to food consumption. In this perspective, this work aimed at monitoring SARS-CoV-2 presence in some food and mains water samples in Northern Italy during the COVID-19 pandemic (2020-2022). A total of 1806 foods, 112 mains water samples, and 580 swabs on meat and dairy product surfaces were analyzed for SARS-CoV-2 RNA detection by Real-time PCR. All the analyzed samples were negative to viral RNA detection with the exception of one vegetable sample. Even if data on foodborne coronavirus transmission suggested a limited importance of this pathway, the impact of the current pandemic in Northern Italy deserved a rigorous investigation to rule out such possibility. Indeed, gaining insight on all SARS-CoV-2 possible transmission pathways, including the foodborne route, seemed of interest to maintain consumers' confidence and trust in food safety, and for the effective management of the current, and future, possible pandemics.
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Affiliation(s)
- Sara Arnaboldi
- Food Safety Department, Istituto Zooprofilattico Sperimentale della Lombardia e dell’Emilia Romagna (IZSLER), Via A. Bianchi 9, 25124 Brescia, Italy; (L.M.); (E.G.); (F.R.); (M.T.); (A.S.); (B.B.); (G.F.); (G.V.); (V.F.); (M.-N.L.)
- National Reference Centre for Emerging Risks in Food Safety (CRESA), Istituto Zooprofilattico Sperimentale della Lombardia e dell’Emilia Romagna (IZSLER), Via Celoria 12, 20133 Milan, Italy
| | - Lucia Mangeri
- Food Safety Department, Istituto Zooprofilattico Sperimentale della Lombardia e dell’Emilia Romagna (IZSLER), Via A. Bianchi 9, 25124 Brescia, Italy; (L.M.); (E.G.); (F.R.); (M.T.); (A.S.); (B.B.); (G.F.); (G.V.); (V.F.); (M.-N.L.)
- National Reference Centre for Emerging Risks in Food Safety (CRESA), Istituto Zooprofilattico Sperimentale della Lombardia e dell’Emilia Romagna (IZSLER), Via Celoria 12, 20133 Milan, Italy
| | - Elisa Galuppini
- Food Safety Department, Istituto Zooprofilattico Sperimentale della Lombardia e dell’Emilia Romagna (IZSLER), Via A. Bianchi 9, 25124 Brescia, Italy; (L.M.); (E.G.); (F.R.); (M.T.); (A.S.); (B.B.); (G.F.); (G.V.); (V.F.); (M.-N.L.)
- National Reference Centre for Emerging Risks in Food Safety (CRESA), Istituto Zooprofilattico Sperimentale della Lombardia e dell’Emilia Romagna (IZSLER), Via Celoria 12, 20133 Milan, Italy
| | - Francesco Righi
- Food Safety Department, Istituto Zooprofilattico Sperimentale della Lombardia e dell’Emilia Romagna (IZSLER), Via A. Bianchi 9, 25124 Brescia, Italy; (L.M.); (E.G.); (F.R.); (M.T.); (A.S.); (B.B.); (G.F.); (G.V.); (V.F.); (M.-N.L.)
- National Reference Centre for Emerging Risks in Food Safety (CRESA), Istituto Zooprofilattico Sperimentale della Lombardia e dell’Emilia Romagna (IZSLER), Via Celoria 12, 20133 Milan, Italy
| | - Michela Tilola
- Food Safety Department, Istituto Zooprofilattico Sperimentale della Lombardia e dell’Emilia Romagna (IZSLER), Via A. Bianchi 9, 25124 Brescia, Italy; (L.M.); (E.G.); (F.R.); (M.T.); (A.S.); (B.B.); (G.F.); (G.V.); (V.F.); (M.-N.L.)
- National Reference Centre for Emerging Risks in Food Safety (CRESA), Istituto Zooprofilattico Sperimentale della Lombardia e dell’Emilia Romagna (IZSLER), Via Celoria 12, 20133 Milan, Italy
| | - Annalisa Scarazzato
- Food Safety Department, Istituto Zooprofilattico Sperimentale della Lombardia e dell’Emilia Romagna (IZSLER), Via A. Bianchi 9, 25124 Brescia, Italy; (L.M.); (E.G.); (F.R.); (M.T.); (A.S.); (B.B.); (G.F.); (G.V.); (V.F.); (M.-N.L.)
| | - Barbara Bertasi
- Food Safety Department, Istituto Zooprofilattico Sperimentale della Lombardia e dell’Emilia Romagna (IZSLER), Via A. Bianchi 9, 25124 Brescia, Italy; (L.M.); (E.G.); (F.R.); (M.T.); (A.S.); (B.B.); (G.F.); (G.V.); (V.F.); (M.-N.L.)
- National Reference Centre for Emerging Risks in Food Safety (CRESA), Istituto Zooprofilattico Sperimentale della Lombardia e dell’Emilia Romagna (IZSLER), Via Celoria 12, 20133 Milan, Italy
| | - Guido Finazzi
- Food Safety Department, Istituto Zooprofilattico Sperimentale della Lombardia e dell’Emilia Romagna (IZSLER), Via A. Bianchi 9, 25124 Brescia, Italy; (L.M.); (E.G.); (F.R.); (M.T.); (A.S.); (B.B.); (G.F.); (G.V.); (V.F.); (M.-N.L.)
- National Reference Centre for Emerging Risks in Food Safety (CRESA), Istituto Zooprofilattico Sperimentale della Lombardia e dell’Emilia Romagna (IZSLER), Via Celoria 12, 20133 Milan, Italy
| | - Giorgio Varisco
- Food Safety Department, Istituto Zooprofilattico Sperimentale della Lombardia e dell’Emilia Romagna (IZSLER), Via A. Bianchi 9, 25124 Brescia, Italy; (L.M.); (E.G.); (F.R.); (M.T.); (A.S.); (B.B.); (G.F.); (G.V.); (V.F.); (M.-N.L.)
- National Reference Centre for Emerging Risks in Food Safety (CRESA), Istituto Zooprofilattico Sperimentale della Lombardia e dell’Emilia Romagna (IZSLER), Via Celoria 12, 20133 Milan, Italy
| | - Virginia Filipello
- Food Safety Department, Istituto Zooprofilattico Sperimentale della Lombardia e dell’Emilia Romagna (IZSLER), Via A. Bianchi 9, 25124 Brescia, Italy; (L.M.); (E.G.); (F.R.); (M.T.); (A.S.); (B.B.); (G.F.); (G.V.); (V.F.); (M.-N.L.)
- National Reference Centre for Emerging Risks in Food Safety (CRESA), Istituto Zooprofilattico Sperimentale della Lombardia e dell’Emilia Romagna (IZSLER), Via Celoria 12, 20133 Milan, Italy
| | - Marina-Nadia Losio
- Food Safety Department, Istituto Zooprofilattico Sperimentale della Lombardia e dell’Emilia Romagna (IZSLER), Via A. Bianchi 9, 25124 Brescia, Italy; (L.M.); (E.G.); (F.R.); (M.T.); (A.S.); (B.B.); (G.F.); (G.V.); (V.F.); (M.-N.L.)
- National Reference Centre for Emerging Risks in Food Safety (CRESA), Istituto Zooprofilattico Sperimentale della Lombardia e dell’Emilia Romagna (IZSLER), Via Celoria 12, 20133 Milan, Italy
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16
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Acute Pancreatitis in Individuals with COVID-19: A Case Report and Critical Review of Literature. Case Rep Med 2022; 2022:1275287. [PMID: 35761951 PMCID: PMC9233612 DOI: 10.1155/2022/1275287] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Accepted: 05/17/2022] [Indexed: 01/08/2023] Open
Abstract
Involvement of gastrointestinal tract has been reported in individuals diagnosed with COVID-19. Herein, we report a case of 65-year-old woman with type 2 diabetes mellitus, hypertension, and end-stage renal disease undergoing hemodialysis who was initially diagnosed with COVID-19 on a screening test. During the course of the disease, her respiratory symptoms remained mild; however, she developed acute pancreatitis leading to severe hypertension and hyperosmolar hyperglycemic state. During the hospitalization and treatment of acute pancreatitis, hyperglycemia, and hypertension, her condition improved and she was discharged in stable condition.
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17
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Ileocolic intussusception in pediatric SARS-CoV-2 patients: experience at a tertiary pediatric center. Pediatr Surg Int 2022; 38:437-443. [PMID: 34999941 PMCID: PMC8742661 DOI: 10.1007/s00383-022-05061-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/02/2022] [Indexed: 11/23/2022]
Abstract
PURPOSE COVID-19 disease can manifest with intussusception in pediatric patients, but prevalence of abnormalities on ultrasounds performed for intussusception is uncertain. We aim to report our experience in children with COVID-19 presenting with suspected intussusception imaged with ultrasound. METHODS Children under 18 years who had an ultrasound for possible intussusception underwent retrospective analysis and were tested for COVID-19 between April 1 and December 14, 2020. Patients' demographic, clinical, radiological and surgical characteristics were reviewed. RESULTS Twenty-four COVID-19-positive patients were identified; 19 boys with mean age 3 years (range: 3 months-18 years). Ultrasound was abnormal in 11 patients (11/24, 46%). Sonographic features of enterocolitis were documented in seven children (7/24, 29%). Three boys (3/24, 13%) were found to have ileocolic intussusception on ultrasound and underwent air enema with failed reduction (3/3, 100%), precipitating surgical reductions, all with favorable outcomes. One patient (1/24, 4%) was found to have a long segment of persistent small bowel-small bowel intussusception which was surgically repaired. CONCLUSION Given the known association between failed reduction at air enema and delayed presentation, heightened awareness for intussusception in the setting of COVID-19 should be maintained, though more often, the etiology was attributed to other GI manifestations of COVID-19.
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18
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Kerslake R, Randeva HS, Jonigk D, Werlein C, Robertus JL, Katopodis P, Jasker P, Spandidos DA, Kyrou I, Karteris E. Protein expression of transmembrane protease serine 4 in the gastrointestinal tract and in healthy, cancer, and SARS‑CoV‑2 infected lungs. Mol Med Rep 2022; 25:138. [PMID: 35211765 PMCID: PMC8908323 DOI: 10.3892/mmr.2022.12654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2021] [Accepted: 02/01/2022] [Indexed: 01/08/2023] Open
Abstract
In addition to the angiotensin-converting enzyme 2 (ACE2), a number of host cell entry mediators have been identified for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), including transmembrane protease serine 4 (TMPRSS4). The authors have recently demonstrated the upregulation of TMPRSS4 in 11 different cancers, as well as its specific expression within the central nervous system using in silico tools. The present study aimed to expand the initial observations and, using immunohistochemistry, TMPRSS4 protein expression in the gastrointestinal (GI) tract and lungs was further mapped. Immunohistochemistry was performed on tissue arrays and lung tissues of patients with non-small cell lung cancer with concurrent coronavirus disease 2019 (COVID-19) infection using TMPRSS4 antibody. The results revealed that TMPRSS4 was abundantly expressed in the oesophagus, stomach, small intestine, jejunum, ileum, colon, liver and pancreas. Moreover, the extensive TMPRSS4 protein expression in the lungs of a deceased patient with COVID-19 with chronic obstructive pulmonary disease and bronchial carcinoma, as well in the adjacent normal tissue, was demonstrated for the first time, at least to the best of our knowledge. On the whole, the immunohistochemistry data of the present study suggest that TMPRSS4 may be implicated in the broader (pulmonary and extra-pulmonary) COVID-19 symptomatology; thus, it may be responsible for the tropism of this coronavirus both in the GI tract and lungs.
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Affiliation(s)
- Rachel Kerslake
- Division of Biosciences, College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge UB8 3PH
| | - Harpal S Randeva
- Warwickshire Institute for The Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire (UHCW) NHS Trust, Coventry CV2 2DX, UK
| | - Danny Jonigk
- Institute for Pathology, Hannover Medical School, D‑30625 Hannover, Germany
| | | | - Jan L Robertus
- National Heart and Lung Institute, Imperial College London, London SW3 6LY, UK
| | - Periklis Katopodis
- Division of Biosciences, College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge UB8 3PH, UK
| | - Petra Jasker
- Pathologie Grünstrasse, D‑40212 Düsseldorf, Germany
| | - Demetrios A Spandidos
- Laboratory of Clinical Virology, Medical School, University of Crete, 71409 Heraklion, Greece
| | - Ioannis Kyrou
- Warwickshire Institute for The Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire (UHCW) NHS Trust, Coventry CV2 2DX, UK
| | - Emmanouil Karteris
- Division of Biosciences, College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge UB8 3PH, UK
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19
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Kageyama Y, Nishizaki Y, Aida K, Yayama K, Ebisui T, Akiyama T, Nakamura T. Lactobacillus plantarum induces innate cytokine responses that potentially provide a protective benefit against COVID-19: A single-arm, double-blind, prospective trial combined with an in vitro cytokine response assay. Exp Ther Med 2022; 23:20. [PMID: 34815772 PMCID: PMC8593926 DOI: 10.3892/etm.2021.10942] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 09/22/2021] [Indexed: 12/13/2022] Open
Abstract
Intestinal microbiota can indirectly modulate airway physiology and immunity through the gut-lung axis. Recent microbiome studies indicate that patients with coronavirus disease 2019 (COVID-19) exhibit a specific intestinal dysbiosis that is closely associated with the disease pathophysiology. Therefore, rebalancing the intestinal microbiome using probiotics may be effective for controlling COVID-19. However, the rationale for using probiotics in COVID-19 remains unclear. In the present study, an in vitro cytokine response assay was conducted, followed by a single-arm, double-blind, prospective trial to evaluate the immunological efficacy of probiotic lactic acid bacteria against COVID-19. The present study focused on Lactobacillus plantarum (L. plantarum), Bifidobacterium longum and Lactococcus lactis ssp. lactis, which exhibit robust protective effects against infection with respiratory RNA viruses. Considering the feasibility of long-term daily intake for prophylactic purposes, healthy uninfected individuals were enrolled as subjects. Our previous pilot trial demonstrated that oral Qingfei Paidu decoction (QFPD), a Chinese herbal medicine formulated specifically against COVID-19, upregulates plasma TNF-α, IL-1β, IL-18 and IL-8. Therefore, the present study utilized the cytokine changes induced by QFPD to define the innate cytokine index QICI [=(TNF-α) x (IL-1β) x (IL-18) x (IL-8)/(IL-6)] as an indicator of the anti-COVID-19 immunomodulatory potential of the lactic acid bacteria. A total of 20 eligible volunteers were enrolled, 18 of whom completed the intervention. L. plantarum demonstrated a strikingly high innate cytokine index in all subjects in the in vitro cytokine response assay. In the subsequent trial, oral intake of L. plantarum significantly increased the innate cytokine index (mean fold change, 17-fold; P=0.0138) and decreased the plasma level of IL-6 (P=0.0128), a key driver of complex immune dysregulation in COVID-19, as compared with the baseline. The cytokine index increased in 16 of 18 subjects (88.9%) with considerable individual differences in the fold change (1- to 128-fold). In line with these innate cytokine changes, L. plantarum ingestion significantly enhanced the activity of natural killer cells. By contrast, oral B. longum failed to induce a significant increase in the innate cytokine index (mean fold change, 2-fold; P=0.474) as compared with the baseline. In conclusion, L. plantarum demonstrated superior QFPD-like immunomodulatory ability and mimicked the blood cytokine environment produced by early immune responses to viral infection. Daily consumption of L. plantarum as an anti-COVID-19 probiotic may be a possible option for preventing COVID-19 during the pandemic. The present study was prospectively registered in the University Hospital Medical Information Network-Clinical Trials Registry under the trial number UMIN000040479 on 22 May 2020 (https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000046202).
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Affiliation(s)
- Yasunari Kageyama
- Takanawa Clinic, Tokyo 108-0074, Japan
- Tokai University Hospital, Isehara-shi, Kanagawa 259-1193, Japan
| | - Yasuhiro Nishizaki
- Tokai University Hospital, Isehara-shi, Kanagawa 259-1193, Japan
- Department of Clinical Health Science, Tokai University Tokyo Hospital, Tokai University School of Medicine, Tokyo 151-0053, Japan
| | | | | | | | - Tetsu Akiyama
- Laboratory of Molecular and Genetic Information, Institute for Quantitative Biosciences, The University of Tokyo, Tokyo 113-0032, Japan
| | - Tsutomu Nakamura
- Takanawa Clinic, Tokyo 108-0074, Japan
- Laboratory of Molecular and Genetic Information, Institute for Quantitative Biosciences, The University of Tokyo, Tokyo 113-0032, Japan
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20
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Acute appendicitis and SARS-CoV-2 in children: imaging findings at a tertiary children's hospital during the COVID-19 pandemic. Pediatr Radiol 2022; 52:460-467. [PMID: 34741178 PMCID: PMC8570768 DOI: 10.1007/s00247-021-05219-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 09/09/2021] [Accepted: 10/05/2021] [Indexed: 10/26/2022]
Abstract
BACKGROUND Evidence suggests severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may be associated with appendicitis or clinical symptoms that mimic appendicitis, but it is not clear if the findings or utility of imaging in pediatric patients with suspected appendicitis have changed since the onset of the coronavirus disease 2019 (COVID-19) pandemic. OBJECTIVE To evaluate for potential differences in SARS-CoV-2 positive and SARS-CoV-2 negative pediatric patients imaged for suspected appendicitis to determine the reliability of the existing medical imaging approach for appendicitis in a population that contains both SARS-CoV-2 positive and SARS-CoV-2 negative pediatric patients. MATERIALS AND METHODS Patients imaged for suspected appendicitis Apr. 1, 2020, to Dec. 31, 2020, were identified via an electronic medical records search. Differences in ultrasound (US) diagnostic performance, use of computed tomography (CT) following US, rates of appendicitis, imaging findings of appendicitis and perforation were compared between SARS-CoV-2 positive and SARS-CoV-2 negative tested patients, using pathology and surgery as reference standards for appendicitis and perforation, respectively. Fisher exact test and Student's t-test were used for statistical analysis. RESULTS One thousand, six hundred and ninety-three patients < 18 years old met inclusion criteria, with 46% (772/1,693) female, 11 imaged with only CT and 1,682 with US. Comparing SARS-CoV-2 positive and SARS-CoV-2 negative patients, no statistically significant differences in sensitivity or specificity of US (P = 1 and P = 1, respectively), or in the US (P-values ranging from 0.1 to 1.0) or CT imaging findings (P-values ranging from 0.2 to 1.0) in appendicitis were found. Perforation rates were similar between SARS-CoV-2 positive (20/57, 35.1% perforated) and SARS-CoV-2 negative (359/785, 45.7% perforated) patients with appendicitis (P = 0.13). Use of CT following first-line US was similar, with 7/125 (5.6%) of SARS-CoV-2 positive imaged with CT after US and 127/1,557 (8.2%) of SARS-CoV-2 negative imaged with CT after US (P = 0.39). CONCLUSION In pediatric patients with suspected appendicitis, no significant difference was found in the diagnostic performance of US, CT usage or perforation rates between SARS-CoV-2 positive and SARS-CoV-2 negative patients.
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21
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Katopodis P, Randeva HS, Spandidos DA, Saravi S, Kyrou I, Karteris E. Host cell entry mediators implicated in the cellular tropism of SARS‑CoV‑2, the pathophysiology of COVID‑19 and the identification of microRNAs that can modulate the expression of these mediators (Review). Int J Mol Med 2021; 49:20. [PMID: 34935057 PMCID: PMC8722767 DOI: 10.3892/ijmm.2021.5075] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 12/15/2021] [Indexed: 11/20/2022] Open
Abstract
The pathophysiology of coronavirus disease 2019 (COVID-19) is mainly dependent on the underlying mechanisms that mediate the entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into the host cells of the various human tissues/organs. Recent studies have indicated a higher order of complexity of the mechanisms of infectivity, given that there is a wide-repertoire of possible cell entry mediators that appear to co-localise in a cell- and tissue-specific manner. The present study provides an over-view of the 'canonical' SARS-CoV-2 mediators, namely angiotensin converting enzyme 2, transmembrane protease serine 2 and 4, and neuropilin-1, expanding on the involvement of novel candidates, including glucose-regulated protein 78, basigin, kidney injury molecule-1, metabotropic glutamate receptor subtype 2, ADAM metallopeptidase domain 17 (also termed tumour necrosis factor-α convertase) and Toll-like receptor 4. Furthermore, emerging data indicate that changes in microRNA (miRNA/miR) expression levels in patients with COVID-19 are suggestive of further complexity in the regulation of these viral mediators. An in silico analysis revealed 160 candidate miRNAs with potential strong binding capacity in the aforementioned genes. Future studies should concentrate on elucidating the association between the cellular tropism of the SARS-CoV-2 cell entry mediators and the mechanisms through which they might affect the clinical outcome. Finally, the clinical utility as a biomarker or therapeutic target of miRNAs in the context of COVID-19 warrants further investigation.
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Affiliation(s)
- Periklis Katopodis
- Biosciences, College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge UB8 3PH, UK
| | - Harpal S Randeva
- Warwickshire Institute for The Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK
| | - Demetrios A Spandidos
- Laboratory of Clinical Virology, Medical School, University of Crete, 71409 Heraklion, Greece
| | - Sayeh Saravi
- Biosciences, College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge UB8 3PH, UK
| | - Ioannis Kyrou
- Warwickshire Institute for The Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK
| | - Emmanouil Karteris
- Biosciences, College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge UB8 3PH, UK
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22
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Jamal M, Bangash HI, Habiba M, Lei Y, Xie T, Sun J, Wei Z, Hong Z, Shao L, Zhang Q. Immune dysregulation and system pathology in COVID-19. Virulence 2021; 12:918-936. [PMID: 33757410 PMCID: PMC7993139 DOI: 10.1080/21505594.2021.1898790] [Citation(s) in RCA: 80] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 01/08/2021] [Accepted: 02/19/2021] [Indexed: 01/08/2023] Open
Abstract
The coronavirus disease 19 (COVID-19) caused by the novel coronavirus known as SARS-CoV-2 has caused a global public health crisis. As of 7 January 2021, 87,640,402 confirmed cases and 1,891,692 mortalities have been reported worldwide. Studies focusing on the epidemiological and clinical characteristics of COVID-19 patients have suggested a dysregulated immune response characterized by lymphopenia and cytokine storm in these patients. The exaggerated immune response induced by the cytokine storm causes septic shock, acute respiratory distress syndrome (ARDS), and/or multiple organs failure, which increases the fatality rate of patients with SARS-CoV-2 infection. Herein, we review the recent research progress on epidemiology, clinical features, and system pathology in COVID-19. Moreover, we summarized the recent therapeutic strategies, which are either approved, under clinical trial, and/or under investigation by the local or global health authorities. We assume that treatments should focus on the use of antiviral drugs in combination with immunomodulators as well as treatment of the underlying comorbidities.
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Affiliation(s)
- Muhammad Jamal
- Department of Immunology, School of Basic Medical Science, Wuhan University, WuhanP.R. China
| | - Hina Iqbal Bangash
- State Key Laboratory of Agricultural Microbiology, College of Life Science and Technology, Huazhong Agricultural University, WuhanChina
| | - Maria Habiba
- Department of Zoology, University of Malakand, Chakdara Dir Lower, Khyber PakhtunkhwaPakistan
| | - Yufei Lei
- Department of Immunology, School of Basic Medical Science, Wuhan University, WuhanP.R. China
| | - Tian Xie
- Department of Immunology, School of Basic Medical Science, Wuhan University, WuhanP.R. China
| | - Jiaxing Sun
- Department of Immunology, School of Basic Medical Science, Wuhan University, WuhanP.R. China
| | - Zimeng Wei
- Department of Immunology, School of Basic Medical Science, Wuhan University, WuhanP.R. China
| | - Zixi Hong
- Department of Immunology, School of Basic Medical Science, Wuhan University, WuhanP.R. China
| | - Liang Shao
- Department of Hematology, Zhongnan Hospital of Wuhan University, WuhanP.R. China
| | - Qiuping Zhang
- Department of Immunology, School of Basic Medical Science, Wuhan University, WuhanP.R. China
- Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan University, WuhanP.R. China
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23
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Al Bataineh MT, Henschel A, Mousa M, Daou M, Waasia F, Kannout H, Khalili M, Kayasseh MA, Alkhajeh A, Uddin M, Alkaabi N, Tay GK, Feng SF, Yousef AF, Alsafar HS. Gut Microbiota Interplay With COVID-19 Reveals Links to Host Lipid Metabolism Among Middle Eastern Populations. Front Microbiol 2021; 12:761067. [PMID: 34803986 PMCID: PMC8603808 DOI: 10.3389/fmicb.2021.761067] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 09/30/2021] [Indexed: 12/15/2022] Open
Abstract
The interplay between the compositional changes in the gastrointestinal microbiome, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) susceptibility and severity, and host functions is complex and yet to be fully understood. This study performed 16S rRNA gene-based microbial profiling of 143 subjects. We observed structural and compositional alterations in the gut microbiota of the SARS-CoV-2-infected group in comparison to non-infected controls. The gut microbiota composition of the SARS-CoV-2-infected individuals showed an increase in anti-inflammatory bacteria such as Faecalibacterium (p-value = 1.72 × 10-6) and Bacteroides (p-value = 5.67 × 10-8). We also revealed a higher relative abundance of the highly beneficial butyrate producers such as Anaerostipes (p-value = 1.75 × 10-230), Lachnospiraceae (p-value = 7.14 × 10-65), and Blautia (p-value = 9.22 × 10-18) in the SARS-CoV-2-infected group in comparison to the control group. Moreover, phylogenetic investigation of communities by reconstructing unobserved state (PICRUSt) functional prediction analysis of the 16S rRNA gene abundance data showed substantial differences in the enrichment of metabolic pathways such as lipid, amino acid, carbohydrate, and xenobiotic metabolism, in comparison between both groups. We discovered an enrichment of linoleic acid, ether lipid, glycerolipid, and glycerophospholipid metabolism in the SARS-CoV-2-infected group, suggesting a link to SARS-CoV-2 entry and replication in host cells. We estimate the major contributing genera to the four pathways to be Parabacteroides, Streptococcus, Dorea, and Blautia, respectively. The identified differences provide a new insight to enrich our understanding of SARS-CoV-2-related changes in gut microbiota, their metabolic capabilities, and potential screening biomarkers linked to COVID-19 disease severity.
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Affiliation(s)
- Mohammad Tahseen Al Bataineh
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates.,Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates.,Center for Biotechnology, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates.,Department of Genetics and Molecular Biology, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
| | - Andreas Henschel
- Center for Biotechnology, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates.,Department of Electrical Engineering and Computer Science, Khalifa University, Abu Dhabi, United Arab Emirates
| | - Mira Mousa
- Center for Biotechnology, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates.,Nuffield Department of Women's and Reproduction Health, Oxford University, Oxford, United Kingdom
| | - Marianne Daou
- Department of Chemistry, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
| | - Fathimathuz Waasia
- Center for Biotechnology, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
| | - Hussein Kannout
- Center for Biotechnology, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
| | - Mariam Khalili
- Center for Biotechnology, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
| | - Mohd Azzam Kayasseh
- Emirates Specialty Hospital, Dubai Healthcare City, Dubai, United Arab Emirates
| | - Abdulmajeed Alkhajeh
- Medical Education and Research Department, Dubai Health Authority, Dubai, United Arab Emirates
| | - Maimunah Uddin
- Department of Pediatric Infectious Disease, Sheikh Khalifa Medical City, Abu Dhabi, United Arab Emirates
| | - Nawal Alkaabi
- Department of Pediatric Infectious Disease, Sheikh Khalifa Medical City, Abu Dhabi, United Arab Emirates
| | - Guan K Tay
- Division of Psychiatry, Faculty of Health and Medical Sciences, The University of Western Australia, Crawley, WA, Australia.,School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia
| | - Samuel F Feng
- Center for Biotechnology, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates.,Department of Mathematics, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
| | - Ahmed F Yousef
- Department of Chemistry, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
| | - Habiba S Alsafar
- Center for Biotechnology, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates.,Department of Mathematics, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates.,Department of Biomedical Engineering, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
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24
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Sivamuni SS, Ngeow WC, Wong RCW. Postdefecation Cleansing in the Asian Population and the Spread of COVID-19. Asia Pac J Public Health 2021; 34:312-313. [PMID: 34696621 DOI: 10.1177/10105395211052181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Sathya Sailashinee Sivamuni
- Department of Oral & Maxillofacial Clinical Sciences, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia
| | - Wei Cheong Ngeow
- Department of Oral & Maxillofacial Clinical Sciences, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia
| | - Raymond Chung Wen Wong
- Department of Oral & Maxillofacial Surgery, Faculty of Dentistry, National University of Singapore, Singapore
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25
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Berdowska I, Matusiewicz M. Cathepsin L, transmembrane peptidase/serine subfamily member 2/4, and other host proteases in COVID-19 pathogenesis – with impact on gastrointestinal tract. World J Gastroenterol 2021; 27:6590-6600. [PMID: 34754154 PMCID: PMC8554394 DOI: 10.3748/wjg.v27.i39.6590] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 06/28/2021] [Accepted: 09/19/2021] [Indexed: 02/06/2023] Open
Abstract
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) seems to employ two routes of entrance to the host cell; via membrane fusion (with the cells expressing both angiotensin converting enzyme 2 (ACE2) and transmembrane peptidase/serine subfamily member 2/4 (TMPRSS2/4)) or via receptor-mediated endocytosis (to the target cells expressing only ACE2). The second mode is associated with cysteine cathepsins (probably cathepsin L) involvement in the virus spike protein (S protein) proteolytic activation. Also furin might activate the virus S protein enabling it to enter cells. Gastrointestinal tract (GIT) involvement in SARS-CoV-2 infection is evident in a subset of coronavirus disease 2019 (COVID-19) patients exhibiting GIT symptoms, such as diarrhea, and presenting viral-shedding in feces. Considering the abundance and co-localization of ACE2 and TMPRSS2 in the lower GIT (especially brush-border enterocytes), these two receptors seem to be mainly involved in SARS-CoV-2 invasion of the digestive tract. Additionally, in vitro studies have demonstrated the virions capability of infection and replication in the human epithelial cells lining GIT. However, also furin and cysteine cathepsins (cathepsin L) might participate in the activation of SARS-CoV-2 spike protein contributing to the virus invasiveness within GIT. Moreover, cathepsin L (due to its involvement in extracellular matrix components degradation and remodeling, the processes enhanced during SARS-CoV-2-induced inflammation) might be responsible for the dysregulation of absorption/ digestion functions of GIT, thus adding to the observed in some COVID-19 patients symptoms such as diarrhea.
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Affiliation(s)
- Izabela Berdowska
- Department of Biochemistry and Immunochemistry, Wroclaw Medical University, Wroclaw 50-368, Lower Silesia, Poland
| | - Malgorzata Matusiewicz
- Department of Biochemistry and Immunochemistry, Wroclaw Medical University, Wroclaw 50-368, Lower Silesia, Poland
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26
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Sonkar C, Doharey PK, Rathore AS, Singh V, Kashyap D, Sahoo AK, Mittal N, Sharma B, Jha HC. Repurposing of gastric cancer drugs against COVID-19. Comput Biol Med 2021; 137:104826. [PMID: 34537409 PMCID: PMC8420180 DOI: 10.1016/j.compbiomed.2021.104826] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 08/26/2021] [Accepted: 08/30/2021] [Indexed: 12/19/2022]
Abstract
Corona Virus Disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has become a global pandemic. Additionally, the SARS-CoV-2 infection in the patients of Gastric Cancer (GC; the third leading cause of death in the world) pose a great challenge for the health management of the patients. Since there have been uncertainties to develop a new drug against COVID-19, there is an urgent need for repurposing drugs that can target key proteins of both SARS-CoV-2 and GC. The SARS-CoV-2-RdRp protein contains the NiRAN domain, which is known to have kinase-like folds. A docking study of the FDA approved drugs against GC was performed using AutoDock 4.2 and Glide Schrodinger suite 2019 against SARS-CoV-2-RdRp protein. MMGBSA and MD simulation studies were performed to investigate the binding and stability of the inhibitors with the target protein. In this study, we have found 12 kinase inhibitors with high binding energies namely Baricitinib, Brepocitinib, Decernotinib, Fasudil, Filgotinib, GSK2606414, Peficitinib, Ruxolitinib, Tofacitinib, Upadacitinib, Pamapimod and Ibrutinib. These FDA approved drugs against GC can play a key role in the treatment of COVID-19 patients along with GC as comorbidity. We also hypothesize that JAK, ITK, Rho-associated kinases, FGFR2, FYN, PERK, TYK2, p38-MAPK and SYK kinases can be considered as key therapeutic targets in COVID-19 treatment. Taken altogether, we have proposed the SARS-CoV-2-RdRp as a potential therapeutic target through in-silico studies. However, further in-vitro and in-vivo studies are required for the validation of the proposed targets and drugs for the treatment of COVID-19 patients already suffering from GC.
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Affiliation(s)
- Charu Sonkar
- Department of Biosciences and Biomedical Engineering (BSBE), Indian Institute of Technology Indore, Khandwa Road, Simrol, Indore, 453552, India
| | - Pawan Kumar Doharey
- Department of Biochemistry, University of Allahabad, Allahabad, 211002, U.P., India
| | - Anuranjan Singh Rathore
- SASTRA Deemed to Be University, Trichy-Tanjore Road, Thirumalaisamudram, Thanjavur, Tamil Nadu, 613401, India
| | - Vishal Singh
- Department of Applied Sciences, Indian Institute of Information Technology Allahabad, Allahabad, 211015, U.P., India
| | - Dharmendra Kashyap
- Department of Biosciences and Biomedical Engineering (BSBE), Indian Institute of Technology Indore, Khandwa Road, Simrol, Indore, 453552, India
| | - Amaresh Kumar Sahoo
- Department of Applied Sciences, Indian Institute of Information Technology Allahabad, Allahabad, 211015, U.P., India
| | - Nitish Mittal
- Computational and Systems Biology, Biozentrum, University of Basel, Klingelbergstrasse 50-70, 4056, Basel, Switzerland
| | - Bechan Sharma
- Department of Biochemistry, University of Allahabad, Allahabad, 211002, U.P., India
| | - Hem Chandra Jha
- Department of Biosciences and Biomedical Engineering (BSBE), Indian Institute of Technology Indore, Khandwa Road, Simrol, Indore, 453552, India.
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Srivastava M, Hall D, Omoru OB, Gill HM, Smith S, Janga SC. Mutational Landscape and Interaction of SARS-CoV-2 with Host Cellular Components. Microorganisms 2021; 9:1794. [PMID: 34576690 PMCID: PMC8464733 DOI: 10.3390/microorganisms9091794] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2021] [Revised: 08/18/2021] [Accepted: 08/19/2021] [Indexed: 12/14/2022] Open
Abstract
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its rapid evolution has led to a global health crisis. Increasing mutations across the SARS-CoV-2 genome have severely impacted the development of effective therapeutics and vaccines to combat the virus. However, the new SARS-CoV-2 variants and their evolutionary characteristics are not fully understood. Host cellular components such as the ACE2 receptor, RNA-binding proteins (RBPs), microRNAs, small nuclear RNA (snRNA), 18s rRNA, and the 7SL RNA component of the signal recognition particle (SRP) interact with various structural and non-structural proteins of the SARS-CoV-2. Several of these viral proteins are currently being examined for designing antiviral therapeutics. In this review, we discuss current advances in our understanding of various host cellular components targeted by the virus during SARS-CoV-2 infection. We also summarize the mutations across the SARS-CoV-2 genome that directs the evolution of new viral strains. Considering coronaviruses are rapidly evolving in humans, this enables them to escape therapeutic therapies and vaccine-induced immunity. In order to understand the virus's evolution, it is essential to study its mutational patterns and their impact on host cellular machinery. Finally, we present a comprehensive survey of currently available databases and tools to study viral-host interactions that stand as crucial resources for developing novel therapeutic strategies for combating SARS-CoV-2 infection.
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Affiliation(s)
- Mansi Srivastava
- Department of BioHealth Informatics, School of Informatics and Computing, Indiana University Purdue University Indianapolis, Informatics and Communications Technology Complex, 535 West Michigan Street, Indianapolis, IN 46202, USA; (M.S.); (D.H.); (O.B.O.); (H.M.G.); (S.S.)
| | - Dwight Hall
- Department of BioHealth Informatics, School of Informatics and Computing, Indiana University Purdue University Indianapolis, Informatics and Communications Technology Complex, 535 West Michigan Street, Indianapolis, IN 46202, USA; (M.S.); (D.H.); (O.B.O.); (H.M.G.); (S.S.)
| | - Okiemute Beatrice Omoru
- Department of BioHealth Informatics, School of Informatics and Computing, Indiana University Purdue University Indianapolis, Informatics and Communications Technology Complex, 535 West Michigan Street, Indianapolis, IN 46202, USA; (M.S.); (D.H.); (O.B.O.); (H.M.G.); (S.S.)
| | - Hunter Mathias Gill
- Department of BioHealth Informatics, School of Informatics and Computing, Indiana University Purdue University Indianapolis, Informatics and Communications Technology Complex, 535 West Michigan Street, Indianapolis, IN 46202, USA; (M.S.); (D.H.); (O.B.O.); (H.M.G.); (S.S.)
| | - Sarah Smith
- Department of BioHealth Informatics, School of Informatics and Computing, Indiana University Purdue University Indianapolis, Informatics and Communications Technology Complex, 535 West Michigan Street, Indianapolis, IN 46202, USA; (M.S.); (D.H.); (O.B.O.); (H.M.G.); (S.S.)
| | - Sarath Chandra Janga
- Department of BioHealth Informatics, School of Informatics and Computing, Indiana University Purdue University Indianapolis, Informatics and Communications Technology Complex, 535 West Michigan Street, Indianapolis, IN 46202, USA; (M.S.); (D.H.); (O.B.O.); (H.M.G.); (S.S.)
- Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, 410 West 10th Street, Indianapolis, IN 46202, USA
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Medical Research and Library Building, 975 West Walnut Street, Indianapolis, IN 46202, USA
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Fardoos R, Asowata OE, Herbert N, Nyquist SK, Zungu Y, Singh A, Ngoepe A, Mbano IM, Mthabela N, Ramjit D, Karim F, Kuhn W, Madela FG, Manzini VT, Anderson F, Berger B, Pers TH, Shalek AK, Leslie A, Kløverpris HN. HIV infection drives interferon signaling within intestinal SARS-CoV-2 target cells. JCI Insight 2021; 6:e148920. [PMID: 34252054 PMCID: PMC8409978 DOI: 10.1172/jci.insight.148920] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
SARS-CoV-2 infects epithelial cells of the human gastrointestinal (GI) tract and causes related symptoms. HIV infection impairs gut homeostasis and is associated with an increased risk of COVID-19 fatality. To investigate the potential link between these observations, we analyzed single-cell transcriptional profiles and SARS-CoV-2 entry receptor expression across lymphoid and mucosal human tissue from chronically HIV-infected individuals and uninfected controls. Absorptive gut enterocytes displayed the highest coexpression of SARS-CoV-2 receptors ACE2, TMPRSS2, and TMPRSS4, of which ACE2 expression was associated with canonical interferon response and antiviral genes. Chronic treated HIV infection was associated with a clear antiviral response in gut enterocytes and, unexpectedly, with a substantial reduction of ACE2 and TMPRSS2 target cells. Gut tissue from SARS-CoV-2–infected individuals, however, showed abundant SARS-CoV-2 nucleocapsid protein in both the large and small intestine, including an HIV-coinfected individual. Thus, upregulation of antiviral response genes and downregulation of ACE2 and TMPRSS2 in the GI tract of HIV-infected individuals does not prevent SARS-CoV-2 infection in this compartment. The impact of these HIV-associated intestinal mucosal changes on SARS-CoV-2 infection dynamics, disease severity, and vaccine responses remains unclear and requires further investigation.
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Affiliation(s)
- Rabiah Fardoos
- Africa Health Research Institute, Durban, South Africa.,Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Osaretin E Asowata
- Africa Health Research Institute, Durban, South Africa.,School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa
| | - Nicholas Herbert
- Africa Health Research Institute, Durban, South Africa.,School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa
| | - Sarah K Nyquist
- Institute for Medical Engineering & Science, Department of Chemistry, and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA.,Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA.,Program in Computational and Systems Biology, MIT, Cambridge, Massachusetts, USA
| | - Yenzekile Zungu
- Africa Health Research Institute, Durban, South Africa.,School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa
| | - Alveera Singh
- Africa Health Research Institute, Durban, South Africa
| | | | - Ian M Mbano
- Africa Health Research Institute, Durban, South Africa.,School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa
| | | | | | - Farina Karim
- Africa Health Research Institute, Durban, South Africa
| | - Warren Kuhn
- ENT Department, General Justice Gizenga Mpanza Regional Hospital (Stanger Hospital), University of KwaZulu-Natal, Durban, South Africa
| | - Fusi G Madela
- Discipline of General Surgery, Inkosi Albert Luthuli Central Hospital, University of KwaZulu-Natal, Durban, South Africa
| | - Vukani T Manzini
- Discipline of General Surgery, Inkosi Albert Luthuli Central Hospital, University of KwaZulu-Natal, Durban, South Africa
| | - Frank Anderson
- Discipline of General Surgery, Inkosi Albert Luthuli Central Hospital, University of KwaZulu-Natal, Durban, South Africa
| | - Bonnie Berger
- Computer Science and Artificial Intelligence Laboratory and Department of Mathematics, MIT, Cambridge, Massachusetts, USA
| | - Tune H Pers
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Alex K Shalek
- Institute for Medical Engineering & Science, Department of Chemistry, and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA.,Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA
| | - Alasdair Leslie
- Africa Health Research Institute, Durban, South Africa.,School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa.,Division of Infection and Immunity, University College London, London, United Kingdom
| | - Henrik N Kløverpris
- Africa Health Research Institute, Durban, South Africa.,Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.,School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa.,Division of Infection and Immunity, University College London, London, United Kingdom
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29
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Johnson SD, Olwenyi OA, Bhyravbhatla N, Thurman M, Pandey K, Klug EA, Johnston M, Dyavar SR, Acharya A, Podany AT, Fletcher CV, Mohan M, Singh K, Byrareddy SN. Therapeutic implications of SARS-CoV-2 dysregulation of the gut-brain-lung axis. World J Gastroenterol 2021; 27:4763-4783. [PMID: 34447225 PMCID: PMC8371510 DOI: 10.3748/wjg.v27.i29.4763] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 05/10/2021] [Accepted: 07/20/2021] [Indexed: 02/06/2023] Open
Abstract
The emergence and rapid spread of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused over 180 million confirmed cases resulting in over 4 million deaths worldwide with no clear end in sight for the coronavirus disease 19 (COVID-19) pandemic. Most SARS-CoV-2 exposed individuals experience mild to moderate symptoms, including fever, cough, fatigue, and loss of smell and taste. However, many individuals develop pneumonia, acute respiratory distress syndrome, septic shock, and multiorgan dysfunction. In addition to these primarily respiratory symptoms, SARS-CoV-2 can also infiltrate the central nervous system, which may damage the blood-brain barrier and the neuron's synapses. Resultant inflammation and neurodegeneration in the brain stem can further prevent efferent signaling to cranial nerves, leading to the loss of anti-inflammatory signaling and normal respiratory and gastrointestinal functions. Additionally, SARS-CoV-2 can infect enterocytes resulting in gut damage followed by microbial dysbiosis and translocation of bacteria and their byproducts across the damaged epithelial barrier. As a result, this exacerbates pro-inflammatory responses both locally and systemically, resulting in impaired clinical outcomes. Recent evidence has highlighted the complex interactions that mutually modulate respiratory, neurological, and gastrointestinal function. In this review, we discuss the ways SARS-CoV-2 potentially disrupts the gut-brain-lung axis. We further highlight targeting specific responses to SARS-CoV-2 for the development of novel, urgently needed therapeutic interventions. Finally, we propose a prospective related to the individuals from Low- and Middle-Income countries. Here, the underlying propensity for heightened gut damage/microbial translocation is likely to result in worse clinical outcomes during this COVID-19 pandemic.
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Affiliation(s)
- Samuel D Johnson
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, United States
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Omalla A Olwenyi
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, United States
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Namita Bhyravbhatla
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Michellie Thurman
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Kabita Pandey
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, United States
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Elizabeth A Klug
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, United States
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Morgan Johnston
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Shetty Ravi Dyavar
- Antiviral Pharmacology Laboratory, University of Nebraska Medical Center (UNMC) Center for Drug Discovery, Omaha, NE 68198, United States
| | - Arpan Acharya
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Anthony T Podany
- Antiviral Pharmacology Laboratory, University of Nebraska Medical Center (UNMC) Center for Drug Discovery, Omaha, NE 68198, United States
| | - Courtney V Fletcher
- Antiviral Pharmacology Laboratory, University of Nebraska Medical Center (UNMC) Center for Drug Discovery, Omaha, NE 68198, United States
| | - Mahesh Mohan
- Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, TX 78227, United States
| | - Kamal Singh
- Department of Molecular Microbiology and Immunology and Bond Life Sciences Center, University of Missouri, Columbia, MO 65212, United States
| | - Siddappa N Byrareddy
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States
- Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, United States
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, United States
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30
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Sarker J, Das P, Sarker S, Roy AK, Momen AZMR. A Review on Expression, Pathological Roles, and Inhibition of TMPRSS2, the Serine Protease Responsible for SARS-CoV-2 Spike Protein Activation. SCIENTIFICA 2021; 2021:2706789. [PMID: 34336361 PMCID: PMC8313365 DOI: 10.1155/2021/2706789] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 05/30/2021] [Accepted: 07/14/2021] [Indexed: 05/08/2023]
Abstract
SARS-CoV-2, the coronavirus responsible for the COVID-19 pandemic, uses the host cell membrane receptor angiotensin-converting enzyme 2 (ACE2) for anchoring its spike protein, and the subsequent membrane fusion process is facilitated by host membrane proteases. Recent studies have shown that transmembrane serine protease 2 (TMPRSS2), a protease known for similar role in previous coronavirus infections, severe acute respiratory syndrome (SARS), and Middle East respiratory syndrome (MERS), is responsible for the proteolytic cleavage of the SARS-CoV-2 spike protein, enabling host cell fusion of the virus. TMPRSS2 is known to be expressed in the epithelial cells of different sites including gastrointestinal, respiratory, and genitourinary system. The infection site of the SARS-CoV-2 correlates with the coexpression sites of ACE2 and TMPRSS2. Besides, age-, sex-, and comorbidity-associated variation in infection rate correlates with the expression rate of TMPRSS2 in those groups. These findings provide valid reasons for the assumption that inhibiting TMPRSS2 can have a beneficial effect in reducing the cellular entry of the virus, ultimately affecting the infection rate and case severity. Several drug development studies are going on to develop potential inhibitors of the protease, using both conventional and computational approaches. Complete understanding of the biological roles of TMPRSS2 is necessary before such therapies are applied.
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Affiliation(s)
- Jyotirmoy Sarker
- Department of Pharmacy, Jagannath University, Dhaka 1100, Bangladesh
- Department of Pharmacy Systems, Outcomes and Policy, University of Illinois at Chicago, Chicago, IL 60607, USA
| | - Pritha Das
- Independent Author, Dhaka 1207, Bangladesh
| | - Sabarni Sarker
- Department of Pharmacy, Jagannath University, Dhaka 1100, Bangladesh
| | - Apurba Kumar Roy
- Department of Genetic Engineering and Biotechnology, University of Rajshahi, Rajshahi 6205, Bangladesh
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31
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Clark JA, Pathan N. Hide and seek in a pandemic: review of SARS-CoV-2 infection and sequelae in children. Exp Physiol 2021; 107:653-664. [PMID: 34242467 PMCID: PMC8447309 DOI: 10.1113/ep089399] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 07/07/2021] [Indexed: 11/17/2022]
Abstract
New Findings
What is the topic of this review? A description of the current literature relating to COVID‐19 infection in children and the associated inflammatory condition, paediatric multi‐inflammatory syndrome temporally associated with SARS‐CoV‐2 (PIMS‐TS). What advances does it highlight? Children with SARS‐CoV‐2 infection have a distinct clinical phenotype when compared to adults. This may relate to relative differences in their adaptive immunity and in the degree and distribution of expression of the SARS‐CoV‐2 receptor (angiotensin‐converting enzyme 2). There are several similarities between PIMS‐TS, Kawasaki disease shock syndrome and other known inflammatory disorders such as macrophage activation syndrome. Few data are available to date regarding vaccination responses of children against COVID‐19. Abstract Children infected with SARS‐CoV‐2 have a clinical phenotype that is distinct from that observed in adult cases. They can present with a range of respiratory, gastrointestinal and neurological symptoms, or with a delayed hyperinflammatory syndrome (paediatric multisystem inflammatory system temporally associated with SARS‐CoV‐2; PIMS‐TS) that frequently requires treatment in an intensive care unit. These manifestations may be related to unique expression of transmembrane receptors and immune physiology in children. The clinical features and inflammatory profile of PIMS‐TS are similar to other inflammatory disorders that occur in children such as Kawasaki disease, macrophage activation syndrome and sepsis. Given children are infected less frequently and have less severe disease due to COVID‐19 compared to adults, their physiological profile is of great interest. An understanding of the unique mechanisms of infection and disease in children could aid the identification of potential therapeutic targets. Like adults, children can have long‐term complications of SARS‐CoV‐2 infection, including neurological and cardiac morbidity. Vaccination against SARS‐CoV‐2 is not yet authorised in children aged <12 years, and hence we anticipate ongoing paediatric presentations of COVID‐19 in the coming months.
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Affiliation(s)
- John A Clark
- Department of Paediatrics, University of Cambridge, Cambridge, Cambridgeshire, CB2 0QQ, UK.,Department of Paediatric Intensive Care, Cambridge University Hospitals NHS Foundation Trust, Hills Rd, Cambridge, Cambridgeshire, CB2 0QQ, UK
| | - Nazima Pathan
- Department of Paediatrics, University of Cambridge, Cambridge, Cambridgeshire, CB2 0QQ, UK.,Department of Paediatric Intensive Care, Cambridge University Hospitals NHS Foundation Trust, Hills Rd, Cambridge, Cambridgeshire, CB2 0QQ, UK
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32
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Niesor EJ, Boivin G, Rhéaume E, Shi R, Lavoie V, Goyette N, Picard ME, Perez A, Laghrissi-Thode F, Tardif JC. Inhibition of the 3CL Protease and SARS-CoV-2 Replication by Dalcetrapib. ACS OMEGA 2021; 6:16584-16591. [PMID: 34235330 PMCID: PMC8230949 DOI: 10.1021/acsomega.1c01797] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Accepted: 06/08/2021] [Indexed: 06/13/2023]
Abstract
The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) 3CL protease is a promising target for inhibition of viral replication by interaction with a cysteine residue (Cys145) at its catalytic site. Dalcetrapib exerts its lipid-modulating effect by binding covalently to cysteine 13 of a cholesteryl ester transfer protein. Because 12 free cysteine residues are present in the 3CL protease, we investigated the potential of dalcetrapib to inhibit 3CL protease activity and SARS-CoV-2 replication. Molecular docking investigations suggested that dalcetrapib-thiol binds to the catalytic site of the 3CL protease with a delta G value of -8.5 kcal/mol. Dalcetrapib inhibited both 3CL protease activity in vitro and viral replication in Vero E6 cells with IC50 values of 14.4 ± 3.3 μM and an EC50 of 17.5 ± 3.5 μM (mean ± SD). Near-complete inhibition of protease activity persisted despite 1000-fold dilution after ultrafiltration with a nominal dalcetrapib-thiol concentration of approximately 100 times below the IC50 of 14.4 μM, suggesting stable protease-drug interaction. The inhibitory effect of dalcetrapib on the SARS-CoV-2 3CL protease and viral replication warrants its clinical evaluation for the treatment of COVID-19.
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Affiliation(s)
| | - Guy Boivin
- Centre
Hospitalier Universitaire de Québec, Université Laval, Québec
City G1V 0A6, Canada
| | - Eric Rhéaume
- Montreal
Heart Institute, Université de Montréal, Montreal H1T 1C8, Canada
| | - Rong Shi
- Department
of Biochemistry, Microbiology and Bioinformatics, Université Laval, Quebec G1V 0A6, Canada
| | - Véronique Lavoie
- Montreal
Heart Institute, Université de Montréal, Montreal H1T 1C8, Canada
| | - Nathalie Goyette
- Centre
Hospitalier Universitaire de Québec, Université Laval, Québec
City G1V 0A6, Canada
| | - Marie-Eve Picard
- Department
of Biochemistry, Microbiology and Bioinformatics, Université Laval, Quebec G1V 0A6, Canada
| | | | | | - Jean-Claude Tardif
- Montreal
Heart Institute, Université de Montréal, Montreal H1T 1C8, Canada
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33
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Miller J, Yan KS. COVID-19 Gastrointestinal Symptoms and Attenuation of the Immune Response to SARS-CoV-2. Gastroenterology 2021; 160:2251-2254. [PMID: 33753106 PMCID: PMC7973071 DOI: 10.1053/j.gastro.2021.03.029] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Accepted: 03/18/2021] [Indexed: 12/29/2022]
Affiliation(s)
- Jonathan Miller
- Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Morgan Stanley Children's Hospital, Columbia University Irving Medical Center and, Columbia Center for Human Development, Columbia Stem Cell Initiative, Department of Medicine, Division of Digestive and Liver Diseases, Department of Genetics and Development, Columbia University Irving Medical Center, New York, New York
| | - Kelley S Yan
- Columbia Center for Human Development, Columbia Stem Cell Initiative, Department of Medicine, Division of Digestive and Liver Diseases, Department of Genetics and Development, Columbia University Irving Medical Center, New York, New York.
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34
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Li Y, Handley SA, Baldridge MT. The dark side of the gut: Virome-host interactions in intestinal homeostasis and disease. J Exp Med 2021; 218:e20201044. [PMID: 33760921 PMCID: PMC8006857 DOI: 10.1084/jem.20201044] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 11/23/2020] [Accepted: 11/25/2020] [Indexed: 12/19/2022] Open
Abstract
The diverse enteric viral communities that infect microbes and the animal host collectively constitute the gut virome. Although recent advances in sequencing and analysis of metaviromes have revealed the complexity of the virome and facilitated discovery of new viruses, our understanding of the enteric virome is still incomplete. Recent studies have uncovered how virome-host interactions can contribute to beneficial or detrimental outcomes for the host. Understanding the complex interactions between enteric viruses and the intestinal immune system is a prerequisite for elucidating their role in intestinal diseases. In this review, we provide an overview of the enteric virome composition and summarize recent findings about how enteric viruses are sensed by and, in turn, modulate host immune responses during homeostasis and disease.
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Affiliation(s)
- Yuhao Li
- Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MO
- Edison Family Center for Genome Sciences & Systems Biology, Washington University School of Medicine, St. Louis, MO
| | - Scott A. Handley
- Edison Family Center for Genome Sciences & Systems Biology, Washington University School of Medicine, St. Louis, MO
- Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO
| | - Megan T. Baldridge
- Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MO
- Edison Family Center for Genome Sciences & Systems Biology, Washington University School of Medicine, St. Louis, MO
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35
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Keuchel M, Bota M, Baltes P. Infectious diseases affecting the small bowel - what not to miss. Curr Opin Gastroenterol 2021; 37:255-266. [PMID: 33769379 DOI: 10.1097/mog.0000000000000720] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
PURPOSE OF REVIEW This review summarizes infectious diseases involving the small bowel (SB) with a focus on recent literature related to diagnosis and pathophysiology. RECENT FINDINGS Typical symptom for SB infections is diarrhea, mostly self-limiting. Pathogens include bacteria, viruses, fungi, protozoan parasites, and helminths. Host-pathogen interaction is of special interest in infections with potentially severe or prolonged course. Research uses increasingly enterocyte cell culture systems. SARS-CoV2 can also infect enterocytes via angiotensin converting enzyme 2 (ACE2) receptor and causes gastrointestinal complaints in some patients. Chronic SB infections as tuberculosis, Cytomegalovirus, or Epstein-Barr virus have to be differentiated from Crohn's and other diseases. Severe rare fungal and protozoan parasitic infections can cause relevant morbidity in immunocompromised patients. Soil-transmitted helminthic infections are a special issue in endemic areas. SUMMARY Many infections involve the SB, typically causing mild and self-limiting diarrhea. Symptomatic therapy, hygiene, and isolation are the mainstay of management. However, some patients develop severe or chronic disease. Immunosuppression is a major cause for severe, but also for rare opportunistic systemic infections that can also affect the SB.
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Affiliation(s)
- Martin Keuchel
- Klinik für Innere Medizin, AGAPLESION Bethesda Krankenhaus Bergedorf, Akademisches Lehrkrankenhaus der Universität Hamburg, Hamburg, Germany
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36
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Llorens S, Nava E, Muñoz-López M, Sánchez-Larsen Á, Segura T. Neurological Symptoms of COVID-19: The Zonulin Hypothesis. Front Immunol 2021; 12:665300. [PMID: 33981312 PMCID: PMC8107207 DOI: 10.3389/fimmu.2021.665300] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Accepted: 04/06/2021] [Indexed: 12/11/2022] Open
Abstract
The irruption of SARS-CoV-2 during 2020 has been of pandemic proportions due to its rapid spread and virulence. COVID-19 patients experience respiratory, digestive and neurological symptoms. Distinctive symptom as anosmia, suggests a potential neurotropism of this virus. Amongst the several pathways of entry to the nervous system, we propose an alternative pathway from the infection of the gut, involving Toll-like receptor 4 (TLR4), zonulin, protease-activated receptor 2 (PAR2) and zonulin brain receptor. Possible use of zonulin antagonists could be investigated to attenuate neurological manifestations caused by SARS-CoV-19 infection.
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Affiliation(s)
- Sílvia Llorens
- Department of Medical Sciences, Faculty of Medicine of Albacete, University of Castilla-La Mancha, Albacete, Spain.,Centro Regional de Investigaciones Biomédicas (CRIB), University of Castilla-La Mancha, Albacete, Spain
| | - Eduardo Nava
- Department of Medical Sciences, Faculty of Medicine of Albacete, University of Castilla-La Mancha, Albacete, Spain.,Centro Regional de Investigaciones Biomédicas (CRIB), University of Castilla-La Mancha, Albacete, Spain
| | - Mónica Muñoz-López
- Department of Medical Sciences, Faculty of Medicine of Albacete, University of Castilla-La Mancha, Albacete, Spain.,Centro Regional de Investigaciones Biomédicas (CRIB), University of Castilla-La Mancha, Albacete, Spain
| | | | - Tomás Segura
- Department of Medical Sciences, Faculty of Medicine of Albacete, University of Castilla-La Mancha, Albacete, Spain.,Servicio de Neurología, Hospital General Universitario de Albacete, Albacete, Spain.,Instituto de Investigación en Discapacidades Neurológicas (IDINE), University of Castilla-La Mancha, Albacete, Spain
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37
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Katopodis P, Kerslake R, Davies J, Randeva HS, Chatha K, Hall M, Spandidos DA, Anikin V, Polychronis A, Robertus JL, Kyrou I, Karteris E. COVID‑19 and SARS‑CoV‑2 host cell entry mediators: Expression profiling of TMRSS4 in health and disease. Int J Mol Med 2021; 47:64. [PMID: 33649798 PMCID: PMC7914073 DOI: 10.3892/ijmm.2021.4897] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Accepted: 02/22/2021] [Indexed: 02/06/2023] Open
Abstract
Severe acute respiratory syndrome (SARS) coronavirus‑2 (SARS‑CoV‑2), the causative viral agent for the ongoing COVID‑19 pandemic, enters its host cells primarily via the binding of the SARS‑CoV‑2 spike (S) proteins to the angiotensin‑converting enzyme 2 (ACE2). A number of other cell entry mediators have also been identified, including neuropilin‑1 (NRP1) and transmembrane protease serine 2 (TMPRSS2). More recently, it has been demonstrated that transmembrane protease serine 4 (TMPRSS4) along with TMPRSS2 activate the SARS‑CoV‑2 S proteins, and enhance the viral infection of human small intestinal enterocytes. To date, a systematic analysis of TMPRSS4 in health and disease is lacking. In the present study, using in silico tools, the gene expression and genetic alteration of TMPRSS4 were analysed across numerous tumours and compared to controls. The observations were also expanded to the level of the central nervous system (CNS). The findings revealed that TMPRSS4 was overexpressed in 11 types of cancer, including lung adenocarcinoma, lung squamous cell carcinoma, cervical squamous cell carcinoma, thyroid carcinoma, ovarian cancer, cancer of the rectum, pancreatic cancer, colon and stomach adenocarcinoma, uterine carcinosarcoma and uterine corpus endometrial carcinoma, whilst it was significantly downregulated in kidney carcinomas, acute myeloid leukaemia, skin cutaneous melanoma and testicular germ cell tumours. Finally, a high TMPRSS4 expression was documented in the olfactory tubercle, paraolfactory gyrus and frontal operculum, all brain regions which are associated with the sense of smell and taste. Collectively, these data suggest that TMPRSS4 may play a role in COVID‑19 symptomatology as another SARS‑CoV‑2 host cell entry mediator responsible for the tropism of this coronavirus both in the periphery and the CNS.
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Affiliation(s)
- Periklis Katopodis
- Department of Life Sciences, College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge UB8 3PH, UK
- Division of Thoracic Surgery, The Royal Brompton and Harefield NHS Foundation Trust, Harefield Hospital, London UB9 6JH, UK
| | - Rachel Kerslake
- Department of Life Sciences, College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge UB8 3PH, UK
- Division of Thoracic Surgery, The Royal Brompton and Harefield NHS Foundation Trust, Harefield Hospital, London UB9 6JH, UK
| | - Julie Davies
- Department of Life Sciences, College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge UB8 3PH, UK
| | - Harpal S. Randeva
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK
- Aston Medical Research Institute, Aston Medical School, College of Health and Life Sciences, Aston University, Birmingham B4 7ET, UK
- Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
| | - Kamaljit Chatha
- Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
- Department of Biochemistry and Immunology, University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK
| | - Marcia Hall
- Department of Life Sciences, College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge UB8 3PH, UK
- Mount Vernon Cancer Centre, Middlesex HA6 2RN, UK
| | - Demetrios A. Spandidos
- Laboratory of Clinical Virology, Medical School, University of Crete, 71409 Heraklion, Greece
| | - Vladimir Anikin
- Department of Life Sciences, College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge UB8 3PH, UK
- Division of Thoracic Surgery, The Royal Brompton and Harefield NHS Foundation Trust, Harefield Hospital, London UB9 6JH, UK
| | | | - Jan L. Robertus
- National Heart and Lung Institute, Imperial College London, London SW3 6LY, UK
| | - Ioannis Kyrou
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK
- Aston Medical Research Institute, Aston Medical School, College of Health and Life Sciences, Aston University, Birmingham B4 7ET, UK
- Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
| | - Emmanouil Karteris
- Department of Life Sciences, College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge UB8 3PH, UK
- Division of Thoracic Surgery, The Royal Brompton and Harefield NHS Foundation Trust, Harefield Hospital, London UB9 6JH, UK
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38
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Cao R, Bao L, Pan M, Zhang C, Liao H, Liu L, Li Y, Li M. Detection of SARS-CoV-2 in fecal samples with different pretreatment methods and PCR kits. BMC Microbiol 2021; 21:56. [PMID: 33607939 PMCID: PMC7893130 DOI: 10.1186/s12866-021-02118-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Accepted: 01/18/2021] [Indexed: 02/06/2023] Open
Abstract
Background Gastrointestinal symptoms are common in COVID-19 patients and SARS-CoV-2 RNA has been detected in the patients’ feces, which could lead to fecal–oral transmission. Therefore, fecal sample testing with real-time RT-PCR is highly recommended as a routine test for SARS-CoV-2 infection. However, varying rates of detection in fecal sample have been reported. The aim of this study was to provide insights into the detection rates of SARS-CoV-2 in COVID-19 patients’ fecal sample by using four real-time RT-PCR kits and two pretreatment methods (inactive and non-inactive). Results The detection rate of Trizol pretreatment group was slightly higher than that of Phosphate Buffered Saline (PBS) groups, showing that pretreatment and inactivation by Trizol had no influence to SARS-CoV-2 nucleic acid test (NAT) results. 39.29% detection rate in fecal sample by DAAN was obtained, while Bio-germ was 40.48%, Sansure 34.52%, and GeneoDx 33.33%. The former three kits had no significant difference. The DAAN kit detection rates of ORF1ab and N gene were nearly equal and Ct value distribution was more scattered, while the Bio-germ kit distribution was more clustered. The positive rate of SARS-COV-2 in fecal samples correlated with the severity of the disease, specifically, severe cases were less likely to be identified than asymptomatic infection in the DAAN group (adjusted OR 0.05, 95%CI = 0.00 ~ 0.91). Conclusions Trizol should be of choice as a valid and safe method for pretreatment of fecal samples of SARS-CoV-2. All real-time RT-PCR kits assessed in this study can be used for routine detection of SARS-CoV-2 in fecal samples. While DAAN, with high NAT positive rate, could be the best out of the 4 kits used in this study. SARS-CoV-2 positive rate in fecal sample was related to the severity of illness. Supplementary Information The online version contains supplementary material available at 10.1186/s12866-021-02118-0.
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Affiliation(s)
- Ranran Cao
- West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, China.,Sichuan Center for Disease Control and Prevention, Chengdu, 610041, China
| | - Lirong Bao
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Ming Pan
- Sichuan Center for Disease Control and Prevention, Chengdu, 610041, China
| | - Cheng Zhang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Hongyu Liao
- Sichuan Center for Disease Control and Prevention, Chengdu, 610041, China
| | - Li Liu
- Sichuan Center for Disease Control and Prevention, Chengdu, 610041, China
| | - Yan Li
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China.
| | - Mingyuan Li
- West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, China.
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39
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Dogra P, Ruiz-Ramírez J, Sinha K, Butner JD, Peláez MJ, Rawat M, Yellepeddi VK, Pasqualini R, Arap W, Sostman HD, Cristini V, Wang Z. Innate Immunity Plays a Key Role in Controlling Viral Load in COVID-19: Mechanistic Insights from a Whole-Body Infection Dynamics Model. ACS Pharmacol Transl Sci 2021; 4:248-265. [PMID: 33615177 PMCID: PMC7805603 DOI: 10.1021/acsptsci.0c00183] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Indexed: 12/18/2022]
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a pathogen of immense public health concern. Efforts to control the disease have only proven mildly successful, and the disease will likely continue to cause excessive fatalities until effective preventative measures (such as a vaccine) are developed. To develop disease management strategies, a better understanding of SARS-CoV-2 pathogenesis and population susceptibility to infection are needed. To this end, mathematical modeling can provide a robust in silico tool to understand COVID-19 pathophysiology and the in vivo dynamics of SARS-CoV-2. Guided by ACE2-tropism (ACE2 receptor dependency for infection) of the virus and by incorporating cellular-scale viral dynamics and innate and adaptive immune responses, we have developed a multiscale mechanistic model for simulating the time-dependent evolution of viral load distribution in susceptible organs of the body (respiratory tract, gut, liver, spleen, heart, kidneys, and brain). Following parameter quantification with in vivo and clinical data, we used the model to simulate viral load progression in a virtual patient with varying degrees of compromised immune status. Further, we ranked model parameters through sensitivity analysis for their significance in governing clearance of viral load to understand the effects of physiological factors and underlying conditions on viral load dynamics. Antiviral drug therapy, interferon therapy, and their combination were simulated to study the effects on viral load kinetics of SARS-CoV-2. The model revealed the dominant role of innate immunity (specifically interferons and resident macrophages) in controlling viral load, and the importance of timing when initiating therapy after infection.
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Affiliation(s)
- Prashant Dogra
- Mathematics
in Medicine Program, Houston Methodist Research
Institute, Houston, Texas 77030, United States
| | - Javier Ruiz-Ramírez
- Mathematics
in Medicine Program, Houston Methodist Research
Institute, Houston, Texas 77030, United States
| | - Kavya Sinha
- DeBakey
Heart and Vascular Center, Houston Methodist
Hospital, Houston, Texas 77030, United States
| | - Joseph D. Butner
- Mathematics
in Medicine Program, Houston Methodist Research
Institute, Houston, Texas 77030, United States
| | - Maria J. Peláez
- Mathematics
in Medicine Program, Houston Methodist Research
Institute, Houston, Texas 77030, United States
| | - Manmeet Rawat
- Department
of Internal Medicine, University of New
Mexico School of Medicine, Albuquerque, New Mexico 87131, United States
| | - Venkata K. Yellepeddi
- Division
of Clinical Pharmacology, Department of Pediatrics, School of Medicine, University of Utah, Salt Lake City, Utah 84132, United States
- Department
of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, University of Utah, Salt Lake City, Utah 84112, United States
| | - Renata Pasqualini
- Rutgers
Cancer Institute of New Jersey, Newark, New Jersey 07101, United States
- Department
of Radiation Oncology, Division of Cancer Biology, Rutgers New Jersey Medical School, Newark, New Jersey 07103, United States
| | - Wadih Arap
- Rutgers
Cancer Institute of New Jersey, Newark, New Jersey 07101, United States
- Department
of Medicine, Division of Hematology/Oncology, Rutgers New Jersey Medical School, Newark, New Jersey 07103, United States
| | - H. Dirk Sostman
- Weill
Cornell Medicine, New York, New York 10065, United States
- Houston
Methodist Research Institute, Houston, Texas 77030, United States
- Houston
Methodist Academic Institute, Houston, Texas 77030, United States
| | - Vittorio Cristini
- Mathematics
in Medicine Program, Houston Methodist Research
Institute, Houston, Texas 77030, United States
- Weill
Cornell Medicine, New York, New York 10065, United States
| | - Zhihui Wang
- Mathematics
in Medicine Program, Houston Methodist Research
Institute, Houston, Texas 77030, United States
- Weill
Cornell Medicine, New York, New York 10065, United States
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40
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Müller JA, Groß R, Conzelmann C, Krüger J, Merle U, Steinhart J, Weil T, Koepke L, Bozzo CP, Read C, Fois G, Eiseler T, Gehrmann J, van Vuuren J, Wessbecher IM, Frick M, Costa IG, Breunig M, Grüner B, Peters L, Schuster M, Liebau S, Seufferlein T, Stenger S, Stenzinger A, MacDonald PE, Kirchhoff F, Sparrer KMJ, Walther P, Lickert H, Barth TFE, Wagner M, Münch J, Heller S, Kleger A. SARS-CoV-2 infects and replicates in cells of the human endocrine and exocrine pancreas. Nat Metab 2021; 3:149-165. [PMID: 33536639 DOI: 10.1038/s42255-021-00347-1] [Citation(s) in RCA: 359] [Impact Index Per Article: 89.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Accepted: 01/14/2021] [Indexed: 02/07/2023]
Abstract
Infection-related diabetes can arise as a result of virus-associated β-cell destruction. Clinical data suggest that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing the coronavirus disease 2019 (COVID-19), impairs glucose homoeostasis, but experimental evidence that SARS-CoV-2 can infect pancreatic tissue has been lacking. In the present study, we show that SARS-CoV-2 infects cells of the human exocrine and endocrine pancreas ex vivo and in vivo. We demonstrate that human β-cells express viral entry proteins, and SARS-CoV-2 infects and replicates in cultured human islets. Infection is associated with morphological, transcriptional and functional changes, including reduced numbers of insulin-secretory granules in β-cells and impaired glucose-stimulated insulin secretion. In COVID-19 full-body postmortem examinations, we detected SARS-CoV-2 nucleocapsid protein in pancreatic exocrine cells, and in cells that stain positive for the β-cell marker NKX6.1 and are in close proximity to the islets of Langerhans in all four patients investigated. Our data identify the human pancreas as a target of SARS-CoV-2 infection and suggest that β-cell infection could contribute to the metabolic dysregulation observed in patients with COVID-19.
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Affiliation(s)
- Janis A Müller
- Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany
| | - Rüdiger Groß
- Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany
| | - Carina Conzelmann
- Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany
| | - Jana Krüger
- Department of Internal Medicine 1, Ulm University Hospital, Ulm, Germany
| | - Uta Merle
- Department of Internal Medicine 4, University of Heidelberg, Heidelberg, Germany
| | | | - Tatjana Weil
- Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany
| | - Lennart Koepke
- Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany
| | | | - Clarissa Read
- Central Facility for Electron Microscopy, Ulm University, Ulm, Germany
- Institute of Virology, Ulm University Medical Center, Ulm, Germany
| | - Giorgio Fois
- Institute of General Physiology, Ulm University, Ulm, Germany
| | - Tim Eiseler
- Department of Internal Medicine 1, Ulm University Hospital, Ulm, Germany
| | - Julia Gehrmann
- Institute for Computational Genomics, RWTH Aachen University, Aachen, Germany
| | - Joanne van Vuuren
- Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, Neuherberg, Germany
- Institute of Stem Cell Research, Helmholtz Zentrum München, Neuherberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- School of Medicine, Technical University of Munich, Munich, Germany
| | - Isabel M Wessbecher
- Tissue Bank of the German Center for Infection Research, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Manfred Frick
- Institute of General Physiology, Ulm University, Ulm, Germany
| | - Ivan G Costa
- Institute for Computational Genomics, RWTH Aachen University, Aachen, Germany
| | - Markus Breunig
- Department of Internal Medicine 1, Ulm University Hospital, Ulm, Germany
| | - Beate Grüner
- Department of Internal Medicine 3, Ulm University Hospital, Ulm, Germany
| | - Lynn Peters
- Department of Internal Medicine 3, Ulm University Hospital, Ulm, Germany
| | - Michael Schuster
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Stefan Liebau
- Institute of Neuroanatomy & Developmental Biology, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Thomas Seufferlein
- Department of Internal Medicine 1, Ulm University Hospital, Ulm, Germany
| | - Steffen Stenger
- Institute for Microbiology and Hygiene, Ulm University Medical Center, Ulm, Germany
| | | | - Patrick E MacDonald
- Alberta Diabetes Institute and Department of Pharmacology, University of Alberta, Edmonton, Canada
| | - Frank Kirchhoff
- Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany
| | | | - Paul Walther
- Central Facility for Electron Microscopy, Ulm University, Ulm, Germany
| | - Heiko Lickert
- Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, Neuherberg, Germany
- Institute of Stem Cell Research, Helmholtz Zentrum München, Neuherberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- School of Medicine, Technical University of Munich, Munich, Germany
| | | | - Martin Wagner
- Department of Internal Medicine 1, Ulm University Hospital, Ulm, Germany.
| | - Jan Münch
- Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany.
| | - Sandra Heller
- Department of Internal Medicine 1, Ulm University Hospital, Ulm, Germany.
| | - Alexander Kleger
- Department of Internal Medicine 1, Ulm University Hospital, Ulm, Germany.
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Zhao Y, Liu Y, Yi F, Zhang J, Xu Z, Liu Y, Tao Y. Type 2 diabetes mellitus impaired nasal immunity and increased the risk of hyposmia in COVID-19 mild pneumonia patients. Int Immunopharmacol 2021; 93:107406. [PMID: 33601246 PMCID: PMC7826056 DOI: 10.1016/j.intimp.2021.107406] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 01/01/2021] [Accepted: 01/14/2021] [Indexed: 01/05/2023]
Abstract
In patients with COVID-19, type 2 diabetes mellitus (T2DM) can impair the function of nasal-associated lymphoid tissue (NALT) and result in olfactory dysfunction. Exploring the causative alterations of T2DM within the nasal mucosa and NALT could provide insight into the pathogenic mechanisms and bridge the gap between innate immunity and adaptive immunity for virus clearance. Here, we designed a case-control study to compare the olfactory function (OF) among the groups of normal control (NC), COVID-19 mild pneumonia (MP), and MP patients with T2DM (MPT) after a 6–8 months’ recovery, in which MPT had a higher risk of hyposmia than MP and NC. No significant difference was found between the MP and NC. This elevated risk of hyposmia indicated that T2DM increased COVID-19 susceptibility in the nasal cavity with unknown causations. Therefore, we used the T2DM animal model (db/db mice) to evaluate how T2DM increased COVID-19 associated susceptibilities in the nasal mucosa and lymphoid tissues. Db/db mice demonstrated upregulated microvasculature ACE2 expression and significant alterations in lymphocytes component of NALT. Specifically, db/db mice NALT had increased immune-suppressive TCRγδ+ CD4−CD8− T and decreased immune-effective CD4+/CD8+ TCRβ+ T cells and decreased mucosa-protective CD19+ B cells. These results indicated that T2DM could dampen the first-line defense of nasal immunity, and further mechanic studies of metabolic damage and NALT restoration should be one of the highest importance for COVID-19 healing.
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Affiliation(s)
- Yi Zhao
- Department of Otolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
| | - Yujie Liu
- Department of Otolaryngology-Head and Neck Surgery, Key Laboratory of Otolaryngology-Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China
| | - Fangzheng Yi
- Department of Otolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
| | - Jun Zhang
- Department of Internal Medicine, University of California at Davis, Davis, 95616, United States
| | - Zhaohui Xu
- Department of Disease Prevention and Control, Xijing 986 Hospital, Fourth Military Medical University, Xi'an 710000, China.
| | - Yehai Liu
- Department of Otolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
| | - Ye Tao
- Department of Otolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
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42
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Alper K. Case Report: Famotidine for Neuropsychiatric Symptoms in COVID-19. Front Med (Lausanne) 2021; 7:614393. [PMID: 33425958 PMCID: PMC7786260 DOI: 10.3389/fmed.2020.614393] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Accepted: 11/16/2020] [Indexed: 12/14/2022] Open
Abstract
Famotidine is of interest as a possible treatment for COVID-19, with effects on disease-related symptoms and survival reported in observational and retrospective studies, as well as in silico predictions of binding to potential SARS-CoV-2 drug targets. Published studies of famotidine for COVID-19 have focused on acute illness, and none have reported on neuropsychiatric symptoms. This case study reports on an 18-year-old man who sought psychiatric treatment for depression and anxiety, disruptive interpersonal conflicts, and impairments in attention and motivation following mildly symptomatic illness with COVID-19. The neuropsychiatric symptoms, which had been present for 16 weeks at the time of the initial evaluation represented a significant departure from the patient's previous behavioral baseline. The patient had no prior psychiatric history preceding his illness with COVID-19, and no history of any prior treatment with psychopharmacological medications. Famotidine 20 mg twice daily administered orally was begun without any additional medications. At 1-week follow-up the patient was much improved. Improvement was sustained through 12 weeks of follow-up during which the patient continued to take famotidine without apparent side effects. With progression of the COVID-19 pandemic it has become evident that persistent disease-related symptoms may follow acute COVID-19 and may include neuropsychiatric symptoms. Controlled clinical research on famotidine for COVID-19 should follow, as well as the development of valid and reliable research diagnostic criteria to define and operationalize the features of a putative COVID-19 neuropsychiatric residual.
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Affiliation(s)
- Kenneth Alper
- Departments of Psychiatry and Neurology, NYU Grossman School of Medicine, New York, NY, United States
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43
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Jones DL, Baluja MQ, Graham DW, Corbishley A, McDonald JE, Malham SK, Hillary LS, Connor TR, Gaze WH, Moura IB, Wilcox MH, Farkas K. Shedding of SARS-CoV-2 in feces and urine and its potential role in person-to-person transmission and the environment-based spread of COVID-19. THE SCIENCE OF THE TOTAL ENVIRONMENT 2020; 749:141364. [PMID: 32836117 PMCID: PMC7836549 DOI: 10.1016/j.scitotenv.2020.141364] [Citation(s) in RCA: 269] [Impact Index Per Article: 53.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 07/27/2020] [Accepted: 07/28/2020] [Indexed: 04/14/2023]
Abstract
The recent detection of SARS-CoV-2 RNA in feces has led to speculation that it can be transmitted via the fecal-oral/ocular route. This review aims to critically evaluate the incidence of gastrointestinal (GI) symptoms, the quantity and infectivity of SARS-CoV-2 in feces and urine, and whether these pose an infection risk in sanitary settings, sewage networks, wastewater treatment plants, and the wider environment (e.g. rivers, lakes and marine waters). A review of 48 independent studies revealed that severe GI dysfunction is only evident in a small number of COVID-19 cases, with 11 ± 2% exhibiting diarrhea and 12 ± 3% exhibiting vomiting and nausea. In addition to these cases, SARS-CoV-2 RNA can be detected in feces from some asymptomatic, mildly- and pre-symptomatic individuals. Fecal shedding of the virus peaks in the symptomatic period and can persist for several weeks, but with declining abundances in the post-symptomatic phase. SARS-CoV-2 RNA is occasionally detected in urine, but reports in fecal samples are more frequent. The abundance of the virus genetic material in both urine (ca. 102-105 gc/ml) and feces (ca. 102-107 gc/ml) is much lower than in nasopharyngeal fluids (ca. 105-1011 gc/ml). There is strong evidence of multiplication of SARS-CoV-2 in the gut and infectious virus has occasionally been recovered from both urine and stool samples. The level and infectious capability of SARS-CoV-2 in vomit remain unknown. In comparison to enteric viruses transmitted via the fecal-oral route (e.g. norovirus, adenovirus), the likelihood of SARS-CoV-2 being transmitted via feces or urine appears much lower due to the lower relative amounts of virus present in feces/urine. The biggest risk of transmission will occur in clinical and care home settings where secondary handling of people and urine/fecal matter occurs. In addition, while SARS-CoV-2 RNA genetic material can be detected by in wastewater, this signal is greatly reduced by conventional treatment. Our analysis also suggests the likelihood of infection due to contact with sewage-contaminated water (e.g. swimming, surfing, angling) or food (e.g. salads, shellfish) is extremely low or negligible based on very low predicted abundances and limited environmental survival of SARS-CoV-2. These conclusions are corroborated by the fact that tens of million cases of COVID-19 have occurred globally, but exposure to feces or wastewater has never been implicated as a transmission vector.
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Affiliation(s)
- David L Jones
- Centre for Environmental Biotechnology, School of Natural Sciences, Bangor University, Bangor, Gwynedd LL57 2UW, UK; UWA School of Agriculture and Environment, The University of Western Australia, Perth, WA 6009, Australia.
| | | | - David W Graham
- School of Engineering, Newcastle University, Newcastle upon Tyne NE1 7RU, UK
| | - Alexander Corbishley
- The Roslin Institute and Royal (Dick) School of Veterinary Studies, Easter Bush Campus Midlothian, EH25 9RG, UK
| | - James E McDonald
- Centre for Environmental Biotechnology, School of Natural Sciences, Bangor University, Bangor, Gwynedd LL57 2UW, UK
| | - Shelagh K Malham
- School of Ocean Sciences, Bangor University, Menai Bridge, Anglesey LL59 5AB, UK
| | - Luke S Hillary
- Centre for Environmental Biotechnology, School of Natural Sciences, Bangor University, Bangor, Gwynedd LL57 2UW, UK
| | - Thomas R Connor
- Organisms and Environment Division, School of Biosciences, Cardiff University, Cardiff CF10 3AX, UK; Public Health Wales, University Hospital of Wales, Cardiff CF14 4XW, UK
| | - William H Gaze
- European Centre for Environment and Human Health, University of Exeter Medical School, ESI, Penryn Campus, TR10 9FE, UK
| | - Ines B Moura
- Leeds Institute for Medical Research, Faculty of Medicine and Health, University of Leeds, Leeds LS1 3EX, UK
| | - Mark H Wilcox
- Healthcare Associated Infections Research Group, Leeds Teaching Hospitals NHS Trust and University of Leeds, Leeds, UK
| | - Kata Farkas
- Centre for Environmental Biotechnology, School of Natural Sciences, Bangor University, Bangor, Gwynedd LL57 2UW, UK; School of Ocean Sciences, Bangor University, Menai Bridge, Anglesey LL59 5AB, UK
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44
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Jones DL, Baluja MQ, Graham DW, Corbishley A, McDonald JE, Malham SK, Hillary LS, Connor TR, Gaze WH, Moura IB, Wilcox MH, Farkas K. Shedding of SARS-CoV-2 in feces and urine and its potential role in person-to-person transmission and the environment-based spread of COVID-19. THE SCIENCE OF THE TOTAL ENVIRONMENT 2020; 749:141364. [PMID: 32836117 DOI: 10.20944/preprints202007.0471.v1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 07/27/2020] [Accepted: 07/28/2020] [Indexed: 05/18/2023]
Abstract
The recent detection of SARS-CoV-2 RNA in feces has led to speculation that it can be transmitted via the fecal-oral/ocular route. This review aims to critically evaluate the incidence of gastrointestinal (GI) symptoms, the quantity and infectivity of SARS-CoV-2 in feces and urine, and whether these pose an infection risk in sanitary settings, sewage networks, wastewater treatment plants, and the wider environment (e.g. rivers, lakes and marine waters). A review of 48 independent studies revealed that severe GI dysfunction is only evident in a small number of COVID-19 cases, with 11 ± 2% exhibiting diarrhea and 12 ± 3% exhibiting vomiting and nausea. In addition to these cases, SARS-CoV-2 RNA can be detected in feces from some asymptomatic, mildly- and pre-symptomatic individuals. Fecal shedding of the virus peaks in the symptomatic period and can persist for several weeks, but with declining abundances in the post-symptomatic phase. SARS-CoV-2 RNA is occasionally detected in urine, but reports in fecal samples are more frequent. The abundance of the virus genetic material in both urine (ca. 102-105 gc/ml) and feces (ca. 102-107 gc/ml) is much lower than in nasopharyngeal fluids (ca. 105-1011 gc/ml). There is strong evidence of multiplication of SARS-CoV-2 in the gut and infectious virus has occasionally been recovered from both urine and stool samples. The level and infectious capability of SARS-CoV-2 in vomit remain unknown. In comparison to enteric viruses transmitted via the fecal-oral route (e.g. norovirus, adenovirus), the likelihood of SARS-CoV-2 being transmitted via feces or urine appears much lower due to the lower relative amounts of virus present in feces/urine. The biggest risk of transmission will occur in clinical and care home settings where secondary handling of people and urine/fecal matter occurs. In addition, while SARS-CoV-2 RNA genetic material can be detected by in wastewater, this signal is greatly reduced by conventional treatment. Our analysis also suggests the likelihood of infection due to contact with sewage-contaminated water (e.g. swimming, surfing, angling) or food (e.g. salads, shellfish) is extremely low or negligible based on very low predicted abundances and limited environmental survival of SARS-CoV-2. These conclusions are corroborated by the fact that tens of million cases of COVID-19 have occurred globally, but exposure to feces or wastewater has never been implicated as a transmission vector.
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Affiliation(s)
- David L Jones
- Centre for Environmental Biotechnology, School of Natural Sciences, Bangor University, Bangor, Gwynedd LL57 2UW, UK; UWA School of Agriculture and Environment, The University of Western Australia, Perth, WA 6009, Australia.
| | | | - David W Graham
- School of Engineering, Newcastle University, Newcastle upon Tyne NE1 7RU, UK
| | - Alexander Corbishley
- The Roslin Institute and Royal (Dick) School of Veterinary Studies, Easter Bush Campus Midlothian, EH25 9RG, UK
| | - James E McDonald
- Centre for Environmental Biotechnology, School of Natural Sciences, Bangor University, Bangor, Gwynedd LL57 2UW, UK
| | - Shelagh K Malham
- School of Ocean Sciences, Bangor University, Menai Bridge, Anglesey LL59 5AB, UK
| | - Luke S Hillary
- Centre for Environmental Biotechnology, School of Natural Sciences, Bangor University, Bangor, Gwynedd LL57 2UW, UK
| | - Thomas R Connor
- Organisms and Environment Division, School of Biosciences, Cardiff University, Cardiff CF10 3AX, UK; Public Health Wales, University Hospital of Wales, Cardiff CF14 4XW, UK
| | - William H Gaze
- European Centre for Environment and Human Health, University of Exeter Medical School, ESI, Penryn Campus, TR10 9FE, UK
| | - Ines B Moura
- Leeds Institute for Medical Research, Faculty of Medicine and Health, University of Leeds, Leeds LS1 3EX, UK
| | - Mark H Wilcox
- Healthcare Associated Infections Research Group, Leeds Teaching Hospitals NHS Trust and University of Leeds, Leeds, UK
| | - Kata Farkas
- Centre for Environmental Biotechnology, School of Natural Sciences, Bangor University, Bangor, Gwynedd LL57 2UW, UK; School of Ocean Sciences, Bangor University, Menai Bridge, Anglesey LL59 5AB, UK
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Jones DL, Baluja MQ, Graham DW, Corbishley A, McDonald JE, Malham SK, Hillary LS, Connor TR, Gaze WH, Moura IB, Wilcox MH, Farkas K. Shedding of SARS-CoV-2 in feces and urine and its potential role in person-to-person transmission and the environment-based spread of COVID-19. THE SCIENCE OF THE TOTAL ENVIRONMENT 2020. [PMID: 32836117 DOI: 10.1016/j.scitotenv.2020.141364pmid-32836117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 05/12/2023]
Abstract
The recent detection of SARS-CoV-2 RNA in feces has led to speculation that it can be transmitted via the fecal-oral/ocular route. This review aims to critically evaluate the incidence of gastrointestinal (GI) symptoms, the quantity and infectivity of SARS-CoV-2 in feces and urine, and whether these pose an infection risk in sanitary settings, sewage networks, wastewater treatment plants, and the wider environment (e.g. rivers, lakes and marine waters). A review of 48 independent studies revealed that severe GI dysfunction is only evident in a small number of COVID-19 cases, with 11 ± 2% exhibiting diarrhea and 12 ± 3% exhibiting vomiting and nausea. In addition to these cases, SARS-CoV-2 RNA can be detected in feces from some asymptomatic, mildly- and pre-symptomatic individuals. Fecal shedding of the virus peaks in the symptomatic period and can persist for several weeks, but with declining abundances in the post-symptomatic phase. SARS-CoV-2 RNA is occasionally detected in urine, but reports in fecal samples are more frequent. The abundance of the virus genetic material in both urine (ca. 102-105 gc/ml) and feces (ca. 102-107 gc/ml) is much lower than in nasopharyngeal fluids (ca. 105-1011 gc/ml). There is strong evidence of multiplication of SARS-CoV-2 in the gut and infectious virus has occasionally been recovered from both urine and stool samples. The level and infectious capability of SARS-CoV-2 in vomit remain unknown. In comparison to enteric viruses transmitted via the fecal-oral route (e.g. norovirus, adenovirus), the likelihood of SARS-CoV-2 being transmitted via feces or urine appears much lower due to the lower relative amounts of virus present in feces/urine. The biggest risk of transmission will occur in clinical and care home settings where secondary handling of people and urine/fecal matter occurs. In addition, while SARS-CoV-2 RNA genetic material can be detected by in wastewater, this signal is greatly reduced by conventional treatment. Our analysis also suggests the likelihood of infection due to contact with sewage-contaminated water (e.g. swimming, surfing, angling) or food (e.g. salads, shellfish) is extremely low or negligible based on very low predicted abundances and limited environmental survival of SARS-CoV-2. These conclusions are corroborated by the fact that tens of million cases of COVID-19 have occurred globally, but exposure to feces or wastewater has never been implicated as a transmission vector.
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Affiliation(s)
- David L Jones
- Centre for Environmental Biotechnology, School of Natural Sciences, Bangor University, Bangor, Gwynedd LL57 2UW, UK; UWA School of Agriculture and Environment, The University of Western Australia, Perth, WA 6009, Australia.
| | | | - David W Graham
- School of Engineering, Newcastle University, Newcastle upon Tyne NE1 7RU, UK
| | - Alexander Corbishley
- The Roslin Institute and Royal (Dick) School of Veterinary Studies, Easter Bush Campus Midlothian, EH25 9RG, UK
| | - James E McDonald
- Centre for Environmental Biotechnology, School of Natural Sciences, Bangor University, Bangor, Gwynedd LL57 2UW, UK
| | - Shelagh K Malham
- School of Ocean Sciences, Bangor University, Menai Bridge, Anglesey LL59 5AB, UK
| | - Luke S Hillary
- Centre for Environmental Biotechnology, School of Natural Sciences, Bangor University, Bangor, Gwynedd LL57 2UW, UK
| | - Thomas R Connor
- Organisms and Environment Division, School of Biosciences, Cardiff University, Cardiff CF10 3AX, UK; Public Health Wales, University Hospital of Wales, Cardiff CF14 4XW, UK
| | - William H Gaze
- European Centre for Environment and Human Health, University of Exeter Medical School, ESI, Penryn Campus, TR10 9FE, UK
| | - Ines B Moura
- Leeds Institute for Medical Research, Faculty of Medicine and Health, University of Leeds, Leeds LS1 3EX, UK
| | - Mark H Wilcox
- Healthcare Associated Infections Research Group, Leeds Teaching Hospitals NHS Trust and University of Leeds, Leeds, UK
| | - Kata Farkas
- Centre for Environmental Biotechnology, School of Natural Sciences, Bangor University, Bangor, Gwynedd LL57 2UW, UK; School of Ocean Sciences, Bangor University, Menai Bridge, Anglesey LL59 5AB, UK
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Kusmartseva I, Wu W, Syed F, Van Der Heide V, Jorgensen M, Joseph P, Tang X, Candelario-Jalil E, Yang C, Nick H, Harbert JL, Posgai AL, Paulsen JD, Lloyd R, Cechin S, Pugliese A, Campbell-Thompson M, Vander Heide RS, Evans-Molina C, Homann D, Atkinson MA. Expression of SARS-CoV-2 Entry Factors in the Pancreas of Normal Organ Donors and Individuals with COVID-19. Cell Metab 2020; 32:1041-1051.e6. [PMID: 33207244 PMCID: PMC7664515 DOI: 10.1016/j.cmet.2020.11.005] [Citation(s) in RCA: 127] [Impact Index Per Article: 25.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 10/19/2020] [Accepted: 11/10/2020] [Indexed: 12/11/2022]
Abstract
Diabetes is associated with increased mortality from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Given literature suggesting a potential association between SARS-CoV-2 infection and diabetes induction, we examined pancreatic expression of angiotensin-converting enzyme 2 (ACE2), the key entry factor for SARS-CoV-2 infection. Specifically, we analyzed five public scRNA-seq pancreas datasets and performed fluorescence in situ hybridization, western blotting, and immunolocalization for ACE2 with extensive reagent validation on normal human pancreatic tissues across the lifespan, as well as those from coronavirus disease 2019 (COVID-19) cases. These in silico and ex vivo analyses demonstrated prominent expression of ACE2 in pancreatic ductal epithelium and microvasculature, but we found rare endocrine cell expression at the mRNA level. Pancreata from individuals with COVID-19 demonstrated multiple thrombotic lesions with SARS-CoV-2 nucleocapsid protein expression that was primarily limited to ducts. These results suggest SARS-CoV-2 infection of pancreatic endocrine cells, via ACE2, is an unlikely central pathogenic feature of COVID-19-related diabetes.
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Affiliation(s)
- Irina Kusmartseva
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida Diabetes Institute, College of Medicine, Gainesville, FL 32610, USA
| | - Wenting Wu
- Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Farooq Syed
- Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Verena Van Der Heide
- Department of Medicine, Diabetes Obesity & Metabolism Institute and Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Marda Jorgensen
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida Diabetes Institute, College of Medicine, Gainesville, FL 32610, USA
| | - Paul Joseph
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida Diabetes Institute, College of Medicine, Gainesville, FL 32610, USA
| | - Xiaohan Tang
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida Diabetes Institute, College of Medicine, Gainesville, FL 32610, USA; Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Eduardo Candelario-Jalil
- Department of Neuroscience, University of Florida, College of Medicine, Gainesville, FL 32601, USA
| | - Changjun Yang
- Department of Neuroscience, University of Florida, College of Medicine, Gainesville, FL 32601, USA
| | - Harry Nick
- Department of Neuroscience, University of Florida, College of Medicine, Gainesville, FL 32601, USA
| | - Jack L Harbert
- Department of Pathology, Louisiana State University, New Orleans, LA 70112, USA
| | - Amanda L Posgai
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida Diabetes Institute, College of Medicine, Gainesville, FL 32610, USA
| | - John David Paulsen
- Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Richard Lloyd
- Department of Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Sirlene Cechin
- Diabetes Research Institute, Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Alberto Pugliese
- Diabetes Research Institute, Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Martha Campbell-Thompson
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida Diabetes Institute, College of Medicine, Gainesville, FL 32610, USA; Department of Biomedical Engineering, University of Florida, College of Engineering, Gainesville, FL 32610, USA
| | | | - Carmella Evans-Molina
- Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Roudebush VA Medical Center, Indianapolis, IN 46202, USA
| | - Dirk Homann
- Department of Medicine, Diabetes Obesity & Metabolism Institute and Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Mark A Atkinson
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida Diabetes Institute, College of Medicine, Gainesville, FL 32610, USA; Department of Pediatrics, University of Florida Diabetes Institute, College of Medicine, Gainesville, FL 32610, USA.
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Villapol S. Gastrointestinal symptoms associated with COVID-19: impact on the gut microbiome. Transl Res 2020; 226:57-69. [PMID: 32827705 PMCID: PMC7438210 DOI: 10.1016/j.trsl.2020.08.004] [Citation(s) in RCA: 217] [Impact Index Per Article: 43.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2020] [Revised: 08/13/2020] [Accepted: 08/17/2020] [Indexed: 02/07/2023]
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the greatest worldwide pandemic since the 1918 flu. The consequences of the coronavirus disease 2019 (COVID-19) are devastating and represent the current major public health issue across the globe. At the onset, SARS-CoV-2 primarily attacks the respiratory system as it represents the main point of entry in the host, but it also can affect multiple organs. Although most of the patients do not present symptoms or are mildly symptomatic, some people infected with SARS-CoV-2 that experience more severe multiorgan dysfunction. The severity of COVID-19 is typically combined with a set of comorbidities such as hypertension, diabetes, obesity, and/or advanced age that seriously exacerbates the consequences of the infection. Also, SARS-CoV-2 can cause gastrointestinal symptoms, such as vomiting, diarrhea, or abdominal pain during the early phases of the disease. Intestinal dysfunction induces changes in intestinal microbes, and an increase in inflammatory cytokines. Thus, diagnosing gastrointestinal symptoms that precede respiratory problems during COVID-19 may be necessary for improved early detection and treatment. Uncovering the composition of the microbiota and its metabolic products in the context of COVID-19 can help determine novel biomarkers of the disease and help identify new therapeutic targets. Elucidating changes to the microbiome as reliable biomarkers in the context of COVID-19 represent an overlooked piece of the disease puzzle and requires further investigation.
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Key Words
- ards, acute respiratory distress syndrome
- ace2, angiotensin-converting enzyme ii
- cns, central nervous system
- covid-19, coronavirus disease 2019
- cpr, c-reactive protein
- h1n1, influenza a virus
- il, interleukin
- mers, middle east respiratory syndrome
- prs, proteomic risk score
- sars, severe acute respiratory syndrome
- sars-cov-2, severe acute respiratory syndrome coronavirus 2
- scfa, short-chain fatty acids
- ras, renin-angiotensin system
- ros, reactive oxygen species
- rt-pcr, reverse transcription-polymerase chain reaction
- tmprss2, transmembrane serine protease 2
- tnfα, tumor necrosis factor alpha
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Affiliation(s)
- Sonia Villapol
- Department of Neurosurgery, Center for Neuroregeneration, Houston Methodist Research Institute, Houston, Texas; Department of Neuroscience in Neurological Surgery, Weill Cornell Medical College, New York.
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Sharma L, Riva A. Intestinal Barrier Function in Health and Disease-Any role of SARS-CoV-2? Microorganisms 2020; 8:E1744. [PMID: 33172188 PMCID: PMC7694956 DOI: 10.3390/microorganisms8111744] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2020] [Revised: 11/01/2020] [Accepted: 11/03/2020] [Indexed: 12/12/2022] Open
Abstract
Alterations in the structure and function of the intestinal barrier play a role in the pathogenesis of a multitude of diseases. During the recent and ongoing coronavirus disease (COVID-19) pandemic, it has become clear that the gastrointestinal system and the gut barrier may be affected by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, and disruption of barrier functions or intestinal microbial dysbiosis may have an impact on the progression and severity of this new disease. In this review, we aim to provide an overview of current evidence on the involvement of gut alterations in human disease including COVID-19, with a prospective outlook on supportive therapeutic strategies that may be investigated to rescue intestinal barrier functions and possibly facilitate clinical improvement in these patients.
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Affiliation(s)
- Lakshya Sharma
- Faculty of Life Sciences and Medicine, King’s College London, London SE1 1UL, UK;
| | - Antonio Riva
- Faculty of Life Sciences and Medicine, King’s College London, London SE1 1UL, UK;
- Foundation for Liver Research, Institute of Hepatology, London SE5 9NT, UK
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49
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Dogra P, Ruiz-Ramírez J, Sinha K, Butner JD, Peláez MJ, Rawat M, Yellepeddi VK, Pasqualini R, Arap W, Sostman HD, Cristini V, Wang Z. Innate immunity plays a key role in controlling viral load in COVID-19: mechanistic insights from a whole-body infection dynamics model. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2020:2020.10.30.20215335. [PMID: 33173913 PMCID: PMC7654909 DOI: 10.1101/2020.10.30.20215335] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/29/2023]
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a pathogen of immense public health concern. Efforts to control the disease have only proven mildly successful, and the disease will likely continue to cause excessive fatalities until effective preventative measures (such as a vaccine) are developed. To develop disease management strategies, a better understanding of SARS-CoV-2 pathogenesis and population susceptibility to infection are needed. To this end, physiologically-relevant mathematical modeling can provide a robust in silico tool to understand COVID-19 pathophysiology and the in vivo dynamics of SARS-CoV-2. Guided by ACE2-tropism (ACE2 receptor dependency for infection) of the virus, and by incorporating cellular-scale viral dynamics and innate and adaptive immune responses, we have developed a multiscale mechanistic model for simulating the time-dependent evolution of viral load distribution in susceptible organs of the body (respiratory tract, gut, liver, spleen, heart, kidneys, and brain). Following calibration with in vivo and clinical data, we used the model to simulate viral load progression in a virtual patient with varying degrees of compromised immune status. Further, we conducted global sensitivity analysis of model parameters and ranked them for their significance in governing clearance of viral load to understand the effects of physiological factors and underlying conditions on viral load dynamics. Antiviral drug therapy, interferon therapy, and their combination was simulated to study the effects on viral load kinetics of SARS-CoV-2. The model revealed the dominant role of innate immunity (specifically interferons and resident macrophages) in controlling viral load, and the importance of timing when initiating therapy following infection.
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Affiliation(s)
- Prashant Dogra
- Mathematics in Medicine Program, Houston Methodist Research Institute, Houston, TX 77030, USA
| | - Javier Ruiz-Ramírez
- Mathematics in Medicine Program, Houston Methodist Research Institute, Houston, TX 77030, USA
| | - Kavya Sinha
- DeBakey Heart and Vascular Center, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Joseph D. Butner
- Mathematics in Medicine Program, Houston Methodist Research Institute, Houston, TX 77030, USA
| | - Maria J Peláez
- Mathematics in Medicine Program, Houston Methodist Research Institute, Houston, TX 77030, USA
| | - Manmeet Rawat
- Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA
| | - Venkata K. Yellepeddi
- Division of Clinical Pharmacology, Department of Pediatrics, School of Medicine, University of Utah, Salt Lake City, UT 84132, USA
- Department of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, University of Utah, Salt Lake City, UT 84112, USA
| | - Renata Pasqualini
- Rutgers Cancer Institute of New Jersey, Newark, NJ, 07101, USA
- Department of Radiation Oncology, Division of Cancer Biology, Rutgers Cancer Institute of New Jersey, Rutgers New Jersey Medical School, Newark, NJ, 07103, USA
| | - Wadih Arap
- Rutgers Cancer Institute of New Jersey, Newark, NJ, 07101, USA
- Department of Medicine, Division of Hematology/Oncology, Rutgers New Jersey Medical School, Newark, NJ, 07103, USA
| | - H. Dirk Sostman
- Weill Cornell Medicine, New York, NY 10065, USA
- Houston Methodist Research Institute, Houston, TX 77030, USA
- Houston Methodist Academic Institute, Houston, TX 77030, USA
| | - Vittorio Cristini
- Mathematics in Medicine Program, Houston Methodist Research Institute, Houston, TX 77030, USA
| | - Zhihui Wang
- Mathematics in Medicine Program, Houston Methodist Research Institute, Houston, TX 77030, USA
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50
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Kanakan A, Mishra N, Srinivasa Vasudevan J, Sahni S, Khan A, Sharma S, Pandey R. Threading the Pieces Together: Integrative Perspective on SARS-CoV-2. Pathogens 2020; 9:E912. [PMID: 33158051 PMCID: PMC7694192 DOI: 10.3390/pathogens9110912] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 10/09/2020] [Accepted: 10/12/2020] [Indexed: 02/07/2023] Open
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has challenged the research community globally to innovate, interact, and integrate findings across hierarchies. Research on SARS-CoV-2 has produced an abundance of data spanning multiple parallels, including clinical data, SARS-CoV-2 genome architecture, host response captured through transcriptome and genetic variants, microbial co-infections (metagenome), and comorbidities. Disease phenotypes in the case of COVID-19 present an intriguing complexity that includes a broad range of symptomatic to asymptomatic individuals, further compounded by a vast heterogeneity within the spectrum of clinical symptoms displayed by the symptomatic individuals. The clinical outcome is further modulated by the presence of comorbid conditions at the point of infection. The COVID-19 pandemic has produced an expansive wealth of literature touching many aspects of SARS-CoV-2 ranging from causal to outcome, predisposition to protective (possible), co-infection to comorbidity, and differential mortality globally. As challenges provide opportunities, the current pandemic's challenge has underscored the need and opportunity to work for an integrative approach that may be able to thread together the multiple variables. Through this review, we have made an effort towards bringing together information spanning across different domains to facilitate researchers globally in pursuit of their response to SARS-CoV-2.
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Affiliation(s)
| | | | | | | | | | | | - Rajesh Pandey
- INtegrative GENomics of HOst-PathogEn (INGEN-HOPE) Laboratory, CSIR-Institute of Genomics and Integrative Biology (CSIR-IGIB), Delhi 110007, India; (A.K.); (N.M.); (J.S.V.); (S.S.); (A.K.); (S.S.)
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