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1
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Colinet M, Chiver I, Bonafina A, Masset G, Almansa D, Di Valentin E, Twizere JC, Nguyen L, Espuny-Camacho I. SARS-CoV2 infection triggers inflammatory conditions and astrogliosis-related gene expression in long-term human cortical organoids. Stem Cells 2025; 43:sxaf010. [PMID: 40103011 PMCID: PMC12121356 DOI: 10.1093/stmcls/sxaf010] [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: 02/03/2024] [Accepted: 02/18/2025] [Indexed: 03/20/2025]
Abstract
SARS-CoV2, severe acute respiratory syndrome coronavirus 2, is frequently associated with neurological manifestations. Despite the presence of mild to severe CNS-related symptoms in a cohort of patients, there is no consensus whether the virus can infect directly brain tissue or if the symptoms in patients are a consequence of peripheral infectivity of the virus. Here, we use long-term human stem cell-derived cortical organoids to assess SARS-CoV2 infectivity of brain cells and unravel the cell-type tropism and its downstream pathological effects. Our results show consistent and reproducible low levels of SARS-CoV2 infection of astrocytes, deep projection neurons, upper callosal neurons, and inhibitory neurons in 6 months of human cortical organoids. Interestingly, astrocytes showed the highest infection rate among all infected cell populations which led to changes in their morphology and upregulation of SERPINA3, CD44, and S100A10 astrogliosis markers. Further, transcriptomic analysis revealed overall changes in expression of genes related to cell metabolism, astrogliosis and, inflammation and further, upregulation of cell survival pathways. Thus, local and minor infectivity of SARS-CoV2 in the brain may induce widespread adverse effects and lead to the resilience of dysregulated neurons and astrocytes within an inflammatory environment.
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Affiliation(s)
- Mathilde Colinet
- Laboratory of Molecular Regulation of Neurogenesis, GIGA Institute, University of Liège, Liège 4000, Belgium
| | - Ioana Chiver
- Laboratory of Molecular Regulation of Neurogenesis, GIGA Institute, University of Liège, Liège 4000, Belgium
| | - Antonela Bonafina
- Laboratory of Molecular Regulation of Neurogenesis, GIGA Institute, University of Liège, Liège 4000, Belgium
| | - Gérald Masset
- Laboratory of Molecular Regulation of Neurogenesis, GIGA Institute, University of Liège, Liège 4000, Belgium
| | - Daniel Almansa
- Laboratory of Molecular Regulation of Neurogenesis, GIGA Institute, University of Liège, Liège 4000, Belgium
| | - Emmanuel Di Valentin
- GIGA Viral Vector Platform, GIGA Institute, University of Liège, Liège 4000, Belgium
| | - Jean-Claude Twizere
- Laboratory of Viral Interactomes, Unit of Molecular Biology of Diseases, GIGA Institute, University of Liège, Liège 4000, Belgium
| | - Laurent Nguyen
- Laboratory of Molecular Regulation of Neurogenesis, GIGA Institute, University of Liège, Liège 4000, Belgium
- WELBIO Department, WEL Research Institute, Wavre 1300, Belgium
| | - Ira Espuny-Camacho
- Laboratory of Molecular Regulation of Neurogenesis, GIGA Institute, University of Liège, Liège 4000, Belgium
- GIGA HIPS, GIGA Institute, University of Liège, Liège 4000, Belgium
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2
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Gao H, Zhao D, Li C, Deng M, Li G, Chen S, Zhao M, Qin L, Zhang K. The Role of Orthobunyavirus Glycoprotein Gc in the Viral Life Cycle: From Viral Entry to Egress. Molecules 2025; 30:503. [PMID: 39942606 PMCID: PMC11820035 DOI: 10.3390/molecules30030503] [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: 12/15/2024] [Revised: 01/17/2025] [Accepted: 01/20/2025] [Indexed: 02/16/2025] Open
Abstract
Orthobunyavirus refers to the virus members within the Genus Orthobunyavirus, which is the largest virus genus in the Family Peribunyaviridae and even Class Bunyaviricetes. To date, over 130 species of Orthobunyaviruses have been identified worldwide. Orthobunyaviruses mainly infect arthropods, while some species are capable of being transmitted to mammals, including humans, via intermediate vectors. As emerging and re-emerging pathogens, orthobunyavirus poses a significant threat to both human and veterinary public health worldwide. Currently, there are no commercial vaccines against orthobunyavirus. The structure of orthobunyavirus is relatively simple, consisting of a typical tri-segmented negative-sense RNA genome that encodes four structural proteins (L, Gn, Gc, and N) and two non-structural proteins (NSm and NSs). The highly glycosylated Gc protein, which has a complex conformation and forms polymers embedded in the viral envelope, plays a critical role in inducing neutralizing antibodies throughout the orthobunyavirus infection cycle from entry to egress. This review provides a comprehensive summary of the virus-encoded Gc protein and its role in the virus life cycle from viral entry to egress, offering researchers with valuable integrated information for further investigations.
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Affiliation(s)
| | | | | | | | | | | | | | - Limei Qin
- School of Animal Science and Technology, Guangdong Provincial Key Laboratory of Animal Molecular Design and Precise Breeding, Foshan University, Foshan 528225, China; (H.G.)
| | - Keshan Zhang
- School of Animal Science and Technology, Guangdong Provincial Key Laboratory of Animal Molecular Design and Precise Breeding, Foshan University, Foshan 528225, China; (H.G.)
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3
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Lee JH, Sergi C, Kast RE, Kanwar BA, Bourbeau J, Oh S, Sohn MG, Lee CJ, Coleman MD. Aggravating mechanisms from COVID-19. Virol J 2024; 21:228. [PMID: 39334442 PMCID: PMC11430051 DOI: 10.1186/s12985-024-02506-8] [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: 08/08/2024] [Accepted: 09/16/2024] [Indexed: 09/30/2024] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces immune-mediated diseases. The pathophysiology of COVID-19 uses the following three mechanisms: (1) inflammasome activation mechanism; (2) cGAS-STING signaling mechanism; and (3) SAMHD1 tetramerization mechanism, which leads to IFN-I production. Interactions between the host and virus govern induction, resulting in multiorgan impacts. The NLRP3 with cGAS-STING constitutes the primary immune response. The expression of SARS-CoV-2 ORF3a, NSP6, NSP7, and NSP8 blocks innate immune activation and facilitates virus replication by targeting the RIG-I/MDA5, TRIF, and cGAS-STING signaling. SAMHD1 has a target motif for CDK1 to protect virion assembly, threonine 592 to modulate a catalytically active tetramer, and antiviral IFN responses to block retroviral infection. Plastic and allosteric nucleic acid binding of SAMHD1 modulates the antiretroviral activity of SAMHD1. Therefore, inflammasome activation, cGAS-STING signaling, and SAMHD1 tetramerization explain acute kidney injury, hepatic, cardiac, neurological, and gastrointestinal injury of COVID-19. It might be necessary to effectively block the pathological courses of diverse diseases.
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Affiliation(s)
- Jong Hoon Lee
- Science and Research Center, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.
- Department of Geriatrics, Gyeonggi Medical Center Pocheon Hospital, 1648 Pocheon-ro Sin-eup-dong, Pocheon-si, Gyeonggi-do, 11142, Republic of Korea.
| | - Consolato Sergi
- Division of Anatomical Pathology, Children's Hospital of Eastern Ontario (CHEO), University of Ottawa, 401 Smyth Road, Ottawa, ON, K1H 8L1, Canada
| | - Richard E Kast
- IIAIGC Study Center, 11 Arlington Ct, Burlington, 05408 VT, USA
| | - Badar A Kanwar
- Haider Associates, 1999 Forest Ridge Dr, Bedford, TX, 76021, USA
| | - Jean Bourbeau
- Respiratory Epidemiology and Clinical Research Unit, McGill University Health Centre, Montréal, QC, Canada
| | - Sangsuk Oh
- Department of Food Engineering, Food Safety Laboratory, Memory Unit, Ewha Womans University, Seoul, 03670, Korea
| | - Mun-Gi Sohn
- Department of Food Science, KyungHee University College of Life Science, Seoul, 17104, Republic of Korea
| | - Chul Joong Lee
- Department of Anesthesiology, Seoul National University Hospital, Seoul, Republic of Korea
| | - Michael D Coleman
- College of Health and Life Sciences, Aston University, Birmingham, B4 7ET, UK.
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4
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Guo ZY, Tang YQ, Zhang ZB, Liu J, Zhuang YX, Li T. COVID-19: from immune response to clinical intervention. PRECISION CLINICAL MEDICINE 2024; 7:pbae015. [PMID: 39139990 PMCID: PMC11319938 DOI: 10.1093/pcmedi/pbae015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Accepted: 07/11/2024] [Indexed: 08/15/2024] Open
Abstract
The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has highlighted the pivotal role of the immune response in determining the progression and severity of viral infections. In this paper, we review the most recent studies on the complicated dynamics between SARS-CoV-2 and the host immune system, highlight the importance of understanding these dynamics in developing effective treatments and formulate potent management strategies for COVID-19. We describe the activation of the host's innate immunity and the subsequent adaptive immune response following infection with SARS-CoV-2. In addition, the review emphasizes the immune evasion strategies of the SARS-CoV-2, including inhibition of interferon production and induction of cytokine storms, along with the resulting clinical outcomes. Finally, we assess the efficacy of current treatment strategies, including antiviral drugs, monoclonal antibodies, and anti-inflammatory treatments, and discuss their role in providing immunity and preventing severe disease.
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Affiliation(s)
- Zheng-yang Guo
- State Key Laboratory of Quality Research in Chinese Medicines, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau 999078, China
| | - Yan-qing Tang
- State Key Laboratory of Quality Research in Chinese Medicines, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau 999078, China
| | - Zi-bo Zhang
- State Key Laboratory of Quality Research in Chinese Medicines, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau 999078, China
| | - Juan Liu
- State Key Laboratory of Quality Research in Chinese Medicines, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau 999078, China
| | - Yu-xin Zhuang
- State Key Laboratory of Quality Research in Chinese Medicines, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau 999078, China
| | - Ting Li
- State Key Laboratory of Quality Research in Chinese Medicines, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau 999078, China
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5
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Hose L, Schürmann M, Sudhoff H. Upregulation of key factors of viral entry of corona- and influenza viruses upon TLR3-signaling in cells from the respiratory tract and clinical treatment options by 1,8-Cineol. Phytother Res 2024; 38:4453-4466. [PMID: 39020450 DOI: 10.1002/ptr.8280] [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: 09/05/2023] [Revised: 06/10/2024] [Accepted: 06/13/2024] [Indexed: 07/19/2024]
Abstract
At the end of the 2019 coronavirus pandemic (COVID-19), highly contagious variants of coronaviruses had emerged. Together with influenza viruses, different variants of the coronavirus currently cause most colds and require appropriate drug treatment. We have investigated the expression of important factors for the replication of these viruses, namely transmembrane protease serine subtype 2 (TMPRSS2), neuropilin1 (NRP1), and angiotensin converting enzyme 2 (ACE2) or tumor necrosis factor-α (TNF-α) after toll like receptor-3 (TLR-3) stimulation using RT-qPCR and flow cytometry (FC) analysis. As model served primary fibroblasts derived from the lung and nasal cavity, as well as epidermal stem cells and fully matured respiratory epithelium. The stimulated cell cultures were treated with pharmaceuticals (Dexamethasone and Enzalutamide) and the outcome was compared with the phytomedicine 1,8-Cineol. The stimulation of TLR3 is sufficient to induce the expression of exactly those targets that were highly expressed in the corresponding culture type, specifically ACE2 and TMPRSS2 in respiratory epithelial stem cells and NRP1 in fibroblast cells. It seems this self-perpetuating cycle of infection-driven upregulation of key viral replication factors by the innate immune system represents an evolutionary advantage for viruses using these transcripts as viral replication factors. Likewise, to the standard pharmaceuticals with proven clinical efficiency, 1,8-Cineol was able to disrupt this self-perpetuating cycle. Considering the minor side effects and negligible pharmacological interactions with other drugs, it is conceivable that an adjuvant or combinatorial therapy with 1,8-Cineol for respiratory diseases caused by corona- or influenza viruses would be beneficial.
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Affiliation(s)
- Leonie Hose
- Department of Otolaryngology, Head and Neck Surgery, Campus Klinikum Bielefeld Mitte, University Hospital OWL of Bielefeld University, Bielefeld, Germany
| | - Matthias Schürmann
- Department of Otolaryngology, Head and Neck Surgery, Campus Klinikum Bielefeld Mitte, University Hospital OWL of Bielefeld University, Bielefeld, Germany
| | - Holger Sudhoff
- Department of Otolaryngology, Head and Neck Surgery, Campus Klinikum Bielefeld Mitte, University Hospital OWL of Bielefeld University, Bielefeld, Germany
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6
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Michaels TM, Essop MF, Joseph DE. Potential Effects of Hyperglycemia on SARS-CoV-2 Entry Mechanisms in Pancreatic Beta Cells. Viruses 2024; 16:1243. [PMID: 39205219 PMCID: PMC11358987 DOI: 10.3390/v16081243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 07/29/2024] [Accepted: 07/30/2024] [Indexed: 09/04/2024] Open
Abstract
The COVID-19 pandemic has revealed a bidirectional relationship between SARS-CoV-2 infection and diabetes mellitus. Existing evidence strongly suggests hyperglycemia as an independent risk factor for severe COVID-19, resulting in increased morbidity and mortality. Conversely, recent studies have reported new-onset diabetes following SARS-CoV-2 infection, hinting at a potential direct viral attack on pancreatic beta cells. In this review, we explore how hyperglycemia, a hallmark of diabetes, might influence SARS-CoV-2 entry and accessory proteins in pancreatic β-cells. We examine how the virus may enter and manipulate such cells, focusing on the role of the spike protein and its interaction with host receptors. Additionally, we analyze potential effects on endosomal processing and accessory proteins involved in viral infection. Our analysis suggests a complex interplay between hyperglycemia and SARS-CoV-2 in pancreatic β-cells. Understanding these mechanisms may help unlock urgent therapeutic strategies to mitigate the detrimental effects of COVID-19 in diabetic patients and unveil if the virus itself can trigger diabetes onset.
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Affiliation(s)
- Tara M. Michaels
- Centre for Cardio-Metabolic Research in Africa, Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch 7600, South Africa;
| | - M. Faadiel Essop
- Centre for Cardio-Metabolic Research in Africa, Division of Medical Physiology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town 7505, South Africa;
| | - Danzil E. Joseph
- Centre for Cardio-Metabolic Research in Africa, Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch 7600, South Africa;
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7
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Tobias J, Steinberger P, Wilkinson J, Klais G, Kundi M, Wiedermann U. SARS-CoV-2 Vaccines: The Advantage of Mucosal Vaccine Delivery and Local Immunity. Vaccines (Basel) 2024; 12:795. [PMID: 39066432 PMCID: PMC11281395 DOI: 10.3390/vaccines12070795] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 07/10/2024] [Accepted: 07/15/2024] [Indexed: 07/28/2024] Open
Abstract
Immunity against respiratory pathogens is often short-term, and, consequently, there is an unmet need for the effective prevention of such infections. One such infectious disease is coronavirus disease 19 (COVID-19), which is caused by the novel Beta coronavirus SARS-CoV-2 that emerged around the end of 2019. The World Health Organization declared the illness a pandemic on 11 March 2020, and since then it has killed or sickened millions of people globally. The development of COVID-19 systemic vaccines, which impressively led to a significant reduction in disease severity, hospitalization, and mortality, contained the pandemic's expansion. However, these vaccines have not been able to stop the virus from spreading because of the restricted development of mucosal immunity. As a result, breakthrough infections have frequently occurred, and new strains of the virus have been emerging. Furthermore, SARS-CoV-2 will likely continue to circulate and, like the influenza virus, co-exist with humans. The upper respiratory tract and nasal cavity are the primary sites of SARS-CoV-2 infection and, thus, a mucosal/nasal vaccination to induce a mucosal response and stop the virus' transmission is warranted. In this review, we present the status of the systemic vaccines, both the approved mucosal vaccines and those under evaluation in clinical trials. Furthermore, we present our approach of a B-cell peptide-based vaccination applied by a prime-boost schedule to elicit both systemic and mucosal immunity.
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Affiliation(s)
- Joshua Tobias
- Institute of Specific Prophylaxis and Tropical Medicine, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, 1090 Vienna, Austria
| | - Peter Steinberger
- Division of Immune Receptors and T Cell Activation, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, 1090 Vienna, Austria;
| | - Joy Wilkinson
- Institute of Specific Prophylaxis and Tropical Medicine, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, 1090 Vienna, Austria
| | - Gloria Klais
- Institute of Specific Prophylaxis and Tropical Medicine, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, 1090 Vienna, Austria
| | - Michael Kundi
- Department of Environmental Health, Center for Public Health, Medical University of Vienna, 1090 Vienna, Austria;
| | - Ursula Wiedermann
- Institute of Specific Prophylaxis and Tropical Medicine, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, 1090 Vienna, Austria
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8
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Lee JH, Sergi C, Kast RE, Kanwar BA, Bourbeau J, Oh S, Sohn MG, Lee CJ, Coleman MD. Basic implications on three pathways associated with SARS-CoV-2. Biomed J 2024:100766. [PMID: 39004185 DOI: 10.1016/j.bj.2024.100766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 07/04/2024] [Accepted: 07/10/2024] [Indexed: 07/16/2024] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) interacts between the host and virus and govern induction, resulting in multiorgan impacts. Its pathophysiology involves the followings: 1) the angiotensin-converting enzyme (ACE2) and Toll-like receptor (TLR) pathways: 2) the neuropilin (NRP) pathway: 3) the spike protein pathway. Therefore, it is necessary to block the pathological course with modulating innate lymphoid cells against diverse corona variants in the future.
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Affiliation(s)
- Jong Hoon Lee
- Science and Research Center, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.
| | - Consolato Sergi
- Division of Anatomical Pathology, Children's Hospital of Eastern Ontario (CHEO), University of Ottawa, 401 Smyth Road, Ottawa, ON, K1H 8L1, Canada
| | - Richard E Kast
- IIAIGC Study Center, 11 Arlington Ct, Burlington, 05408, VT, USA
| | - Badar A Kanwar
- Haider Associates, 1999 Forest Ridge Dr, Bedford, TX, 76021, USA
| | - Jean Bourbeau
- Respiratory Epidemiology and Clinical Research Unit, McGill University Health Centre, Montréal, QC, Canada
| | - Sangsuk Oh
- Department of Food Engineering, Food Safety Laboratory, Memory Unit, Ewha Womans University, Seoul, 03670, Republic of Korea
| | - Mun-Gi Sohn
- Department of Food Science, KyungHee University College of Life Science, Seoul, 17104, Republic of Korea
| | - Chul Joong Lee
- Department of Anesthesiology, Seoul National University Hospital, Seoul, Republic of Korea
| | - Michael D Coleman
- College of Health and Life Sciences, Aston University, Birmingham, B4 7ET, UK.
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9
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Krčmová LK, Javorská L, Matoušová K, Šmahel P, Skála M, Kopecký M, Suwanvecho C, Přívratská N, Turoňová D, Melichar B. Evaluation of inflammatory biomarkers and vitamins in hospitalized patients with SARS-CoV-2 infection and post-COVID syndrome. Clin Chem Lab Med 2024; 62:1217-1227. [PMID: 38374668 DOI: 10.1515/cclm-2023-1297] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Accepted: 02/06/2024] [Indexed: 02/21/2024]
Abstract
OBJECTIVES Concentrations of neopterin, kynurenine and kynurenine/tryptophan ratios predict prognosis and the need for oxygen therapy in patients hospitalized for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The aims of the present study were to evaluate the changes of these biomarkers early in the course of infection, the association with the prior coronavirus disease (COVID-19) vaccination and therapeutic administration of Anti-SARS-CoV-2 monoclonal antibodies, investigation of other potential biomarkers including neuropilin, 8-hydroxy-2-deoxyguanosine and 8-hydroxyguanosine in patients hospitalized with SARS-CoV-2 infection and an assessment of these biomarkers and vitamins A, E and D in patients with post-COVID syndrome. METHODS Urine and blood samples were obtained on the 1st to the 4th day and 4th to 7th day from 108 patients hospitalized with COVID-19. Chromatography tandem mass spectrometry methods were used to analyse neopterin, kynurenine, tryptophan, liposoluble vitamins, and DNA damage biomarkers. RESULTS A statistically significant decrease of neopterin, kynurenine and kynurenine/tryptophan ratios was observed on after 4th to 7th day of hospitalization, and concentrations of these biomarkers were increased in patients with poor prognosis and subsequent post-COVID syndrome. The concentrations of remaining biomarker and vitamins were not associated with outcomes, although markedly decreased concentrations of vitamin A, E and D were noted. CONCLUSIONS The concentrations of neopterin, kynurenine and kynurenine/tryptophan ratios decrease during the course of infection SARS-CoV-2 and are associated with the post-COVID syndrome. No other prognostic biomarkers were identified.
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Affiliation(s)
- Lenka Kujovská Krčmová
- Department of Clinical Biochemistry and Diagnostics, University Hospital Hradec Králové, Hradec Králové, Czech Republic
- Department of Analytical Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic
| | - Lenka Javorská
- Department of Clinical Biochemistry and Diagnostics, University Hospital Hradec Králové, Hradec Králové, Czech Republic
| | - Kateřina Matoušová
- Department of Clinical Biochemistry and Diagnostics, University Hospital Hradec Králové, Hradec Králové, Czech Republic
| | - Petr Šmahel
- Deparment of Infectious Diseases, University Hospital Hradec Králové, Hradec Králové, Czech Republic
| | - Mikuláš Skála
- Department of Pneumology, University Hospital Hradec Králové, Hradec Králové, Czech Republic
| | - Michal Kopecký
- Department of Pneumology, University Hospital Hradec Králové, Hradec Králové, Czech Republic
| | - Chaweewan Suwanvecho
- Department of Clinical Biochemistry and Diagnostics, University Hospital Hradec Králové, Hradec Králové, Czech Republic
- Department of Analytical Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic
| | - Nikola Přívratská
- Department of Clinical Biochemistry and Diagnostics, University Hospital Hradec Králové, Hradec Králové, Czech Republic
- Department of Analytical Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic
| | - Dorota Turoňová
- Department of Clinical Biochemistry and Diagnostics, University Hospital Hradec Králové, Hradec Králové, Czech Republic
| | - Bohuslav Melichar
- Department of Oncology, Faculty of Medicine and Dentistry, Palacký University, Olomouc, Czech Republic
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10
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González-Paz L, Lossada C, Hurtado-León ML, Vera-Villalobos J, Paz JL, Marrero-Ponce Y, Martinez-Rios F, Alvarado Y. Biophysical Analysis of Potential Inhibitors of SARS-CoV-2 Cell Recognition and Their Effect on Viral Dynamics in Different Cell Types: A Computational Prediction from In Vitro Experimental Data. ACS OMEGA 2024; 9:8923-8939. [PMID: 38434903 PMCID: PMC10905729 DOI: 10.1021/acsomega.3c06968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 01/20/2024] [Accepted: 02/05/2024] [Indexed: 03/05/2024]
Abstract
Recent reports have suggested that the susceptibility of cells to SARS-CoV-2 infection can be influenced by various proteins that potentially act as receptors for the virus. To investigate this further, we conducted simulations of viral dynamics using different cellular systems (Vero E6, HeLa, HEK293, and CaLu3) in the presence and absence of drugs (anthelmintic, ARBs, anticoagulant, serine protease inhibitor, antimalarials, and NSAID) that have been shown to impact cellular recognition by the spike protein based on experimental data. Our simulations revealed that the susceptibility of the simulated cell systems to SARS-CoV-2 infection was similar across all tested systems. Notably, CaLu3 cells exhibited the highest susceptibility to SARS-CoV-2 infection, potentially due to the presence of receptors other than ACE2, which may account for a significant portion of the observed susceptibility. Throughout the study, all tested compounds showed thermodynamically favorable and stable binding to the spike protein. Among the tested compounds, the anticoagulant nafamostat demonstrated the most favorable characteristics in terms of thermodynamics, kinetics, theoretical antiviral activity, and potential safety (toxicity) in relation to SARS-CoV-2 spike protein-mediated infections in the tested cell lines. This study provides mathematical and bioinformatic models that can aid in the identification of optimal cell lines for compound evaluation and detection, particularly in studies focused on repurposed drugs and their mechanisms of action. It is important to note that these observations should be experimentally validated, and this research is expected to inspire future quantitative experiments.
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Affiliation(s)
- Lenin González-Paz
- Centro
de Biomedicina Molecular (CBM). Laboratorio de Biocomputación
(LB),Instituto Venezolano de Investigaciones
Científicas (IVIC),Maracaibo, Zulia 4001, República Bolivariana de Venezuela
| | - Carla Lossada
- Centro
de Biomedicina Molecular (CBM). Laboratorio de Biocomputación
(LB),Instituto Venezolano de Investigaciones
Científicas (IVIC),Maracaibo, Zulia 4001, República Bolivariana de Venezuela
| | - María Laura Hurtado-León
- Facultad
Experimental de Ciencias (FEC). Departamento de Biología. Laboratorio
de Genética y Biología Molecular (LGBM),Universidad del Zulia (LUZ),Maracaibo 4001, República Bolivariana de Venezuela
| | - Joan Vera-Villalobos
- Facultad
de Ciencias Naturales y Matemáticas, Departamento de Química
y Ciencias Ambientales, Laboratorio de Análisis Químico
Instrumental (LAQUINS), Escuela Superior
Politécnica del Litoral, Guayaquil EC090112, Ecuador
| | - José L. Paz
- Departamento
Académico de Química Inorgánica, Facultad de
Química e Ingeniería Química, Universidad Nacional Mayor de San Marcos. Cercado de Lima, Lima 15081, Perú
| | - Yovani Marrero-Ponce
- Grupo
de Medicina Molecular y Traslacional (MeM&T), Colegio de Ciencias
de la Salud (COCSA), Escuela de Medicina, Edificio de Especialidades
Médicas; e Instituto de Simulación Computacional (ISC-USFQ),
Diego de Robles y vía Interoceánica, Universidad San Francisco de Quito (USFQ), Quito, Pichincha 170157, Ecuador
| | - Felix Martinez-Rios
- Universidad
Panamericana. Facultad de Ingeniería. Augusto Rodin 498, Ciudad de México 03920, México
| | - Ysaías.
J. Alvarado
- Centro
de Biomedicina Molecular (CBM). Laboratorio de Química Biofísica
Teórica y Experimental (LQBTE),Instituto
Venezolano de Investigaciones Científicas (IVIC),Maracaibo, Zulia 4001, República Bolivariana
de Venezuela
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11
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Modrzejewska M, Cyrankiewicz J, Zdanowska O, Bosy-Gąsior W. Isolated Depo-Medrol Administration under Tenon's Capsule for Post-COVID-19 Uveitis in a Child: A Case Report and Literature Review. J Clin Med 2024; 13:1341. [PMID: 38592169 PMCID: PMC10932394 DOI: 10.3390/jcm13051341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 02/07/2024] [Accepted: 02/16/2024] [Indexed: 04/10/2024] Open
Abstract
Coronavirus disease 2019 (COVID-19) can manifest with ocular symptoms. These symptoms can be divided into isolated events attributed to COVID-19, and those occurring in multisystem inflammatory syndrome in children (MIS-C), a newly diagnosed disease entity associated with COVID-19 infection. Currently, the literature lacks specific guidelines and treatment regimens for COVID-19 ocular symptoms, especially in children. The authors present the case of a 14-and-a-half-year-old boy with bilateral uveitis of the anterior and posterior segments along with vasculitis and optic neuritis associated with SARS-CoV-2 infection. The authors also perform an up-to-date review of all available publications on the treatment of post-COVID-19 uveitis in children described in the literature between 2020 and 2023. In the case described by the authors, the treatment involved a Depo-Medrol 40 mg/mL injection uder the Tenon capsule, with two subconjunctival injections of epinephrine, topical steroid therapy and non-steroidal anti-inflammatory drugs: dexamethasone 0.1%; diclofenac eye drops. In addition, acetylsalicylic acid (150 mg) and pentoxifylline (100 mg, orally) were administered throughout the course of the disease as well as up to 12 months after its termination, until a complete improvement in visual acuity and the withdrawal of ocular lesions were achieved. It can be assumed that this type of treatment is far more beneficial for pediatric patients, with an effect comparable to systemic steroid administration with a preserved improvement in retinal-vascular circulation, without exposing the child to systemic post-steroid complications.
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Affiliation(s)
- Monika Modrzejewska
- Second Chair and Department of Ophthalmology, Pomeranian Medical University in Szczecin, Al. Powstańców Wlkp. 72, 70-111 Szczecin, Poland
| | | | - Oliwia Zdanowska
- Szpital Uniwersytecki im. Karola Marcinkowskiego w Zielonej Górze, 65-046 Zielona Góra, Poland
| | - Wiktoria Bosy-Gąsior
- Scientific Association of Students 2nd Department of Ophthalmology, Pomeranian Medical University in Szczecin, 70-111 Szczecin, Poland
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12
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Xing G, Yu X, Zhang Y, Sheng S, Jin L, Zhu D, Mei L, Dong X, Lv F. Macrophages-Based Biohybrid Microrobots for Breast Cancer Photothermal Immunotherapy by Inducing Pyroptosis. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2024; 20:e2305526. [PMID: 37798678 DOI: 10.1002/smll.202305526] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 09/19/2023] [Indexed: 10/07/2023]
Abstract
Pyroptosis-based immunotherapy can escape drug resistance as well as inhibit metastasis. It is urgently required to develop a delivery platform to induce targeted tumor-specific pyroptosis for cancer immunotherapy. Herein, macrophages-based biohybrid microrobots (IDN@MC) are constructed with IR-macrophage and decitabine-loaded Metal-organic frameworks (DZNPs). The integration of fluorescence photosensitizers and pH-sensitive DZNPs endow the microrobots properties such as photothermal conversion, fluorescent navigation, targeted drug delivery, and controlled drug release. In light of the inherent tumor targeting, tumor accumulation of IDN@MC is facilitated. Due to the sustained release of decitabine from packaged DZNPs, the host macrophages are differentiated into M1 phenotypes to exert the tumor phagocytosis at the tumor site, directly transporting the therapeutic agents into cancer cells. With laser control, the rapid and durable caspase 3-cleaved gasdermin E (GSDME)-related tumor pyroptosis is achieved with combined photothermal-chemotherapy, releasing inflammatory factors such as lactate dehydrogenase and interleukin-18. Subsequently, the robust and adaptive immune response is primed with dendritic cell maturation to initiate T-cell clone expansion and modulation of the immune suppressive microenvironment, thus enhancing the tumor immunotherapy to inhibit tumor proliferation and metastasis. This macrophages-based biohybrid microrobot is an efficient strategy for breast cancer treatment to trigger photo-induced pyroptosis and augment the immune response.
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Affiliation(s)
- Guozheng Xing
- Tianjin Key Laboratory of Biomedical Materials, Key Laboratory of Biomaterials and Nanotechnology for Cancer Immunotherapy, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300192, P. R. China
| | - Xuya Yu
- Tianjin Key Laboratory of Biomedical Materials, Key Laboratory of Biomaterials and Nanotechnology for Cancer Immunotherapy, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300192, P. R. China
| | - Yan Zhang
- Tianjin Key Laboratory of Biomedical Materials, Key Laboratory of Biomaterials and Nanotechnology for Cancer Immunotherapy, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300192, P. R. China
| | - Shupei Sheng
- Tianjin Key Laboratory of Biomedical Materials, Key Laboratory of Biomaterials and Nanotechnology for Cancer Immunotherapy, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300192, P. R. China
| | - Limin Jin
- Tianjin Key Laboratory of Biomedical Materials, Key Laboratory of Biomaterials and Nanotechnology for Cancer Immunotherapy, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300192, P. R. China
| | - Dunwan Zhu
- Tianjin Key Laboratory of Biomedical Materials, Key Laboratory of Biomaterials and Nanotechnology for Cancer Immunotherapy, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300192, P. R. China
| | - Lin Mei
- Tianjin Key Laboratory of Biomedical Materials, Key Laboratory of Biomaterials and Nanotechnology for Cancer Immunotherapy, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300192, P. R. China
| | - Xia Dong
- Tianjin Key Laboratory of Biomedical Materials, Key Laboratory of Biomaterials and Nanotechnology for Cancer Immunotherapy, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300192, P. R. China
| | - Feng Lv
- Tianjin Key Laboratory of Biomedical Materials, Key Laboratory of Biomaterials and Nanotechnology for Cancer Immunotherapy, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300192, P. R. China
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13
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Özkan Oktay E, Kaman T, Karasakal ÖF, Enisoğlu Atalay V. In Silico Prediction and Molecular Docking of SNPs in NRP1 Gene Associated with SARS-COV-2. Biochem Genet 2024; 62:156-175. [PMID: 37296335 PMCID: PMC10255949 DOI: 10.1007/s10528-023-10409-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 05/19/2023] [Indexed: 06/12/2023]
Abstract
Neuropilin-1 (NRP1) which is a main transmembrane cell surface receptor acts as a host cell mediator resulting in increasing the SARS-Cov-2 infectivity and also plays a role in neuronal development, angiogenesis and axonal outgrowth. The goal of this study is to estimate the impact of single nucleotide polymorphisms (SNPs) in the NRP1 gene on the function, structure and stabilization of protein as well as on the miRNA-mRNA binding regions using bioinformatical tools. It is also aimed to investigate the changes caused by SNPs in NRP1 on interactions with drug molecule and spike protein. The missense type of SNPs was analyzed using SIFT, PolyPhen-2, SNAP2, PROVEAN, Mutation Assessor, SNPs&GO, PhD-SNP, I-Mutant 3.0, MUpro, STRING, Project HOPE, ConSurf, and PolymiRTS. Docking analyses were conducted by AutoDock Vina program. As a result, a total of 733 missense SNPs were determined within the NRP1 gene and nine SNPs were specified as damaging to the protein. The modelling results showed that wild and mutant type amino acids had some different properties such as size, charge, and hydrophobicity. Additionally, their three-dimensional structures of protein were utilized for confirmation of these differences. After evaluating the results, nine polymorphisms rs141633354, rs142121081, rs145954532, rs200028992, rs200660300, rs369312020, rs370117610, rs370551432, rs370641686 were determined to be damaging on the structure and function of NRP1 protein and located in conserved regions. The results of molecular docking showed that the binding affinity values are nearly the same for wild-type and mutant structures support that the mutations carried out are not in the focus of the binding site, therefore the ligand does not affect the binding energy. It is expected that the results will be useful for future studies.
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Affiliation(s)
- Ebru Özkan Oktay
- Vocational School of Health Services, Laboratory Technology, Üsküdar University, Üsküdar, Istanbul, Turkey.
| | - Tuğba Kaman
- Vocational School of Health Services, Medical and Aromatic Plants, Üsküdar University, Üsküdar, Istanbul, Turkey
| | - Ömer Faruk Karasakal
- Vocational School of Health Services, Medical Laboratory Techniques, Üsküdar University, Üsküdar, Istanbul, Turkey
| | - Vildan Enisoğlu Atalay
- Department of Molecular Biology and Genetics, Üsküdar University, Üsküdar, Istanbul, Turkey
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14
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Shafiq A, Khalid U, Abdur Rehman U, Abdullah Almuqri E, Muddassir M, Ahmad S, Khan MI, Khan A, Wei DQ. Structural basis for the mechanism of interaction of SARS-CoV-2 B.1.640.2 variant RBD with the host receptors hACE2 and GRP78. J Biomol Struct Dyn 2024; 42:2034-2042. [PMID: 37286365 DOI: 10.1080/07391102.2023.2220053] [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] [Received: 01/23/2023] [Accepted: 04/09/2023] [Indexed: 06/09/2023]
Abstract
The inflicted chaos instigated by the SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2) globally continues with the emergence of novel variants. The current global outbreak is aggravated by the manifestation of novel variants, which affect the effectiveness of the vaccine, attachment with hACE2 (human Angiotensin-converting enzyme 2) and immune evasion. Recently, a new variant named University Hospital Institute (IHU) (B.1.640.2) was reported in France in November 2021 and is spreading globally affecting public healthcare. The B.1.640.2 SARS-CoV-2 strain revealed 14 mutations and 9 deletions in spike protein. Thus, it is important to understand how these variations in the spike protein impact the communication with the host. A protein coupling approach along with molecular simulation protocols was used to interpret the variation in the binding of the wild type (WT) and B.1.640.2 variant with hACE2 and Glucose-regulating protein 78 (GRP78) receptors. The initial docking scores revealed a stronger binding of the B.1.640.2-RBD with both the hACE2 and GRP78. To further understand the crucial dynamic changes, we looked at the structural and dynamic characteristics and also explored the variations in the bonding networks between the WT and B.1.640.2-RBD (receptor-binding domain) in association with hACE2 and GRP78, respectively. Our findings revealed that the variant complex demonstrated distinct dynamic properties in contrast to the wild type due to the acquired mutations. Finally, to provide conclusive evidence on the higher binding by the B.1.640.2 variant the TBE was computed for each complex. For the WT with hACE2 the TBE was quantified to be-61.38 ± 0.96 kcal/mol and for B.1.640.2 variant the TBE was estimated to be -70.47 ± 1.00 kcal/mol. For the WT-RBD-GRP78 the TBE -was computed to be 32.32 ± 0.56 kcal/mol and for the B.1.640.2-RBD a TBE of -50.39 ± 0.88 kcal/mol was reported. This show that these mutations are the basis for higher binding and infectivity produced by B.1.640.2 variant and can be targeted for drug designing against it.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Athar Shafiq
- Department of Bioinformatics and Biological Statistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, P.R. China
| | - Ujala Khalid
- Fatima Jinnah Medical University, Lahore, Punjab, Pakistan
| | - Umar Abdur Rehman
- Aziz Fatimah Medical and Dental College, Faisalabad, Punjab, Pakistan
| | - Eman Abdullah Almuqri
- Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
| | - Maria Muddassir
- Institute of Molecular Biology & Biotechnology, The University of Lahore (UOL), Lahore, Punjab, Pakistan
| | - Sajjad Ahmad
- Department of Health and Biological Sciences, Abasyn University, Khyber Pakhtunkhwa, Pakistan
| | - Muhammad Idrees Khan
- Department of Instrument Science and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, Shanghai, P.R. China
| | - Abbas Khan
- Department of Bioinformatics and Biological Statistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, P.R. China
- Zhongjing Research and Industrialization Institute of Chinese Medicine, Nayang, Henan, P.R. China
| | - Dong-Qing Wei
- Department of Bioinformatics and Biological Statistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, P.R. China
- Zhongjing Research and Industrialization Institute of Chinese Medicine, Nayang, Henan, P.R. China
- State Key Laboratory of Microbial Metabolism, Shanghai-Islamabad-Belgrade Joint Innovation Center on Antibacterial Resistances, Joint Laboratory of International Laboratory of Metabolic and Developmental Sciences, Ministry of Education and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, P.R. China
- Peng Cheng Laboratory, Shenzhen, Guangdong, P.R. China
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15
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Mei S, Zou Y, Jiang S, Xue L, Wang Y, Jing H, Yang P, Niu MM, Li J, Yuan K, Zhang Y. Highly potent dual-targeting angiotensin-converting enzyme 2 (ACE2) and Neuropilin-1 (NRP1) peptides: A promising broad-spectrum therapeutic strategy against SARS-CoV-2 infection. Eur J Med Chem 2024; 263:115908. [PMID: 37981444 DOI: 10.1016/j.ejmech.2023.115908] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 10/12/2023] [Accepted: 10/21/2023] [Indexed: 11/21/2023]
Abstract
The efficacy of approved vaccines has been diminishing due to the increasing advent of SARS-CoV-2 variants with diverse mutations that favor sneak entry. Nonetheless, these variants recognize the conservative host receptors angiotensin-converting enzyme 2 (ACE2) and neuropilin-1 (NRP1) for entry, rendering the dual blockade of ACE2 and NRP1 an advantageous pan-inhibition strategy. Here, we identified a highly potent dual-targeting peptide AP-1 using structure-based virtual screening protocol. AP-1 had nanoscale binding affinities for ACE2 (Kd = 6.1 ± 0.2 nM) and NRP1 (Kd = 13.4 ± 1.2 nM) and approximately 102- and 8-fold stronger than positive inhibitors S471-503 and NMTP-5, respectively. Further evidence in pseudovirus cell infection and cytotoxicity assays demonstrated that AP-1 exhibited remarkable entry inhibition of variants of concern (VOCs) of SARS-CoV-2 without impairing host cell viability. Together, our findings suggest that AP-1 with dual-targeting ACE2/NRP1 efficacy could be a promising broad-spectrum agent for treating SARS-CoV-2 emerging VOCs.
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Affiliation(s)
- Shuang Mei
- Key Laboratory of Drug Quality Control and Pharmacovigilance, Jiangsu Key Laboratory of Drug Design and Optimization, Ministry of Education, China Pharmaceutical University, Nanjing, 211198, China
| | - Yunting Zou
- Key Laboratory of Drug Quality Control and Pharmacovigilance, Jiangsu Key Laboratory of Drug Design and Optimization, Ministry of Education, China Pharmaceutical University, Nanjing, 211198, China
| | - Su Jiang
- Department of Pharmacy, Institute of Clinical Medicine, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou, China
| | - Lu Xue
- Department of Pharmacy, Institute of Clinical Medicine, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou, China
| | - Yuting Wang
- Key Laboratory of Drug Quality Control and Pharmacovigilance, Jiangsu Key Laboratory of Drug Design and Optimization, Ministry of Education, China Pharmaceutical University, Nanjing, 211198, China
| | - Han Jing
- Key Laboratory of Drug Quality Control and Pharmacovigilance, Jiangsu Key Laboratory of Drug Design and Optimization, Ministry of Education, China Pharmaceutical University, Nanjing, 211198, China
| | - Peng Yang
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, China
| | - Miao-Miao Niu
- Key Laboratory of Drug Quality Control and Pharmacovigilance, Jiangsu Key Laboratory of Drug Design and Optimization, Ministry of Education, China Pharmaceutical University, Nanjing, 211198, China
| | - Jindong Li
- Department of Pharmacy, Institute of Clinical Medicine, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou, China.
| | - Kai Yuan
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, China.
| | - Yan Zhang
- Department of Pharmacy, Institute of Clinical Medicine, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou, China.
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16
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Perico L, Benigni A, Remuzzi G. SARS-CoV-2 and the spike protein in endotheliopathy. Trends Microbiol 2024; 32:53-67. [PMID: 37393180 PMCID: PMC10258582 DOI: 10.1016/j.tim.2023.06.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 06/05/2023] [Accepted: 06/08/2023] [Indexed: 07/03/2023]
Abstract
SARS-CoV-2, the causative agent of COVID-19, primarily affects the epithelial compartment in the upper and lower airways. There is evidence that the microvasculature in both the pulmonary and extrapulmonary systems is a major target of SARS-CoV-2. Consistent with this, vascular dysfunction and thrombosis are the most severe complications in COVID-19. The proinflammatory milieu triggered by the hyperactivation of the immune system by SARS-CoV-2 has been suggested to be the main trigger for endothelial dysfunction during COVID-19. More recently, a rapidly growing number of reports have indicated that SARS-CoV-2 can interact directly with endothelial cells through the spike protein, leading to multiple instances of endothelial dysfunction. Here, we describe all the available findings showing the direct effect of the SARS-CoV-2 spike protein on endothelial cells and offer mechanistic insights into the molecular basis of vascular dysfunction in severe COVID-19.
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Affiliation(s)
- Luca Perico
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori, Bergamo, Italy.
| | - Ariela Benigni
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori, Bergamo, Italy
| | - Giuseppe Remuzzi
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori, Bergamo, Italy
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17
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Ma Y, Lei M, Chen H, Huang P, Sun J, Sun Q, Hu Y, Shi J. Susceptibility of bovine to SARS-CoV-2 variants of concern: insights from ACE2, AXL, and NRP1 receptors. Virol J 2023; 20:276. [PMID: 38012648 PMCID: PMC10680262 DOI: 10.1186/s12985-023-02222-9] [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] [Received: 08/27/2023] [Accepted: 10/30/2023] [Indexed: 11/29/2023] Open
Abstract
The possibilities of cross-species transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) between humans and important livestock species are not yet known. Herein, we used the structural and genetic alignment and surface potential analysis of the amino acid (aa) in angiotensin-converting enzyme 2 (ACE2), tyrosine kinase receptor UFO (AXL), and neuropilin 1 (NRP1) in different species with substantial public health importance. The residues interfacing with the N-terminal domain (NTD) or receptor-binding domain (RBD) of S were aligned to screen the critical aa sites that determined the susceptibility of the SARS-CoV-2 to the host. We found that AXL and NRP1 proteins might be used as the receptors of SARS-CoV-2 in bovines. However, ACE2 protein may not be considered to be involved in the cross-species transmission of SARS-CoV-2 VOCs in cattle because the key residues of the ACE2-S-binding interface were different from those in known susceptible species. This study indicated that emerging SARS-CoV-2 variants potentially expand species tropism to bovines through AXL and NRP1 proteins.
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Affiliation(s)
- Ying Ma
- Yunnan Provincial Key Laboratory of Vector-Borne Diseases Control and Research, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 935 Jiaoling Road, Kunming, 650118, Yunnan Province, China
| | - Mengyue Lei
- Yunnan Provincial Key Laboratory of Vector-Borne Diseases Control and Research, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 935 Jiaoling Road, Kunming, 650118, Yunnan Province, China
| | - Hongli Chen
- Yunnan Provincial Key Laboratory of Vector-Borne Diseases Control and Research, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 935 Jiaoling Road, Kunming, 650118, Yunnan Province, China
- Kunming Medical University, Kunming, Yunnan Province, China
| | - Pu Huang
- Yunnan Provincial Key Laboratory of Vector-Borne Diseases Control and Research, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 935 Jiaoling Road, Kunming, 650118, Yunnan Province, China
| | - Jing Sun
- Yunnan Provincial Key Laboratory of Vector-Borne Diseases Control and Research, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 935 Jiaoling Road, Kunming, 650118, Yunnan Province, China.
| | - Qiangming Sun
- National Kunming High-Level Biosafety Primate Research Center, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 935 Jiaoling Road, Kunming, 650118, Yunnan Province, China.
| | - Yunzhang Hu
- Yunnan Provincial Key Laboratory of Vector-Borne Diseases Control and Research, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 935 Jiaoling Road, Kunming, 650118, Yunnan Province, China.
| | - Jiandong Shi
- Yunnan Provincial Key Laboratory of Vector-Borne Diseases Control and Research, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 935 Jiaoling Road, Kunming, 650118, Yunnan Province, China.
- National Kunming High-Level Biosafety Primate Research Center, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 935 Jiaoling Road, Kunming, 650118, Yunnan Province, China.
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18
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Eberhardt N, Noval MG, Kaur R, Amadori L, Gildea M, Sajja S, Das D, Cilhoroz B, Stewart O, Fernandez DM, Shamailova R, Guillen AV, Jangra S, Schotsaert M, Newman JD, Faries P, Maldonado T, Rockman C, Rapkiewicz A, Stapleford KA, Narula N, Moore KJ, Giannarelli C. SARS-CoV-2 infection triggers pro-atherogenic inflammatory responses in human coronary vessels. NATURE CARDIOVASCULAR RESEARCH 2023; 2:899-916. [PMID: 38076343 PMCID: PMC10702930 DOI: 10.1038/s44161-023-00336-5] [Citation(s) in RCA: 52] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Accepted: 08/23/2023] [Indexed: 12/19/2023]
Abstract
Patients with coronavirus disease 2019 (COVID-19) present increased risk for ischemic cardiovascular complications up to 1 year after infection. Although the systemic inflammatory response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection likely contributes to this increased cardiovascular risk, whether SARS-CoV-2 directly infects the coronary vasculature and attendant atherosclerotic plaques remains unknown. Here we report that SARS-CoV-2 viral RNA is detectable and replicates in coronary lesions taken at autopsy from severe COVID-19 cases. SARS-CoV-2 targeted plaque macrophages and exhibited a stronger tropism for arterial lesions than adjacent perivascular fat, correlating with macrophage infiltration levels. SARS-CoV-2 entry was increased in cholesterol-loaded primary macrophages and dependent, in part, on neuropilin-1. SARS-CoV-2 induced a robust inflammatory response in cultured macrophages and human atherosclerotic vascular explants with secretion of cytokines known to trigger cardiovascular events. Our data establish that SARS-CoV-2 infects coronary vessels, inducing plaque inflammation that could trigger acute cardiovascular complications and increase the long-term cardiovascular risk.
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Affiliation(s)
- Natalia Eberhardt
- Department of Medicine, Division of Cardiology, NYU Cardiovascular Research Center, New York University School of Medicine, New York, NY, USA
| | - Maria Gabriela Noval
- Department of Microbiology, New York University School of Medicine, New York, NY, USA
| | - Ravneet Kaur
- Department of Medicine, Division of Cardiology, NYU Cardiovascular Research Center, New York University School of Medicine, New York, NY, USA
| | - Letizia Amadori
- Department of Medicine, Division of Cardiology, NYU Cardiovascular Research Center, New York University School of Medicine, New York, NY, USA
| | - Michael Gildea
- Department of Medicine, Division of Cardiology, NYU Cardiovascular Research Center, New York University School of Medicine, New York, NY, USA
| | - Swathy Sajja
- Department of Medicine, Division of Cardiology, NYU Cardiovascular Research Center, New York University School of Medicine, New York, NY, USA
| | - Dayasagar Das
- Department of Medicine, Division of Cardiology, NYU Cardiovascular Research Center, New York University School of Medicine, New York, NY, USA
| | - Burak Cilhoroz
- Department of Medicine, Division of Cardiology, NYU Cardiovascular Research Center, New York University School of Medicine, New York, NY, USA
| | - O’Jay Stewart
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Dawn M. Fernandez
- Department of Medicine, Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Roza Shamailova
- Department of Medicine, Division of Cardiology, NYU Cardiovascular Research Center, New York University School of Medicine, New York, NY, USA
| | - Andrea Vasquez Guillen
- Department of Medicine, Division of Cardiology, NYU Cardiovascular Research Center, New York University School of Medicine, New York, NY, USA
| | - Sonia Jangra
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Michael Schotsaert
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Jonathan D. Newman
- Department of Medicine, Division of Cardiology, NYU Cardiovascular Research Center, New York University School of Medicine, New York, NY, USA
| | - Peter Faries
- Department of Surgery, Vascular Division, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Thomas Maldonado
- Department of Surgery, Vascular Division, New York University Langone Health, New York, NY, USA
| | - Caron Rockman
- Department of Surgery, Vascular Division, New York University Langone Health, New York, NY, USA
| | - Amy Rapkiewicz
- Department of Pathology, NYU Winthrop Hospital, Long Island School of Medicine, New York, NY, USA
| | - Kenneth A. Stapleford
- Department of Microbiology, New York University School of Medicine, New York, NY, USA
| | - Navneet Narula
- Department of Pathology, New York University School of Medicine, New York, NY, USA
| | - Kathryn J. Moore
- Department of Medicine, Division of Cardiology, NYU Cardiovascular Research Center, New York University School of Medicine, New York, NY, USA
| | - Chiara Giannarelli
- Department of Medicine, Division of Cardiology, NYU Cardiovascular Research Center, New York University School of Medicine, New York, NY, USA
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Pathology, New York University School of Medicine, New York, NY, USA
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19
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Hou D, Cao W, Kim S, Cui X, Ziarnik M, Im W, Zhang XF. Biophysical investigation of interactions between SARS-CoV-2 spike protein and neuropilin-1. Protein Sci 2023; 32:e4773. [PMID: 37656811 PMCID: PMC10510470 DOI: 10.1002/pro.4773] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2023] [Revised: 08/19/2023] [Accepted: 08/29/2023] [Indexed: 09/03/2023]
Abstract
Recent studies have suggested that neuropilin-1 (NRP1) may serve as a potential receptor in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, the biophysical characteristics of interactions between NRP1 and SARS-CoV-2 remain unclear. In this study, we examined the interactions between NRP1 and various SARS-CoV-2 spike (S) fragments, including the receptor-binding domain (RBD) and the S protein trimer in a soluble form or expressed on pseudovirions, using atomic force microscopy and structural modeling. Our measurements shows that NRP1 interacts with the RBD and trimer at a higher binding frequency (BF) compared to ACE2. This NRP1-RBD interaction has also been predicted and simulated via AlphaFold2 and molecular dynamics simulations, and the results indicate that their binding patterns are very similar to RBD-ACE2 interactions. Additionally, under similar loading rates, the most probable unbinding forces between NRP1 and S trimer (both soluble form and on pseudovirions) are larger than the forces between NRP1 and RBD and between trimer and ACE2. Further analysis indicates that NRP1 has a stronger binding affinity to the SARS-CoV-2 S trimer with a dissociation rate of 0.87 s-1 , four times lower than the dissociation rate of 3.65 s-1 between NRP1 and RBD. Moreover, additional experiments show that RBD-neutralizing antibodies can significantly reduce the BF for both ACE2 and NRP1. Together, the study suggests that NRP1 can be an alternative receptor for SARS-CoV-2 attachment to human cells, and the neutralizing antibodies targeting SARS-CoV-2 RBD can reduce the binding between SARS-CoV-2 and NRP1.
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Affiliation(s)
- Decheng Hou
- Department of BioengineeringLehigh UniversityBethlehemPennsylvaniaUSA
- Department of Biomedical EngineeringUniversity of Massachusetts AmherstAmherstMassachusettsUSA
| | - Wenpeng Cao
- Department of BioengineeringLehigh UniversityBethlehemPennsylvaniaUSA
| | - Seonghan Kim
- Department of BioengineeringLehigh UniversityBethlehemPennsylvaniaUSA
| | - Xinyu Cui
- Department of BioengineeringLehigh UniversityBethlehemPennsylvaniaUSA
- Department of Biomedical EngineeringUniversity of Massachusetts AmherstAmherstMassachusettsUSA
| | - Matthew Ziarnik
- Department of BioengineeringLehigh UniversityBethlehemPennsylvaniaUSA
| | - Wonpil Im
- Department of BioengineeringLehigh UniversityBethlehemPennsylvaniaUSA
- Departments of Biological Sciences, Chemistry, and Computer Science and EngineeringLehigh UniversityBethlehemUSA
| | - X. Frank Zhang
- Department of BioengineeringLehigh UniversityBethlehemPennsylvaniaUSA
- Department of Biomedical EngineeringUniversity of Massachusetts AmherstAmherstMassachusettsUSA
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20
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Eberhardt N, Noval MG, Kaur R, Sajja S, Amadori L, Das D, Cilhoroz B, Stewart O, Fernandez DM, Shamailova R, Guillen AV, Jangra S, Schotsaert M, Gildea M, Newman JD, Faries P, Maldonado T, Rockman C, Rapkiewicz A, Stapleford KA, Narula N, Moore KJ, Giannarelli C. SARS-CoV-2 infection triggers pro-atherogenic inflammatory responses in human coronary vessels. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.08.14.553245. [PMID: 37645908 PMCID: PMC10461985 DOI: 10.1101/2023.08.14.553245] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/31/2023]
Abstract
COVID-19 patients present higher risk for myocardial infarction (MI), acute coronary syndrome, and stroke for up to 1 year after SARS-CoV-2 infection. While the systemic inflammatory response to SARS-CoV-2 infection likely contributes to this increased cardiovascular risk, whether SARS-CoV-2 directly infects the coronary vasculature and attendant atherosclerotic plaques to locally promote inflammation remains unknown. Here, we report that SARS-CoV-2 viral RNA (vRNA) is detectable and replicates in coronary atherosclerotic lesions taken at autopsy from patients with severe COVID-19. SARS-CoV-2 localizes to plaque macrophages and shows a stronger tropism for arterial lesions compared to corresponding perivascular fat, correlating with the degree of macrophage infiltration. In vitro infection of human primary macrophages highlights that SARS-CoV-2 entry is increased in cholesterol-loaded macrophages (foam cells) and is dependent, in part, on neuropilin-1 (NRP-1). Furthermore, although viral replication is abortive, SARS-CoV-2 induces a robust inflammatory response that includes interleukins IL-6 and IL-1β, key cytokines known to trigger ischemic cardiovascular events. SARS-CoV-2 infection of human atherosclerotic vascular explants recapitulates the immune response seen in cultured macrophages, including pro-atherogenic cytokine secretion. Collectively, our data establish that SARS-CoV-2 infects macrophages in coronary atherosclerotic lesions, resulting in plaque inflammation that may promote acute CV complications and long-term risk for CV events.
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21
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Mahajan S, Sen D, Sunil A, Srikanth P, Marathe SD, Shaw K, Sahare M, Galande S, Abraham NM. Knockout of angiotensin converting enzyme-2 receptor leads to morphological aberrations in rodent olfactory centers and dysfunctions associated with sense of smell. Front Neurosci 2023; 17:1180868. [PMID: 37404465 PMCID: PMC10315482 DOI: 10.3389/fnins.2023.1180868] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Accepted: 05/15/2023] [Indexed: 07/06/2023] Open
Abstract
Neuronal morphological characterization and behavioral phenotyping in mouse models help dissecting neural mechanisms of brain disorders. Olfactory dysfunctions and other cognitive problems were widely reported in asymptomatic carriers and symptomatic patients infected with Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). This led us to generate the knockout mouse model for Angiotensin Converting Enzyme-2 (ACE2) receptor, one of the molecular factors mediating SARS-CoV-2 entry to the central nervous system, using CRISPR-Cas9 based genome editing tools. ACE2 receptors and Transmembrane Serine Protease-2 (TMPRSS2) are widely expressed in the supporting (sustentacular) cells of human and rodent olfactory epithelium, however, not in the olfactory sensory neurons (OSNs). Hence, acute inflammation induced changes due to viral infection in the olfactory epithelium may explain transient changes in olfactory detectabilities. As ACE2 receptors are expressed in different olfactory centers and higher brain areas, we studied the morphological changes in the olfactory epithelium (OE) and olfactory bulb (OB) of ACE2 KO mice in comparison with wild type animals. Our results showed reduced thickness of OSN layer in the OE, and a decrease in cross-sectional area of glomeruli in the OB. Aberrations in the olfactory circuits were revealed by lowered immunoreactivity toward microtubule associated protein 2 (MAP2) in the glomerular layer of ACE2 KO mice. Further, to understand if these morphological alterations lead to compromised sensory and cognitive abilities, we performed an array of behavioral assays probing their olfactory subsystems' performances. ACE2 KO mice exhibited slower learning of odor discriminations at the threshold levels and novel odor identification impairments. Further, ACE2 KO mice failed to memorize the pheromonal locations while trained on a multimodal task implying the aberrations of neural circuits involved in higher cognitive functions. Our results thus provide the morphological basis for the sensory and cognitive disabilities caused by the deletion of ACE2 receptors and offer a potential experimental approach to study the neural circuit mechanisms of cognitive impairments observed in long COVID.
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Affiliation(s)
- Sarang Mahajan
- Laboratory of Neural Circuits and Behaviour (LNCB), Department of Biology, Indian Institute of Science Education and Research (IISER), Pune, Maharashtra, India
- Department of Biology, Indian Institute of Science Education and Research (IISER), Pune, Maharashtra, India
| | - Deepshikha Sen
- Laboratory of Neural Circuits and Behaviour (LNCB), Department of Biology, Indian Institute of Science Education and Research (IISER), Pune, Maharashtra, India
- Department of Biology, Indian Institute of Science Education and Research (IISER), Pune, Maharashtra, India
| | - Anantu Sunil
- Laboratory of Neural Circuits and Behaviour (LNCB), Department of Biology, Indian Institute of Science Education and Research (IISER), Pune, Maharashtra, India
- Indian Institute of Science Education and Research (IISER), Kolkata, West Bengal, India
| | - Priyadharshini Srikanth
- Laboratory of Neural Circuits and Behaviour (LNCB), Department of Biology, Indian Institute of Science Education and Research (IISER), Pune, Maharashtra, India
- Department of Biology, Indian Institute of Science Education and Research (IISER), Pune, Maharashtra, India
| | - Shruti D. Marathe
- Laboratory of Neural Circuits and Behaviour (LNCB), Department of Biology, Indian Institute of Science Education and Research (IISER), Pune, Maharashtra, India
- Department of Biology, Indian Institute of Science Education and Research (IISER), Pune, Maharashtra, India
| | - Karishma Shaw
- Laboratory of Neural Circuits and Behaviour (LNCB), Department of Biology, Indian Institute of Science Education and Research (IISER), Pune, Maharashtra, India
- Department of Biology, Indian Institute of Science Education and Research (IISER), Pune, Maharashtra, India
| | - Mahesh Sahare
- Department of Biology, Indian Institute of Science Education and Research (IISER), Pune, Maharashtra, India
| | - Sanjeev Galande
- Department of Biology, Indian Institute of Science Education and Research (IISER), Pune, Maharashtra, India
- Laboratory of Chromatin Biology and Epigenetics, Department of Biology, Indian Institute of Science Education and Research (IISER), Pune, Maharashtra, India
- Center of Excellence in Epigenetics, Department of Life Sciences, Shiv Nadar University, Delhi-NCR, India
| | - Nixon M. Abraham
- Laboratory of Neural Circuits and Behaviour (LNCB), Department of Biology, Indian Institute of Science Education and Research (IISER), Pune, Maharashtra, India
- Department of Biology, Indian Institute of Science Education and Research (IISER), Pune, Maharashtra, India
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22
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Gupta Y, Savytskyi OV, Coban M, Venugopal A, Pleqi V, Weber CA, Chitale R, Durvasula R, Hopkins C, Kempaiah P, Caulfield TR. Protein structure-based in-silico approaches to drug discovery: Guide to COVID-19 therapeutics. Mol Aspects Med 2023; 91:101151. [PMID: 36371228 PMCID: PMC9613808 DOI: 10.1016/j.mam.2022.101151] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Revised: 10/19/2022] [Accepted: 10/21/2022] [Indexed: 11/06/2022]
Abstract
With more than 5 million fatalities and close to 300 million reported cases, COVID-19 is the first documented pandemic due to a coronavirus that continues to be a major health challenge. Despite being rapid, uncontrollable, and highly infectious in its spread, it also created incentives for technology development and redefined public health needs and research agendas to fast-track innovations to be translated. Breakthroughs in computational biology peaked during the pandemic with renewed attention to making all cutting-edge technology deliver agents to combat the disease. The demand to develop effective treatments yielded surprising collaborations from previously segregated fields of science and technology. The long-standing pharmaceutical industry's aversion to repurposing existing drugs due to a lack of exponential financial gain was overrun by the health crisis and pressures created by front-line researchers and providers. Effective vaccine development even at an unprecedented pace took more than a year to develop and commence trials. Now the emergence of variants and waning protections during the booster shots is resulting in breakthrough infections that continue to strain health care systems. As of now, every protein of SARS-CoV-2 has been structurally characterized and related host pathways have been extensively mapped out. The research community has addressed the druggability of a multitude of possible targets. This has been made possible due to existing technology for virtual computer-assisted drug development as well as new tools and technologies such as artificial intelligence to deliver new leads. Here in this article, we are discussing advances in the drug discovery field related to target-based drug discovery and exploring the implications of known target-specific agents on COVID-19 therapeutic management. The current scenario calls for more personalized medicine efforts and stratifying patient populations early on for their need for different combinations of prognosis-specific therapeutics. We intend to highlight target hotspots and their potential agents, with the ultimate goal of using rational design of new therapeutics to not only end this pandemic but also uncover a generalizable platform for use in future pandemics.
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Affiliation(s)
- Yash Gupta
- Department of Medicine, Infectious Diseases, Mayo Clinic, Jacksonville, FL, USA
| | - Oleksandr V Savytskyi
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA; In Vivo Biosystems, Eugene, OR, USA
| | - Matt Coban
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA; Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA
| | | | - Vasili Pleqi
- Department of Medicine, Infectious Diseases, Mayo Clinic, Jacksonville, FL, USA
| | - Caleb A Weber
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA
| | - Rohit Chitale
- Department of Medicine, Infectious Diseases, Mayo Clinic, Jacksonville, FL, USA; The Council on Strategic Risks, 1025 Connecticut Ave NW, Washington, DC, USA
| | - Ravi Durvasula
- Department of Medicine, Infectious Diseases, Mayo Clinic, Jacksonville, FL, USA
| | | | - Prakasha Kempaiah
- Department of Medicine, Infectious Diseases, Mayo Clinic, Jacksonville, FL, USA
| | - Thomas R Caulfield
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA; Department of QHS Computational Biology, Mayo Clinic, Jacksonville, FL, USA; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA; Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA; Department of Neurosurgery, Mayo Clinic, Jacksonville, FL, USA.
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23
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Thirumugam G, Radhakrishnan Y, Ramamurthi S, Bhaskar JP, Krishnaswamy B. A systematic review on impact of SARS-CoV-2 infection. Microbiol Res 2023; 271:127364. [PMID: 36989761 PMCID: PMC10015779 DOI: 10.1016/j.micres.2023.127364] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2023] [Revised: 03/13/2023] [Accepted: 03/13/2023] [Indexed: 03/17/2023]
Abstract
Innumerable pathogens including RNA viruses have catastrophic pandemic propensity, in turn, SARS-CoV-2 infection is highly contagious. Emergence of SARS-CoV-2 variants with high mutation rate additionally codifies infectious ability of virus and arisen clinical imputations to human health. Although, our knowledge of mechanism of virus infection and its impact on host system has been substantially demystified, uncertainties about the emergence of virus are still not fully understood. To date, there are no potentially curative drugs are identified against the viral infection. Even though, drugs are repurposed in the initial period of infection, many are significantly negative in clinical trials. Moreover, the infection is dependent on organ status, co-morbid conditions, variant of virus and geographic region. This review article aims to comprehensively describe the SARS-CoV-2 infection and the impacts in the host cellular system. This review also briefly provides an overview of genome, proteome and metabolome associated risk to infection and the advancement of therapeutics in SARS-CoV-2 infection management.
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Key Words
- sars-cov-2, severe acute respiratory syndrome coronavirus 2
- who, world health organization
- mers-cov-middle, east respiratory syndrome coronavirus
- ig, immunoglobulin
- rgd, arginine-glycine-aspartic
- nk-natural, killer cells
- s1 and s2, subunits of s protein
- nsp, non-structural proteins
- voi, varian of interest
- voc, variant of concern
- vum-variant, under monitoring
- ace2, angiotensin converting enzyme 2
- nsp-non-structural, proteins
- orf-open, reading frame
- sars-cov-2
- variants
- omics
- alternative medicines
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Affiliation(s)
- Gowripriya Thirumugam
- Department of Biotechnology, Science Campus, Alagappa University, Karaikudi 630 003, Tamil Nadu, India
| | - Yashwanth Radhakrishnan
- ITC - Life Sciences and Technology Centre, Peenya Industrial Area, 1(st) Phase, Bangalore 560058, Karnataka, India
| | - Suresh Ramamurthi
- ITC - Life Sciences and Technology Centre, Peenya Industrial Area, 1(st) Phase, Bangalore 560058, Karnataka, India
| | - James Prabhanand Bhaskar
- ITC - Life Sciences and Technology Centre, Peenya Industrial Area, 1(st) Phase, Bangalore 560058, Karnataka, India
| | - Balamurugan Krishnaswamy
- Department of Biotechnology, Science Campus, Alagappa University, Karaikudi 630 003, Tamil Nadu, India,Corresponding author
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24
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New insights for infection mechanism and potential targets of COVID-19: Three Chinese patent medicines and three Chinese medicine formulas as promising therapeutic approaches. CHINESE HERBAL MEDICINES 2023; 15:157-168. [PMCID: PMC9993661 DOI: 10.1016/j.chmed.2022.06.014] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 04/08/2022] [Accepted: 06/11/2022] [Indexed: 03/11/2023] Open
Abstract
The coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with high pathogenicity and infectiousness has become a sudden and lethal pandemic worldwide. Currently, there is no accepted specific drug for COVID-19 treatment. Therefore, it is extremely urgent to clarify the pathogenic mechanism and develop effective therapies for patients with COVID-19. According to several reliable reports from China, traditional Chinese medicine (TCM), especially for three Chinese patent medicines and three Chinese medicine formulas, has been demonstrated to effectively alleviate the symptoms of COVID-19 either used alone or in combination with Western medicines. In this review, we systematically summarized and analyzed the pathogenesis of COVID-19, the detailed clinical practice, active ingredients investigation, network pharmacology prediction and underlying mechanism verification of three Chinese patent medicines and three Chinese medicine formulas in the COVID-19 combat. Additionally, we summarized some promising and high-frequency drugs of these prescriptions and discussed their regulatory mechanism, which provides guidance for the development of new drugs against COVID-19. Collectively, by addressing critical challenges, for example, unclear targets and complicated active ingredients of these medicines and formulas, we believe that TCM will represent promising and efficient strategies for curing COVID-19 and related pandemics.
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25
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Bhowmik R, Pardasani M, Mahajan S, Magar R, Joshi SV, Nair GA, Bhattacharjee AS, Abraham NM. Persistent olfactory learning deficits during and post-COVID-19 infection. CURRENT RESEARCH IN NEUROBIOLOGY 2023; 4:100081. [PMID: 36919010 PMCID: PMC9985517 DOI: 10.1016/j.crneur.2023.100081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 12/31/2022] [Accepted: 02/12/2023] [Indexed: 03/07/2023] Open
Abstract
Quantifying olfactory impairments can facilitate early detection of Coronavirus disease 2019 (COVID-19). Despite being a debated topic, many reports provide evidence for the neurotropism of SARS-CoV-2. However, a sensitive, specific, and accurate non-invasive method for quantifying persistent neurological impairments is missing to date. To quantify olfactory detectabilities and neurocognitive impairments in symptomatic COVID-19 patients during and post-infection periods, we used a custom-built olfactory-action meter (OAM) providing accurate behavioral readouts. Ten monomolecular odors were used for quantifying olfactory detectabilities and two pairs of odors were employed for olfactory matching tests. We followed cohorts of healthy subjects, symptomatic patients, and recovered subjects for probing olfactory learning deficits, before the Coronavirus Omicron variant was reported in India. Our method identifies severe and persistent olfactory dysfunctions in symptomatic patients during COVID-19 infection. Symptomatic patients and recovered subjects showed significant olfactory learning deficits during and post-infection periods, 4-18 months, in comparison to healthy subjects. On comparing olfactory fitness, we found differential odor detectabilities and olfactory function scores in symptomatic patients and asymptomatic carriers. Our results indicate probable long-term neurocognitive deficits in COVID-19 patients imploring the necessity of long-term tracking during post-infection period. Differential olfactory fitness observed in symptomatic patients and asymptomatic carriers demand probing mechanisms of potentially distinct infection routes.
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Affiliation(s)
- Rajdeep Bhowmik
- Laboratory of Neural Circuits and Behaviour (LNCB), Department of Biology, Indian Institute of Science Education and Research (IISER), Pune, Maharashtra, 411008, India
| | - Meenakshi Pardasani
- Laboratory of Neural Circuits and Behaviour (LNCB), Department of Biology, Indian Institute of Science Education and Research (IISER), Pune, Maharashtra, 411008, India
| | - Sarang Mahajan
- Laboratory of Neural Circuits and Behaviour (LNCB), Department of Biology, Indian Institute of Science Education and Research (IISER), Pune, Maharashtra, 411008, India
| | - Rahul Magar
- Byramjee Jeejeebhoy Government Medical College and Sassoon General Hospitals (BJGMC & SGH), Pune, Maharashtra, 411001, India
| | - Samir V. Joshi
- Byramjee Jeejeebhoy Government Medical College and Sassoon General Hospitals (BJGMC & SGH), Pune, Maharashtra, 411001, India
| | - Ganesh Ashish Nair
- Laboratory of Neural Circuits and Behaviour (LNCB), Department of Biology, Indian Institute of Science Education and Research (IISER), Pune, Maharashtra, 411008, India
| | - Anindya S. Bhattacharjee
- Laboratory of Neural Circuits and Behaviour (LNCB), Department of Biology, Indian Institute of Science Education and Research (IISER), Pune, Maharashtra, 411008, India
| | - Nixon M. Abraham
- Laboratory of Neural Circuits and Behaviour (LNCB), Department of Biology, Indian Institute of Science Education and Research (IISER), Pune, Maharashtra, 411008, India
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26
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Sadeghdoust M, Aligolighasemabadi F, Dehesh T, Taefehshokr N, Sadeghdoust A, Kotfis K, Hashemiattar A, Ravandi A, Aligolighasemabadi N, Vakili O, Grabarek B, Staszkiewicz R, Łos MJ, Mokarram P, Ghavami S. The Effects of Statins on Respiratory Symptoms and Pulmonary Fibrosis in COVID-19 Patients with Diabetes Mellitus: A Longitudinal Multicenter Study. Arch Immunol Ther Exp (Warsz) 2023; 71:8. [PMID: 36853269 PMCID: PMC9972324 DOI: 10.1007/s00005-023-00672-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Accepted: 12/14/2022] [Indexed: 03/01/2023]
Abstract
The aim of this prospective cohort study was to explore the effect of statins on long-term respiratory symptoms and pulmonary fibrosis in coronavirus disease 2019 (COVID-19) patients with diabetes mellitus (DM). Patients were recruited from three tertiary hospitals, categorized into Statin or Non-statin groups, and assessed on days 0, 28, and 90 after symptoms onset to record the duration of symptoms. Pulmonary fibrosis was scored at baseline and follow-up time points by high-resolution computed tomography scans. Each group comprised 176 patients after propensity score matching. Data analysis revealed that the odds of having cough and dyspnea were significantly higher in the Non-statin group compared to the Statin group during the follow-up period. Overall, there was no significant difference in the change in pulmonary fibrosis score between groups. However, Non-statin patients with > 5 years of DM were more likely to exhibit a significantly higher fibrosis score during the follow-up period as compared to their peers in the Statin group. Our results suggest that the use of statins is associated with a lower risk of developing chronic cough and dyspnea in diabetic patients with COVID-19, and may reduce pulmonary fibrosis associated with COVID-19 in patients with long-term (> 5 years) DM.
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Affiliation(s)
- Mohammadamin Sadeghdoust
- grid.411768.d0000 0004 1756 1744Department of Internal Medicine, Mashhad Medical Sciences Branch, Islamic Azad University, Mashhad, Iran
| | - Farnaz Aligolighasemabadi
- grid.411768.d0000 0004 1756 1744Department of Internal Medicine, Mashhad Medical Sciences Branch, Islamic Azad University, Mashhad, Iran
| | - Tania Dehesh
- grid.412105.30000 0001 2092 9755Department of Biostatistics and Epidemiology, School of Public Health, Kerman University of Medical Sciences, Kerman, Iran
| | - Nima Taefehshokr
- grid.39381.300000 0004 1936 8884Department of Microbiology and Immunology, Center for Human Immunology, The University of Western Ontario, London, ON Canada
| | - Adel Sadeghdoust
- grid.412237.10000 0004 0385 452XDepartment of Internal Medicine, School of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Katarzyna Kotfis
- grid.107950.a0000 0001 1411 4349Department of Anesthesiology, Intensive Therapy and Acute Intoxications, Pomeranian Medical University in Szczecin, Szczecin, Poland
| | - Amirhossein Hashemiattar
- grid.411768.d0000 0004 1756 1744Department of Radiology, Mashhad Medical Sciences Branch, Islamic Azad University, Mashhad, Iran
| | - Amir Ravandi
- grid.21613.370000 0004 1936 9609Institute of Cardiovascular Sciences, Sr. Boniface Research Centre, University of Manitoba, Winnipeg, Canada
| | - Neda Aligolighasemabadi
- grid.411874.f0000 0004 0571 1549Department of Internal Medicine, School of Medicine, Razi Hospital, Guilan University of Medical Sciences, Rasht, Iran
| | - Omid Vakili
- grid.411036.10000 0001 1498 685XDepartment of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Beniamin Grabarek
- Department of Histology, Cytophysiology and Embryology, Faculty of Medicine in Zabrze, Academy of Silesia in Katowice, Zabrze, Poland ,Department of Gynaecology and Obstetrics, Faculty of Medicine in Zabrze, Academy of Silesia in Katowice, Zabrze, Poland ,Laboratory of Molecular Biology and Virology, GynCentrum, Katowice, Poland
| | - Rafał Staszkiewicz
- Department of Histology, Cytophysiology and Embryology, Faculty of Medicine in Zabrze, Academy of Silesia in Katowice, Zabrze, Poland ,Department of Neurosurgery, 5Th Military Clinical Hospital with the SP ZOZ Polyclinic in Krakow, Krakow, Poland
| | - Marek J. Łos
- grid.6979.10000 0001 2335 3149Biotechnology Center, Silesian University of Technology, Gliwice, Poland ,grid.412571.40000 0000 8819 4698Autophagy Research Center, Department of Biochemistry, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Pooneh Mokarram
- Autophagy Research Center, Department of Biochemistry, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Saeid Ghavami
- Autophagy Research Center, Department of Biochemistry, Shiraz University of Medical Sciences, Shiraz, Iran. .,Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Canada. .,Faculty of Medicine in Zabrze, University of Technology in Katowice, Academia of Silesia, Zabrze, Poland. .,Research Institute of Oncology and Hematology, Cancer Care, Manitoba University of Manitoba, Winnipeg, Canada. .,Biology of Breathing Theme, Children Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, Canada.
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27
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Samadian E, Aghcheli B, Gharaei R, Tabarraei A. A review on human reproductive systems encountering with the severe acute respiratory syndrome coronavirus 2 infection. Int J Reprod Biomed 2023; 21:1-16. [PMID: 36875501 PMCID: PMC9982318 DOI: 10.18502/ijrm.v21i1.12661] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 10/06/2022] [Accepted: 11/13/2022] [Indexed: 02/11/2023] Open
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) is the leading cause of the new deadly pneumonia named coronavirus disease 2019 (COVID-19) pandemic. This pathogen has different co-receptors on various tissues, resulting in vast pathophysiological circumstances. Here, we present a comprehensive narrative review focusing on the impact of SARS-CoV2 on human reproduction. Evidence-based literature revealed inconsistent results for this virus in the reproductive organs of patients with COVID-19, even in the critical phase. Conversely, numerous satisfactory data represented those different reproductive activities, from gametogenesis to pregnancy, can be targeted by SARS-CoV2. The severity of COVID-19 depends on the differential expression of the host cellular components required to enter SARS-CoV2. The cytokine storm and oxidative stress coming out during COVID-19 are associated with complications in reproductive endocrinopathies. Men are naturally more susceptible to COVID-19, especially accompanied by orchitis and varicocele. Synergistically the interaction of SARS-CoV2 and female reproductive failures (polycystic ovary syndrome and endometriosis) increases the susceptibility to COVID-19. Thus, pharmaceutical interventions that ameliorate the complications in individuals with reproductive disorders can be helpful to achieve good outcomes in assisted reproductive techniques. Soon, an increase in the infertility rate will likely be an overall impact of SARS-CoV2 in patients who recovered from COVID-19.
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Affiliation(s)
- Esmaeil Samadian
- Laboratory Sciences Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Bahman Aghcheli
- Infection Diseases Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Roghaye Gharaei
- Department of Obstetrics and Gynecology, School of Medicine, Golestan University of Medical Sciences, Gorgan, Iran
| | - Alijan Tabarraei
- Infection Diseases Research Center, Golestan University of Medical Sciences, Gorgan, Iran
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Neurological disorders of COVID-19: insights to applications of natural products from plants and microorganisms. Arch Pharm Res 2022; 45:909-937. [PMCID: PMC9702705 DOI: 10.1007/s12272-022-01420-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Accepted: 11/22/2022] [Indexed: 11/29/2022]
Abstract
In addition to the typical respiratory manifestations, various disorders including involvement of the nerve system have been detected in COVID-19 ranging from 22 to 36%. Although growing records are focusing on neurological aspects of COVID-19, the pathophysiological mechanisms and related therapeutic methods remain obscure. Considering the increased concerns of SARS-CoV-2 potential for more serious neuroinvasion conditions, the present review attempts to focus on the neuroprotective effects of natural compounds as the principle source of therapeutics inhibiting multiple steps of the SARS-CoV-2 infection cycle. The great majority of the natural products with anti-SARS-CoV-2 activity mainly inhibit the attachment, entry and gene expression rather than the replication, assembly, or release. Although microbial-derived natural products comprise 38.5% of the known natural products with neuroprotective effects following viral infection, the neuroprotective potential of the majority of microorganisms is still undiscovered. Among natural products, chrysin, huperzine A, ginsenoside Rg1, pterostilbene, and terrein have shown potent in vitro neuroprotective activity and can be promising for new or repurpose drugs for neurological complications of SARS-CoV-2.
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29
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Yin S, Mei S, Li Z, Xu Z, Wu Y, Chen X, Liu D, Niu MM, Li J. Non-covalent cyclic peptides simultaneously targeting Mpro and NRP1 are highly effective against Omicron BA.2.75. Front Pharmacol 2022; 13:1037993. [PMID: 36408220 PMCID: PMC9666779 DOI: 10.3389/fphar.2022.1037993] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Accepted: 10/21/2022] [Indexed: 11/05/2022] Open
Abstract
Available vaccine-based immunity may at high risk of being evaded due to substantial mutations in the variant Omicron. The main protease (Mpro) of SARS-CoV-2 and human neuropilin-1 (NRP1), two less mutable proteins, have been reported to be crucial for SARS-CoV-2 replication and entry into host cells, respectively. Their dual blockade may avoid vaccine failure caused by continuous mutations of the SARS-CoV-2 genome and exert synergistic antiviral efficacy. Herein, four cyclic peptides non-covalently targeting both Mpro and NRP1 were identified using virtual screening. Among them, MN-2 showed highly potent affinity to Mpro (Kd = 18.2 ± 1.9 nM) and NRP1 (Kd = 12.3 ± 1.2 nM), which was about 3,478-fold and 74-fold stronger than that of the positive inhibitors Peptide-21 and EG3287. Furthermore, MN-2 exhibited significant inhibitory activity against Mpro and remarkable anti-infective activity against the pseudotyped variant Omicron BA.2.75 without obvious cytotoxicity. These data demonstrated that MN-2, a novel non-covalent cyclic peptide, is a promising agent against Omicron BA.2.75.
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Affiliation(s)
- Shengnan Yin
- Department of Pharmacy, Taizhou Hospital Affiliated to Nanjing University of Chinese Medicine, Taizhou, China
| | - Shuang Mei
- Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, China
| | - Zhiqin Li
- Institute of Clinical Medicine, Department of Pharmacy, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou, China
| | - Zhen Xu
- Institute of Clinical Medicine, Department of Pharmacy, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou, China
| | - Yuting Wu
- Institute of Clinical Medicine, Department of Pharmacy, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou, China
| | - Xiujuan Chen
- Institute of Clinical Medicine, Department of Pharmacy, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou, China
- *Correspondence: Xiujuan Chen, ; Jindong Li, ; Dongmei Liu, ; Miao-Miao Niu,
| | - Dongmei Liu
- Department of Pharmacy, Taizhou Hospital Affiliated to Nanjing University of Chinese Medicine, Taizhou, China
- *Correspondence: Xiujuan Chen, ; Jindong Li, ; Dongmei Liu, ; Miao-Miao Niu,
| | - Miao-Miao Niu
- Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, China
- *Correspondence: Xiujuan Chen, ; Jindong Li, ; Dongmei Liu, ; Miao-Miao Niu,
| | - Jindong Li
- Institute of Clinical Medicine, Department of Pharmacy, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou, China
- *Correspondence: Xiujuan Chen, ; Jindong Li, ; Dongmei Liu, ; Miao-Miao Niu,
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Wei X, Rong N, Liu J. Prospects of animal models and their application in studies on adaptive immunity to SARS-CoV-2. Front Immunol 2022; 13:993754. [PMID: 36189203 PMCID: PMC9523127 DOI: 10.3389/fimmu.2022.993754] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 09/05/2022] [Indexed: 01/08/2023] Open
Abstract
The adaptive immune response induced by SARS-CoV-2 plays a key role in the antiviral process and can protect the body from the threat of infection for a certain period of time. However, owing to the limitations of clinical studies, the antiviral mechanisms, protective thresholds, and persistence of the immune memory of adaptive immune responses remain unclear. This review summarizes existing research models for SARS-CoV-2 and elaborates on the advantages of animal models in simulating the clinical symptoms of COVID-19 in humans. In addition, we systematically summarize the research progress on the SARS-CoV-2 adaptive immune response and the remaining key issues, as well as the application and prospects of animal models in this field. This paper provides direction for in-depth analysis of the anti-SARS-CoV-2 mechanism of the adaptive immune response and lays the foundation for the development and application of vaccines and drugs.
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Affiliation(s)
- Xiaohui Wei
- National Health Commission Key Laboratory of Human Disease Comparative Medicine, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China
| | | | - Jiangning Liu
- National Health Commission Key Laboratory of Human Disease Comparative Medicine, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China
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31
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Al-Thomali AW, Al-kuraishy HM, Al-Gareeb AI, K. Al-buhadiliy A, De Waard M, Sabatier JM, Khan Khalil AA, Saad HM, Batiha GES. Role of Neuropilin 1 in COVID-19 Patients with Acute Ischemic Stroke. Biomedicines 2022; 10:2032. [PMID: 36009579 PMCID: PMC9405641 DOI: 10.3390/biomedicines10082032] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 08/13/2022] [Accepted: 08/17/2022] [Indexed: 12/13/2022] Open
Abstract
Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection can trigger the adaptive and innate immune responses, leading to uncontrolled inflammatory reactions and associated local and systematic tissue damage, along with thromboembolic disorders that may increase the risk of acute ischemic stroke (AIS) in COVID-19 patients. The neuropilin (NRP-1) which is a co-receptor for the vascular endothelial growth factor (VEGF), integrins, and plexins, is involved in the pathogenesis of AIS. NRP-1 is also regarded as a co-receptor for the entry of SARS-CoV-2 and facilitates its entry into the brain through the olfactory epithelium. NRP-1 is regarded as a cofactor for binding of SARS-CoV-2 with angiotensin-converting enzyme 2 (ACE2), since the absence of ACE2 reduces SARS-CoV-2 infectivity even in presence of NRP-1. Therefore, the aim of the present study was to clarify the potential role of NRP-1 in COVID-19 patients with AIS. SARS-CoV-2 may transmit to the brain through NRP-1 in the olfactory epithelium of the nasal cavity, leading to different neurological disorders, and therefore about 45% of COVID-19 patients had neurological manifestations. NRP-1 has the potential capability to attenuate neuroinflammation, blood-brain barrier (BBB) permeability, cerebral endothelial dysfunction (ED), and neuronal dysfunction that are uncommon in COVID-19 with neurological involvement, including AIS. Similarly, high NRP-1 serum level is linked with ED, oxidative stress, and the risk of pulmonary thrombosis in patients with severe COVID-19, suggesting a compensatory mechanism to overcome immuno-inflammatory disorders. In conclusion, NRP-1 has an important role in the pathogenesis of COVID-19 and AIS, and could be the potential biomarker linking the development of AIS in COVID-19. The present findings cannot provide a final conclusion, and thus in silico, experimental, in vitro, in vivo, preclinical, and clinical studies are recommended to confirm the potential role of NRP-1 in COVID-19, and to elucidate the pharmacological role of NRP-1 receptor agonists and antagonists in COVID-19.
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Affiliation(s)
- Asma W. Al-Thomali
- Department of Biology, College of Science, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia
| | - Hayder M. Al-kuraishy
- Department of Pharmacology, Toxicology and Medicine, Medical Faculty, College of Medicine, Al-Mustansiriyah University, MBChB, MRCP, FRCP, Baghdad P.O. Box 14132, Iraq
| | - Ali I. Al-Gareeb
- Department of Pharmacology, Toxicology and Medicine, Medical Faculty, College of Medicine, Al-Mustansiriyah University, Baghdad P.O. Box 14132, Iraq
| | - Ali K. Al-buhadiliy
- Department of Clinical Pharmacology, Medicine and Therapeutic, Medical Faculty, College of Medicine, Al-Mustansiriyah University, Baghdad P.O. Box 14132, Iraq
| | - Michel De Waard
- Smartox Biotechnology, 6 rue des Platanes, 38120 Saint-Egrève, France
- L’institut du Thorax, INSERM, CNRS, UNIV NANTES, 44007 Nantes, France
- LabEx «Ion Channels, Science & Therapeutics», Université de Nice Sophia-Antipolis, 06560 Valbonne, France
| | - Jean-Marc Sabatier
- Institut de Neurophysiopathologie (INP), Aix-Marseille Université, CNRS UMR 7051, Faculté des Sciences Médicales et Paramédicales, 27 Bd Jean Moulin, 13005 Marseille, France
| | - Atif Ali Khan Khalil
- Department of Biological Sciences, National University of Medical Sciences, Rawalpindi 46000, Pakistan
| | - Hebatallah M. Saad
- Department of Pathology, Faculty of Veterinary Medicine, Matrouh University, Matrouh 51744, Egypt
| | - Gaber El-Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour 22511, Egypt
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32
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Temena MA, Acar A. Increased TRIM31 gene expression is positively correlated with SARS-CoV-2 associated genes TMPRSS2 and TMPRSS4 in gastrointestinal cancers. Sci Rep 2022; 12:11763. [PMID: 35970857 PMCID: PMC9378649 DOI: 10.1038/s41598-022-15911-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Accepted: 06/30/2022] [Indexed: 01/08/2023] Open
Abstract
Besides typical respiratory symptoms, COVID-19 patients also have gastrointestinal symptoms. Studies focusing on the gastrointestinal tumors derived from gastrointestinal tissues have raised a question whether these tumors might express higher levels of SARS-CoV-2 associated genes and therefore patients diagnosed with GI cancers may be more susceptible to the infection. In this study, we have analyzed the expression of SARS-CoV-2 associated genes and their co-expressions in gastrointestinal solid tumors, cancer cell lines and patient-derived organoids relative to their normal counterparts. Moreover, we have found increased co-expression of TMPRSS2-TMPRSS4 in gastrointestinal cancers suggesting that SARS-CoV-2 viral infection known to be mediated by this protease pair might facilitate the effects of viral infection in GI cancer patients. Further, our findings also demonstrate that TRIM31 expression is upregulated in gastrointestinal tumors, while the inhibition of TRIM31 significantly altered viral replication and viral processes associated with cellular pathways in gastrointestinal cancer samples. Taken together, these findings indicate that in addition to the co-expression of TMPRSS2-TMPRSS4 protease pair in GI cancers, TRIM31 expression is positively correlated with this pair and TRIM31 may play a role in providing an increased susceptibility in GI cancer patients to be infected with SARS-CoV-2 virus.
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Affiliation(s)
- Mehmet Arda Temena
- Department of Biological Sciences, Middle East Technical University, Universiteler Mah. Dumlupınar Bulvarı 1, 06800, Çankaya, Ankara, Turkey
| | - Ahmet Acar
- Department of Biological Sciences, Middle East Technical University, Universiteler Mah. Dumlupınar Bulvarı 1, 06800, Çankaya, Ankara, Turkey.
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33
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Alshawaf E, Hammad MM, Marafie SK, Ali H, Al-Mulla F, Abubaker J, Mohammad A. Discovery of natural products to block SARS-CoV-2 S-protein interaction with Neuropilin-1 receptor: A molecular dynamics simulation approach. Microb Pathog 2022; 170:105701. [PMID: 35963279 PMCID: PMC9364730 DOI: 10.1016/j.micpath.2022.105701] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 07/28/2022] [Accepted: 07/29/2022] [Indexed: 10/26/2022]
Abstract
Neuropilin-1 (NRP1) is a widely expressed cell surface receptor protein characterized by its pleiotropic function. Recent reports highlighted NRP1 as an additional entry point of the SARS-CoV-2 virus, enhancing viral infectivity by interacting with the S-protein of SARS-CoV-2. The ubiquitous distribution and mechanism of action of NRP1 enable the SARS-CoV-2 virus to attack multiple organs in the body simultaneously. Therefore, blocking NRP1 is a potential therapeutic approach against SARS-CoV-2 infection. The current study screened the South African natural compounds database (SANCDB) for molecules that can disrupt the SARS-CoV-2 S protein-NRP1 interaction as a potential antiviral target for SARS-CoV-2 cellular entry. Following excessive screening and validation analysis 3-O-Methylquercetin and Esculetin were identified as potential compounds to disrupt the S-protein-NRP1 interaction. Furthermore, to understand the conformational stability and dynamic features between NRP1 interaction with the selected natural products, we performed 200 ns molecular dynamics (MD) simulations. In addition, molecular mechanics-generalized Born surface area (MM/GBSA) was utilized to calculate the free binding energies of the natural products interacting with NRP1. 3-O-methylquercetin showed an inhibitory effect with binding energies ΔG of -25.52 ± 0.04 kcal/mol to NRP1, indicating the possible disruption of the NRP1-S-protein interaction. Our analysis demonstrated that 3-O-methylquercetin presents a potential antiviral compound against SARS-CoV-2 infectivity. These results set the path for future functional in-vitro and in-vivo studies in SARS-CoV-2 research.
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Affiliation(s)
- Eman Alshawaf
- Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Dasman, Kuwait, 15462
| | - Maha M Hammad
- Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Dasman, Kuwait, 15462
| | - Sulaiman K Marafie
- Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Dasman, Kuwait, 15462
| | - Hamad Ali
- Faculty of Department of Medical Laboratory Sciences 2, Faculty of Allied Health Sciences, Health Sciences Center (HSC), Kuwait University, Jabriya, Kuwait University, Kuwait; Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Dasman, Kuwait, 15462
| | - Fahd Al-Mulla
- Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Dasman, Kuwait, 15462
| | - Jehad Abubaker
- Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Dasman, Kuwait, 15462
| | - Anwar Mohammad
- Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Dasman, Kuwait, 15462.
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34
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Sengupta A, Roldan N, Kiener M, Froment L, Raggi G, Imler T, de Maddalena L, Rapet A, May T, Carius P, Schneider-Daum N, Lehr CM, Kruithof-de Julio M, Geiser T, Marti TM, Stucki JD, Hobi N, Guenat OT. A New Immortalized Human Alveolar Epithelial Cell Model to Study Lung Injury and Toxicity on a Breathing Lung-On-Chip System. FRONTIERS IN TOXICOLOGY 2022; 4:840606. [PMID: 35832493 PMCID: PMC9272139 DOI: 10.3389/ftox.2022.840606] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Accepted: 05/09/2022] [Indexed: 12/13/2022] Open
Abstract
The evaluation of inhalation toxicity, drug safety and efficacy assessment, as well as the investigation of complex disease pathomechanisms, are increasingly relying on in vitro lung models. This is due to the progressive shift towards human-based systems for more predictive and translational research. While several cellular models are currently available for the upper airways, modelling the distal alveolar region poses several constraints that make the standardization of reliable alveolar in vitro models relatively difficult. In this work, we present a new and reproducible alveolar in vitro model, that combines a human derived immortalized alveolar epithelial cell line (AXiAEC) and organ-on-chip technology mimicking the lung alveolar biophysical environment (AXlung-on-chip). The latter mimics key features of the in vivo alveolar milieu: breathing-like 3D cyclic stretch (10% linear strain, 0.2 Hz frequency) and an ultrathin, porous and elastic membrane. AXiAECs cultured on-chip were characterized for their alveolar epithelial cell markers by gene and protein expression. Cell barrier properties were examined by TER (Transbarrier Electrical Resistance) measurement and tight junction formation. To establish a physiological model for the distal lung, AXiAECs were cultured for long-term at air-liquid interface (ALI) on-chip. To this end, different stages of alveolar damage including inflammation (via exposure to bacterial lipopolysaccharide) and the response to a profibrotic mediator (via exposure to Transforming growth factor β1) were analyzed. In addition, the expression of relevant host cell factors involved in SARS-CoV-2 infection was investigated to evaluate its potential application for COVID-19 studies. This study shows that AXiAECs cultured on the AXlung-on-chip exhibit an enhanced in vivo-like alveolar character which is reflected into: 1) Alveolar type 1 (AT1) and 2 (AT2) cell specific phenotypes, 2) tight barrier formation (with TER above 1,000 Ω cm2) and 3) reproducible long-term preservation of alveolar characteristics in nearly physiological conditions (co-culture, breathing, ALI). To the best of our knowledge, this is the first time that a primary derived alveolar epithelial cell line on-chip representing both AT1 and AT2 characteristics is reported. This distal lung model thereby represents a valuable in vitro tool to study inhalation toxicity, test safety and efficacy of drug compounds and characterization of xenobiotics.
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Affiliation(s)
- Arunima Sengupta
- Organs-on-Chip Technologies, ARTORG Center for Biomedical Engineering, University of Bern, Bern, Switzerland
| | - Nuria Roldan
- Alveolix AG, Swiss Organs-on-Chip Innovation, Bern, Switzerland
| | - Mirjam Kiener
- Department of Pulmonary Medicine, Inselspital, Bern University Hospital, Bern, Switzerland.,Department for BioMedical Research DBMR, Urology Research Laboratory, University of Bern, Bern, Switzerland
| | - Laurène Froment
- Alveolix AG, Swiss Organs-on-Chip Innovation, Bern, Switzerland
| | - Giulia Raggi
- Alveolix AG, Swiss Organs-on-Chip Innovation, Bern, Switzerland
| | - Theo Imler
- Alveolix AG, Swiss Organs-on-Chip Innovation, Bern, Switzerland
| | | | - Aude Rapet
- Alveolix AG, Swiss Organs-on-Chip Innovation, Bern, Switzerland
| | | | - Patrick Carius
- Department of Drug Delivery (DDEL), Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), Saarbrücken, Germany.,Department of Pharmacy, Biopharmaceutics and Pharmaceutical Technology, Saarland University, Saarbrücken, Germany
| | - Nicole Schneider-Daum
- Department of Drug Delivery (DDEL), Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), Saarbrücken, Germany.,Department of Pharmacy, Biopharmaceutics and Pharmaceutical Technology, Saarland University, Saarbrücken, Germany
| | - Claus-Michael Lehr
- Department of Drug Delivery (DDEL), Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), Saarbrücken, Germany.,Department of Pharmacy, Biopharmaceutics and Pharmaceutical Technology, Saarland University, Saarbrücken, Germany
| | - Marianna Kruithof-de Julio
- Department for BioMedical Research DBMR, Urology Research Laboratory, University of Bern, Bern, Switzerland
| | - Thomas Geiser
- Department of Pulmonary Medicine, Inselspital, Bern University Hospital, Bern, Switzerland
| | - Thomas Michael Marti
- Department of General Thoracic Surgery, Inselspital, Bern University Hospital, Bern, Switzerland
| | - Janick D Stucki
- Alveolix AG, Swiss Organs-on-Chip Innovation, Bern, Switzerland
| | - Nina Hobi
- Alveolix AG, Swiss Organs-on-Chip Innovation, Bern, Switzerland
| | - Olivier T Guenat
- Organs-on-Chip Technologies, ARTORG Center for Biomedical Engineering, University of Bern, Bern, Switzerland.,Department of Pulmonary Medicine, Inselspital, Bern University Hospital, Bern, Switzerland.,Department of General Thoracic Surgery, Inselspital, Bern University Hospital, Bern, Switzerland
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Paik H, Kim J, Seo S. Analysis of the docking property of host variants of hACE2 for SARS-CoV-2 in a large cohort. PLoS Comput Biol 2022; 18:e1009834. [PMID: 35816517 PMCID: PMC9302733 DOI: 10.1371/journal.pcbi.1009834] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Revised: 07/21/2022] [Accepted: 07/01/2022] [Indexed: 01/08/2023] Open
Abstract
The recent novel coronavirus disease (COVID-19) outbreak, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is threatening global health. However, an understanding of the interaction of SARS-CoV-2 with human cells, including the physical docking property influenced by the host's genetic diversity, is still lacking. Here, based on germline variants in the UK Biobank covering 502,543 individuals, we revealed the molecular interactions between human angiotensin-converting enzyme 2 (hACE2), which is the representative receptor for SARS-CoV-2 entry, and COVID-19 infection. We identified six nonsense and missense variants of hACE2 from 2585 subjects in the UK Biobank covering 500000 individuals. Using our molecular dynamics simulations, three hACE2 variants from 2585 individuals we selected showed higher levels of binding free energy for docking in the range of 1.44-3.69 kcal/mol. Although there are diverse contributors to SARS-CoV-2 infections, including the mobility of individuals, we analyzed the diagnosis records of individuals with these three variants of hACE2. Our molecular dynamics simulations combined with population-based genomic data provided an atomistic understanding of the interaction between hACE2 and the spike protein of SARS-CoV-2.
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Affiliation(s)
- Hyojung Paik
- Division of Supercomputing, Center for supercomputing application and research, Korea Institute of Science and Technology Information (KISTI), Daejeon, South Korea
- Department of Data and HPC science, University of Science and Technology (UST), Daejeon, South Korea
| | - Jimin Kim
- Division of Supercomputing, Center for supercomputing application and research, Korea Institute of Science and Technology Information (KISTI), Daejeon, South Korea
| | - Sangjae Seo
- Division of Supercomputing, Center for supercomputing application and research, Korea Institute of Science and Technology Information (KISTI), Daejeon, South Korea
- * E-mail:
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36
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Glab-ampai K, Kaewchim K, Saenlom T, Thepsawat W, Mahasongkram K, Sookrung N, Chaicumpa W, Chulanetra M. Human Superantibodies to 3CL pro Inhibit Replication of SARS-CoV-2 across Variants. Int J Mol Sci 2022; 23:ijms23126587. [PMID: 35743031 PMCID: PMC9223907 DOI: 10.3390/ijms23126587] [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: 05/18/2022] [Revised: 06/08/2022] [Accepted: 06/11/2022] [Indexed: 11/16/2022] Open
Abstract
Broadly effective and safe anti-coronavirus agent is existentially needed. Major protease (3CLpro) is a highly conserved enzyme of betacoronaviruses. The enzyme plays pivotal role in the virus replication cycle. Thus, it is a good target of a broadly effective anti-Betacoronavirus agent. In this study, human single-chain antibodies (HuscFvs) of the SARS-CoV-2 3CLpro were generated using phage display technology. The 3CLpro-bound phages were used to infect Escherichia coli host for the production the 3CLpro-bound HuscFvs. Computerized simulation was used to guide the selection of the phage infected-E. coli clones that produced HuscFvs with the 3CLpro inhibitory potential. HuscFvs of three phage infected-E. coli clones were predicted to form contact interface with residues for 3CLpro catalytic activity, substrate binding, and homodimerization. These HuscFvs were linked to a cell-penetrating peptide to make them cell-penetrable, i.e., became superantibodies. The superantibodies blocked the 3CLpro activity in vitro, were not toxic to human cells, traversed across membrane of 3CLpro-expressing cells to co-localize with the intracellular 3CLpro and most of all, they inhibited replication of authentic SARS-CoV-2 Wuhan wild type and α, β, δ, and Omicron variants that were tested. The superantibodies should be investigated further towards clinical application as a safe and broadly effective anti-Betacoronavirus agent.
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Affiliation(s)
- Kittirat Glab-ampai
- Center of Research Excellence in Therapeutic Proteins and Antibody Engineering, Department of Parasitology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand; (K.G.-a.); (K.K.); (T.S.); (W.T.); (K.M.); (N.S.); (W.C.)
| | - Kanasap Kaewchim
- Center of Research Excellence in Therapeutic Proteins and Antibody Engineering, Department of Parasitology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand; (K.G.-a.); (K.K.); (T.S.); (W.T.); (K.M.); (N.S.); (W.C.)
- Graduate Program in Immunology, Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Thanatsaran Saenlom
- Center of Research Excellence in Therapeutic Proteins and Antibody Engineering, Department of Parasitology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand; (K.G.-a.); (K.K.); (T.S.); (W.T.); (K.M.); (N.S.); (W.C.)
| | - Watayagorn Thepsawat
- Center of Research Excellence in Therapeutic Proteins and Antibody Engineering, Department of Parasitology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand; (K.G.-a.); (K.K.); (T.S.); (W.T.); (K.M.); (N.S.); (W.C.)
| | - Kodchakorn Mahasongkram
- Center of Research Excellence in Therapeutic Proteins and Antibody Engineering, Department of Parasitology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand; (K.G.-a.); (K.K.); (T.S.); (W.T.); (K.M.); (N.S.); (W.C.)
| | - Nitat Sookrung
- Center of Research Excellence in Therapeutic Proteins and Antibody Engineering, Department of Parasitology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand; (K.G.-a.); (K.K.); (T.S.); (W.T.); (K.M.); (N.S.); (W.C.)
- Biomedical Research Incubator Unit, Department of Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Wanpen Chaicumpa
- Center of Research Excellence in Therapeutic Proteins and Antibody Engineering, Department of Parasitology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand; (K.G.-a.); (K.K.); (T.S.); (W.T.); (K.M.); (N.S.); (W.C.)
| | - Monrat Chulanetra
- Center of Research Excellence in Therapeutic Proteins and Antibody Engineering, Department of Parasitology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand; (K.G.-a.); (K.K.); (T.S.); (W.T.); (K.M.); (N.S.); (W.C.)
- Correspondence: ; Tel.: +662-419-2934
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One Health and Cattle Genetic Resources: Mining More than 500 Cattle Genomes to Identify Variants in Candidate Genes Potentially Affecting Coronavirus Infections. Animals (Basel) 2022; 12:ani12070838. [PMID: 35405828 PMCID: PMC8997118 DOI: 10.3390/ani12070838] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 03/14/2022] [Accepted: 03/24/2022] [Indexed: 12/17/2022] Open
Abstract
Simple Summary The conservation and exploitation of cattle genetic resources for selection and breeding purposes are important for the definition of sustainable livestock production sectors. One Health approaches should be integrated into these activities to reduce the risk posed by many zoonoses. Coronaviruses are emerging as important zoonotic agents, with the potential to easily cross species barriers, as also recently demonstrated by the COVID-19 pandemic derived by SARS-CoV-2. Genetic resistance to coronavirus infections can be determined by variants of the host (animal) genome segregating within species. In this study, we mined the genome of more than 500 cattle to identify variants that could be involved so as to define different levels of susceptibility and/or resistance to coronavirus diseases in this important livestock species. Using comparative analyses across species, we identified several single amino acid polymorphisms that might alter the function of key proteins involved in the basic biological mechanisms underlying the infection processes in cattle. This study provided new elements to consider genetic variability of the host (cattle) as a potential risk factor to be considered in One Health perspectives. Abstract Epidemiological and biological characteristics of coronaviruses and their ability to cross species barriers are a matter of increasing concerns for these zoonotic agents. To prevent their spread, One Health approaches should be designed to include the host (animal) genome variability as a potential risk factor that might confer genetic resistance or susceptibility to coronavirus infections. At present, there is no example that considers cattle genetic resources for this purpose. In this study, we investigated the variability of six genes (ACE2, ANPEP, CEACAM1 and DPP4 encoding for host receptors of coronaviruses; FURIN and TMPRSS2 encoding for host proteases involved in coronavirus infection) by mining whole genome sequencing datasets from more than 500 cattle of 34 Bos taurus breeds and three related species. We identified a total of 180 protein variants (44 already known from the ARS-UCD1.2 reference genome). Some of them determine altered protein functions or the virus–host interaction and the related virus entry processes. The results obtained in this study constitute a first step towards the definition of a One Health strategy that includes cattle genetic resources as reservoirs of host gene variability useful to design conservation and selection programs to increase resistance to coronavirus diseases.
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Eslami N, Aghbash PS, Shamekh A, Entezari-Maleki T, Nahand JS, Sales AJ, Baghi HB. SARS-CoV-2: Receptor and Co-receptor Tropism Probability. Curr Microbiol 2022; 79:133. [PMID: 35292865 PMCID: PMC8923825 DOI: 10.1007/s00284-022-02807-7] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Accepted: 02/09/2022] [Indexed: 02/07/2023]
Abstract
The recent pandemic which arose from China, is caused by a pathogenic virus named "severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2)". Its rapid global expansion has inflicted an extreme public health concern. The attachment of receptor-binding domains (RBD) of the spike proteins (S) to the host cell's membrane, with or without the help of other cellular components such as proteases and especially co-receptors, is required for the first stage of its pathogenesis. In addition to humans, angiotensin-converting enzyme 2 (ACE2) is found on a wide range of vertebrate host's cellular surface. SARS-CoV-2 has a broad spectrum of tropism; thus, it can infect a vast range of tissues, organs, and hosts; even though the surface amino acids of the spike protein conflict in the receptor-binding region. Due to the heterogeneous ACE2 distribution and the presence of different domains on the SARS-CoV-2 spike protein for binding, the virus entry into diverse host cell types may depend on the host cells' receptor presentation with or without co-receptors. This review investigates multiple current types of receptor and co-receptor tropisms, with other molecular factors alongside their respective mechanisms, which facilitate the binding and entry of SARS-CoV-2 into the cells, extending the severity of the coronavirus disease 2019 (COVID-19). Understanding the pathogenesis of COVID-19 from this perspective can effectively help prevent this disease and provide more potent treatment strategies, particularly in vulnerable people with various cellular-level susceptibilities.
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Affiliation(s)
- Narges Eslami
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, 5166/15731, Tabriz, Iran
| | - Parisa Shiri Aghbash
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Drug Applied Research Centre, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Shamekh
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Virology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Taher Entezari-Maleki
- Department of Clinical Pharmacy, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
- Cardiovascular Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Javid Sadri Nahand
- Department of Virology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Abolfazl Jafari Sales
- Department of Microbiology School of Basic Sciences, Islamic Azad University, Kazerun BranchKazerun, Iran
| | - Hossein Bannazadeh Baghi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, 5166/15731, Tabriz, Iran.
- Department of Virology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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Ito GNW, Rodrigues VAC, Hümmelgen J, Meschino GSPG, Abou‐Rejaile GM, Brenny ID, de Castro Júnior CR, Artigas RC, Munhoz JPS, Cardoso GC, Picheth GF. COVID-19 pathophysiology and ultrasound imaging: A multiorgan review. JOURNAL OF CLINICAL ULTRASOUND : JCU 2022; 50:326-338. [PMID: 35218034 PMCID: PMC9088355 DOI: 10.1002/jcu.23160] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 02/05/2022] [Accepted: 02/09/2022] [Indexed: 05/09/2023]
Abstract
COVID-19 is a dynamic disease and may affect different tissues and organs as it progresses. Therefore, the impact generated by the disease in all its stages and organs requires a functional and versatile imaging technique able to detect particularities or artifacts dynamically. Ultrasonography fulfills all these requirements and exhibit several advantages relative to other imaging modalities, including portability, lower cost and biosafety. Throughout the COVID-19 pandemic, ultrasonography displayed a crucial role in the triage, monitoring, indicating organ damages and enabling individualized therapeutical decisions in COVID-19 patients. This review is dedicated to highlight the main pathological effects correlated with ultrasound changes caused by COVID-19 in the lungs, heart and liver.
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Affiliation(s)
- Giovana N. W. Ito
- School of MedicinePontifical Catholic University of ParanáCuritibaBrazil
| | | | - Juliana Hümmelgen
- School of MedicinePontifical Catholic University of ParanáCuritibaBrazil
| | | | | | - Isadora D. Brenny
- School of MedicinePontifical Catholic University of ParanáCuritibaBrazil
| | | | - Rafaela C. Artigas
- School of MedicinePontifical Catholic University of ParanáCuritibaBrazil
| | | | | | - Guilherme F. Picheth
- School of MedicinePontifical Catholic University of ParanáCuritibaBrazil
- Department of Basic PathologyFederal University of ParanáCuritibaBrazil
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Petrenko VA, Gillespie JW, De Plano LM, Shokhen MA. Phage-Displayed Mimotopes of SARS-CoV-2 Spike Protein Targeted to Authentic and Alternative Cellular Receptors. Viruses 2022; 14:v14020384. [PMID: 35215976 PMCID: PMC8879608 DOI: 10.3390/v14020384] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 02/08/2022] [Accepted: 02/10/2022] [Indexed: 12/11/2022] Open
Abstract
The evolution of the SARS-CoV-2 virus during the COVID-19 pandemic was accompanied by the emergence of new heavily mutated viral variants with increased infectivity and/or resistance to detection by the human immune system. To respond to the urgent need for advanced methods and materials to empower a better understanding of the mechanisms of virus’s adaptation to human host cells and to the immuno-resistant human population, we suggested using recombinant filamentous bacteriophages, displaying on their surface foreign peptides termed “mimotopes”, which mimic the structure of viral receptor-binding sites on the viral spike protein and can serve as molecular probes in the evaluation of molecular mechanisms of virus infectivity. In opposition to spike-binding antibodies that are commonly used in studying the interaction of the ACE2 receptor with SARS-CoV-2 variants in vitro, phage spike mimotopes targeted to other cellular receptors would allow discovery of their role in viral infection in vivo using cell culture, tissue, organs, or the whole organism. Phage mimotopes of the SARS-CoV-2 Spike S1 protein have been developed using a combination of phage display and molecular mimicry concepts, termed here “phage mimicry”, supported by bioinformatics methods. The key elements of the phage mimicry concept include: (1) preparation of a collection of p8-type (landscape) phages, which interact with authentic active receptors of live human cells, presumably mimicking the binding interactions of human coronaviruses such as SARS-CoV-2 and its variants; (2) discovery of closely related amino acid clusters with similar 3D structural motifs on the surface of natural ligands (FGF1 and NRP1), of the model receptor of interest FGFR and the S1 spike protein; and (3) an ELISA analysis of the interaction between candidate phage mimotopes with FGFR3 (a potential alternative receptor) in comparison with ACE2 (the authentic receptor).
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Affiliation(s)
- Valery A. Petrenko
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA
- Correspondence: (V.A.P.); (J.W.G.); Tel.: +1-334-844-2897 (V.A.P.); +1-334-844-2625 (J.W.G.)
| | - James W. Gillespie
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA
- Correspondence: (V.A.P.); (J.W.G.); Tel.: +1-334-844-2897 (V.A.P.); +1-334-844-2625 (J.W.G.)
| | - Laura Maria De Plano
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98122 Messina, Italy;
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Gusev E, Sarapultsev A, Solomatina L, Chereshnev V. SARS-CoV-2-Specific Immune Response and the Pathogenesis of COVID-19. Int J Mol Sci 2022; 23:1716. [PMID: 35163638 PMCID: PMC8835786 DOI: 10.3390/ijms23031716] [Citation(s) in RCA: 154] [Impact Index Per Article: 51.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 01/31/2022] [Accepted: 02/01/2022] [Indexed: 12/13/2022] Open
Abstract
The review aims to consolidate research findings on the molecular mechanisms and virulence and pathogenicity characteristics of coronavirus disease (COVID-19) causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and their relevance to four typical stages in the development of acute viral infection. These four stages are invasion; primary blockade of antiviral innate immunity; engagement of the virus's protection mechanisms against the factors of adaptive immunity; and acute, long-term complications of COVID-19. The invasion stage entails the recognition of the spike protein (S) of SARS-CoV-2 target cell receptors, namely, the main receptor (angiotensin-converting enzyme 2, ACE2), its coreceptors, and potential alternative receptors. The presence of a diverse repertoire of receptors allows SARS-CoV-2 to infect various types of cells, including those not expressing ACE2. During the second stage, the majority of the polyfunctional structural, non-structural, and extra proteins SARS-CoV-2 synthesizes in infected cells are involved in the primary blockage of antiviral innate immunity. A high degree of redundancy and systemic action characterizing these pathogenic factors allows SARS-CoV-2 to overcome antiviral mechanisms at the initial stages of invasion. The third stage includes passive and active protection of the virus from factors of adaptive immunity, overcoming of the barrier function at the focus of inflammation, and generalization of SARS-CoV-2 in the body. The fourth stage is associated with the deployment of variants of acute and long-term complications of COVID-19. SARS-CoV-2's ability to induce autoimmune and autoinflammatory pathways of tissue invasion and development of both immunosuppressive and hyperergic mechanisms of systemic inflammation is critical at this stage of infection.
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Affiliation(s)
- Evgenii Gusev
- Laboratory of Immunology of Inflammation, Institute of Immunology and Physiology, Ural Branch of the Russian Academy of Science, 620049 Ekaterinburg, Russia
| | - Alexey Sarapultsev
- Laboratory of Immunology of Inflammation, Institute of Immunology and Physiology, Ural Branch of the Russian Academy of Science, 620049 Ekaterinburg, Russia
- Russian-Chinese Education and Research Center of System Pathology, South Ural State University, 454080 Chelyabinsk, Russia
| | - Liliya Solomatina
- Laboratory of Immunology of Inflammation, Institute of Immunology and Physiology, Ural Branch of the Russian Academy of Science, 620049 Ekaterinburg, Russia
| | - Valeriy Chereshnev
- Laboratory of Immunology of Inflammation, Institute of Immunology and Physiology, Ural Branch of the Russian Academy of Science, 620049 Ekaterinburg, Russia
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The roles of Eph receptors, neuropilin-1, P2X7, and CD147 in COVID-19-associated neurodegenerative diseases: inflammasome and JaK inhibitors as potential promising therapies. Cell Mol Biol Lett 2022; 27:10. [PMID: 35109786 PMCID: PMC8809072 DOI: 10.1186/s11658-022-00311-1] [Citation(s) in RCA: 63] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 01/14/2022] [Indexed: 12/20/2022] Open
Abstract
The novel coronavirus disease 2019 (COVID-19) pandemic has spread worldwide, and finding a safe therapeutic strategy and effective vaccine is critical to overcoming severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Therefore, elucidation of pathogenesis mechanisms, especially entry routes of SARS-CoV-2 may help propose antiviral drugs and novel vaccines. Several receptors have been demonstrated for the interaction of spike (S) protein of SARS-CoV-2 with host cells, including angiotensin-converting enzyme (ACE2), ephrin ligands and Eph receptors, neuropilin 1 (NRP-1), P2X7, and CD147. The expression of these entry receptors in the central nervous system (CNS) may make the CNS prone to SARS-CoV-2 invasion, leading to neurodegenerative diseases. The present review provides potential pathological mechanisms of SARS-CoV-2 infection in the CNS, including entry receptors and cytokines involved in neuroinflammatory conditions. Moreover, it explains several neurodegenerative disorders associated with COVID-19. Finally, we suggest inflammasome and JaK inhibitors as potential therapeutic strategies for neurodegenerative diseases.
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Humayun F, Khan A, Ahmad S, Yuchen W, Wei G, Nizam-Uddin N, Hussain Z, Khan W, Zaman N, Rizwan M, Waseem M, Wei DQ. Abrogation of SARS-CoV-2 interaction with host (NRP1) neuropilin-1 receptor through high-affinity marine natural compounds to curtail the infectivity: A structural-dynamics data. Comput Biol Med 2022; 141:104714. [PMID: 34772509 PMCID: PMC8324387 DOI: 10.1016/j.compbiomed.2021.104714] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 07/05/2021] [Accepted: 07/27/2021] [Indexed: 01/07/2023]
Abstract
The evolution of new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants around the globe has made the coronavirus disease 2019 (COVID-19) pandemic more worrisome, pressuring the health care system and resulting in an increased mortality rate. Recent studies recognized neuropilin-1 (NRP1) as a key facilitator in the invasion of the new SARS-CoV-2 into the host cell. Therefore, it is considered an imperative drug target for the treatment of COVID-19. Hence, a thorough analysis was needed to understand the impact and to guide new therapeutics development. In this study, we used structural and biomolecular simulation techniques to identify novel marine natural products which could block this receptor and stop the virus entry. We discovered that the binding affinity of CMNPD10175, CMNPD10017, CMNPD10114, CMNPD10115, CMNPD10020. CMNPD10018, CMNPD10153, CMNPD10149 CMNPD10464 and CMNPD10019 were substantial during the virtual screening (VS). We further explored these compounds by analyzing their absorption, distribution, metabolism, and excretion and toxicity (ADMET) properties and structural-dynamics features. Free energy calculations further established that all the compounds exhibit stronger binding energy for NRP1. Consequently, we hypothesized that these compounds might be the best lead candidates for therapeutic interventions hindering virus binding to the host cell. This study provides a strong impetus to develop novel drugs against the SARS-CoV-2 by targeting NRP1.
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Affiliation(s)
- Fahad Humayun
- Department of Bioinformatics and Biological Statistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, PR China.
| | - Abbas Khan
- Department of Bioinformatics and Biological Statistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, PR China.
| | - Sajjad Ahmad
- Department of Health and Biological Sciences, Abasyn University, Khyber Pakhtunkhwa, Pakistan.
| | - Wang Yuchen
- Beijing 161 High School, No. 94, Nanheng West Street, Xicheng District, Beijing, PR China.
| | - Guoshen Wei
- Yangpu High School, Yangpu, Shanghai, PR China.
| | - N Nizam-Uddin
- Biomedical Engineering Department, HITEC University, Taxila, Pakistan.
| | - Zahid Hussain
- Center for Biotechnology and Microbiology, University of Swat, Swat, KP, Pakistan
| | - Wajid Khan
- Center for Biotechnology and Microbiology, University of Swat, Swat, KP, Pakistan
| | - Nasib Zaman
- Center for Biotechnology and Microbiology, University of Swat, Swat, KP, Pakistan
| | - Muhammad Rizwan
- Center for Biotechnology and Microbiology, University of Swat, Swat, KP, Pakistan
| | - Muhammad Waseem
- Faculty of Rehabilitation and Allied Health Science, Riphah International University, Islamabad, Pakistan
| | - Dong-Qing Wei
- Department of Bioinformatics and Biological Statistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, PR China; Peng Cheng Laboratory, Vanke Cloud City Phase I Building 8, Xili Street, Nashan District, Shenzhen, Guangdong, 518055, PR China; State Key Laboratory of Microbial Metabolism, Shanghai-Islamabad-Belgrade Joint Innovation Center on Antibacterial Resistances, Joint Laboratory of International Cooperation in Metabolic and Developmental Sciences, Ministry of Education and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200030, PR China.
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Louis TJ, Qasem A, Abdelli LS, Naser SA. Extra-Pulmonary Complications in SARS-CoV-2 Infection: A Comprehensive Multi Organ-System Review. Microorganisms 2022; 10:153. [PMID: 35056603 PMCID: PMC8781813 DOI: 10.3390/microorganisms10010153] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 01/07/2022] [Accepted: 01/10/2022] [Indexed: 02/07/2023] Open
Abstract
Coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, is typically presented with acute symptoms affecting upper and lower respiratory systems. As the current pandemic progresses, COVID-19 patients are experiencing a series of nonspecific or atypical extra-pulmonary complications such as systemic inflammation, hypercoagulability state, and dysregulation of the renin-angiotensin-aldosterone system (RAAS). These manifestations often delay testing, diagnosis, and the urge to seek effective treatment. Although the pathophysiology of these complications is not clearly understood, the incidence of COVID-19 increases with age and the presence of pre-existing conditions. This review article outlines the pathophysiology and clinical impact of SARS-CoV-2 infection on extra-pulmonary systems. Understanding the broad spectrum of atypical extra-pulmonary manifestations of COVID-19 should increase disease surveillance, restrict transmission, and most importantly prevent multiple organ-system complications.
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Affiliation(s)
- Taylor J Louis
- Division of Molecular Microbiology, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32816, USA
| | - Ahmad Qasem
- Division of Molecular Microbiology, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32816, USA
| | - Latifa S Abdelli
- Division of Molecular Microbiology, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32816, USA
| | - Saleh A Naser
- Division of Molecular Microbiology, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32816, USA
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Bassani D, Ragazzi E, Lapolla A, Sartore G, Moro S. Omicron Variant of SARS-CoV-2 Virus: In Silico Evaluation of the Possible Impact on People Affected by Diabetes Mellitus. Front Endocrinol (Lausanne) 2022; 13:847993. [PMID: 35321335 PMCID: PMC8935058 DOI: 10.3389/fendo.2022.847993] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Accepted: 02/08/2022] [Indexed: 12/15/2022] Open
Abstract
The Omicron variant of SARS-CoV-2 (Spike mutant B.1.1.529) carrying more than 30-point mutations in its structure, of which 15 are localized in the receptor-binding domain (RBD), allows to hypothesize a relevant change in interactivity with ACE2. In previous reports we hypothesized that the worse outcome of the COVID-19 disease in diabetes mellitus condition could be related to the non-enzymatic glycation of ACE2 receptor and an in silico evaluation led to the demonstration that the number of interactions is decreased in comparison to the unmodified model, possibly shifting the virus attack through different, multiple alternative entry routes. Given the evidenced features of this variant, we aimed to investigate with a computational approach the characteristics of Omicron SARS-CoV-2 with respect to its binding to human ACE-2 receptor, in a particular population, namely people affected by diabetes mellitus, at risk for unfavorable outcomes of the COVID-19. The computational analysis, considering the case in which all the lysine residues in the system are subjected to non-enzymatic glycation, confirmed that lysine glycation causes a general loss of interactivity between wild-type (WT)-Spike-RBD and ACE2. In the Omicron variant, Lys417 mutates into an asparagine, preventing the possible non-enzymatic glycation of this residue. Therefore, if non-enzymatic glycation seemed to cause a shift in the way in which the virus enters the cell from the ACE2-mediated mechanism to other pathways, in the case of the Omicron variant the ACE2-mediated approach of the virus seems to remain an important event to take into account. Indeed, interaction profile analysis, together with molecular mechanics-generalized Born surface area (MM-GBSA) calculations, suggests that the Omicron-Spike-RBD maintains a higher affinity for ACE2 subsequently to non-enzymatic glycation with respect to WT-Spike-RBD. The finding of the present computational study may suggest a different clinical relevance of the Omicron variant for the diabetes mellitus field, also in the possible direction of a lower severity of the disease.
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Affiliation(s)
- Davide Bassani
- Department of Pharmaceutical and Pharmacological Sciences (DSF), Molecular Modeling Section (MMS), University of Padova School of Medicine and Surgery, Padua, Italy
| | - Eugenio Ragazzi
- Department of Pharmaceutical and Pharmacological Sciences (DSF), University of Padova School of Medicine and Surgery, Padua, Italy
- *Correspondence: Eugenio Ragazzi,
| | - Annunziata Lapolla
- Department of Medicine (DIMED), University of Padova School of Medicine and Surgery, Padua, Italy
| | - Giovanni Sartore
- Department of Medicine (DIMED), University of Padova School of Medicine and Surgery, Padua, Italy
| | - Stefano Moro
- Department of Pharmaceutical and Pharmacological Sciences (DSF), Molecular Modeling Section (MMS), University of Padova School of Medicine and Surgery, Padua, Italy
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Singh S, Garcia G, Shah R, Kramerov AA, Wright RE, Spektor TM, Ljubimov AV, Arumugaswami V, Kumar A. SARS-CoV-2 and its beta variant of concern infect human conjunctival epithelial cells and induce differential antiviral innate immune response. Ocul Surf 2022; 23:184-194. [PMID: 34583089 PMCID: PMC8464027 DOI: 10.1016/j.jtos.2021.09.007] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 09/17/2021] [Accepted: 09/23/2021] [Indexed: 02/06/2023]
Abstract
PURPOSE SARS-CoV-2 RNA has been detected in ocular tissues, but their susceptibility to SARS-CoV-2 infection is unclear. Here, we tested whether SARS-CoV-2 can infect human conjunctival epithelial cells (hCECs) and induce innate immune response. METHODS Conjunctival tissue from COVID-19 donors was used to detect SARS-CoV-2 spike and envelope proteins. Primary hCECs isolated from cadaver eyes were infected with the parental SARS-CoV-2 and its beta variant of concern (VOC). Viral genome copy number, and expression of viral entry receptors, TLRs, interferons, and innate immune response genes were determined by qPCR. Viral entry receptors were examined in hCECs and tissue sections by immunostaining. Spike protein was detected in the cell culture supernatant by dot blot. RESULTS Spike and envelope proteins were found in conjunctiva from COVID-19 patients. SARS-CoV-2 infected hCECs showed high viral copy numbers at 24-72h post-infection; spike protein levels were the highest at 24hpi. Viral entry receptors ACE2, TMPRSS2, CD147, Axl, and NRP1 were detected in conjunctival tissue and hCECs. SARS-CoV-2 infection-induced receptor gene expression peaked at early time points post-infection, but gene expression of most TLRs peaked at 48 or 72hpi. SARS-CoV-2 infected hCECs showed higher expression of genes regulating antiviral response, RIG-I, interferons (α, β, & λ), ISG15 & OAS2, cytokines (IL6, IL1β, TNFα), and chemokines (CXCL10, CCL5). Compared to the parental strain, beta VOC induced increased viral copy number and innate response in hCECs. CONCLUSIONS Conjunctival epithelial cells are susceptible to SARS-CoV-2 infection. Beta VOC is more infectious than the parental strain and evokes a higher antiviral and inflammatory response.
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Affiliation(s)
- Sneha Singh
- Department of Ophthalmology, Visual and Anatomical Sciences / Kresge Eye Institute, Wayne State University School of Medicine, Detroit, MI, USA
| | - Gustavo Garcia
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Ruchi Shah
- Eye Program, Board of Governors Regenerative Medicine Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Andrei A Kramerov
- Eye Program, Board of Governors Regenerative Medicine Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Robert Emery Wright
- Department of Ophthalmology, Visual and Anatomical Sciences / Kresge Eye Institute, Wayne State University School of Medicine, Detroit, MI, USA
| | - Tanya M Spektor
- Eye Program, Board of Governors Regenerative Medicine Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Alexander V Ljubimov
- Eye Program, Board of Governors Regenerative Medicine Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
| | - Vaithilingaraja Arumugaswami
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
| | - Ashok Kumar
- Department of Ophthalmology, Visual and Anatomical Sciences / Kresge Eye Institute, Wayne State University School of Medicine, Detroit, MI, USA.
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The Disease-Modifying Role of Taurine and Its Therapeutic Potential in Coronavirus Disease 2019 (COVID-19). ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1370:3-21. [DOI: 10.1007/978-3-030-93337-1_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/16/2022]
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48
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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: 19] [Impact Index Per Article: 4.8] [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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49
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Lashgari NA, Momeni Roudsari N, Momtaz S, Abdolghaffari AH. Transmembrane serine protease 2 and angiotensin-converting enzyme 2 anti-inflammatory receptors for COVID-19/inflammatory bowel diseases treatment. World J Gastroenterol 2021; 27:7943-7955. [PMID: 35046622 PMCID: PMC8678820 DOI: 10.3748/wjg.v27.i46.7943] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 05/12/2021] [Accepted: 11/28/2021] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel diseases (IBD) refer to a subgroup of chronic, progressive, long-term, and relapsing inflammatory disorders. IBD may spontaneously grow in the colon, and in severe cases may result in tumor lesions such as invasive carcinoma in inflamed regions of the intestine. Recent epidemiological reports indicate that old age and underlying diseases such as IBD contribute to severity and mortality in patients with coronavirus disease 2019 (COVID-19). Currently, the ongoing COVID-19 pandemic caused serious morbidity and mortality worldwide. It has also been shown that the transmembrane serine protease 2 is an essential factor for viral activation and viral engulfment. Generally, viral entry causes a 'cytokine storm' that induces excessive generation of proinflammatory cytokines/chemokines including interleukin (IL)-6, IL-2, IL-7, tumor necrosis factor-α, and interferon-γ. Future research could concentrate on developing inflammatory immunological responses that are efficient to encounter COVID-19. Current analysis elucidates the role of inflammation and immune responses during IBD infection with COVID-19 and provides a list of possible targets for IBD-regulated therapies in particular. Data from clinical, in vitro, and in vivo studies were collected in English from PubMed, Google Scholar, Scopus, and the Cochrane library until May 2021.
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Affiliation(s)
- Naser-Aldin Lashgari
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran 1941933111, Iran
| | - Nazanin Momeni Roudsari
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran 1941933111, Iran
| | - Saeideh Momtaz
- Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Karaj 141554364, Iran
- Toxicology and Diseases Group (TDG), Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran 1941933111, Iran
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran 1941933111, Iran
- Gastrointestinal Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran 1941933111, Iran
| | - Amir Hossein Abdolghaffari
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran 1941933111, Iran
- Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Karaj 141554364, Iran
- Toxicology and Diseases Group (TDG), Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran 1941933111, Iran
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran 1941933111, Iran
- Gastrointestinal Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran 1941933111, Iran
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50
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Ma Z, Yang KY, Huang Y, Lui KO. Endothelial contribution to COVID-19: an update on mechanisms and therapeutic implications. J Mol Cell Cardiol 2021; 164:69-82. [PMID: 34838588 PMCID: PMC8610843 DOI: 10.1016/j.yjmcc.2021.11.010] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 11/05/2021] [Accepted: 11/08/2021] [Indexed: 12/15/2022]
Abstract
The global propagation of SARS-CoV-2 leads to an unprecedented public health emergency. Despite that the lungs are the primary organ targeted by COVID-19, systemic endothelial inflammation and dysfunction is observed particularly in patients with severe COVID-19, manifested by elevated endothelial injury markers, endotheliitis, and coagulopathy. Here, we review the clinical characteristics of COVID-19 associated endothelial dysfunction; and the likely pathological mechanisms underlying the disease including direct cell entry or indirect immune overreactions after SARS-CoV-2 infection. In addition, we discuss potential biomarkers that might indicate the disease severity, particularly related to the abnormal development of thrombosis that is a fatal vascular complication of severe COVID-19. Furthermore, we summarize clinical trials targeting the direct and indirect pathological pathways after SARS-CoV-2 infection to prevent or inhibit the virus induced endothelial disorders.
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Affiliation(s)
- Zhangjing Ma
- Department of Chemical Pathology, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
| | - Kevin Y Yang
- Department of Chemical Pathology, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
| | - Yu Huang
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China
| | - Kathy O Lui
- Department of Chemical Pathology, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China; Li Ka Shing Institute of Health Science, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China; Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China.
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