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Xu X, Zhang Y, Huang G, Perekatt A, Wang Y, Chen L. Advances and applications of gut organoids: modeling intestinal diseases and therapeutic development. LIFE MEDICINE 2025; 4:lnaf012. [PMID: 40276096 PMCID: PMC12018802 DOI: 10.1093/lifemedi/lnaf012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/21/2024] [Accepted: 03/04/2025] [Indexed: 04/26/2025]
Abstract
Gut organoids are 3D cellular structures derived from adult or pluripotent stem cells, capable of closely replicating the physiological properties of the gut. These organoids serve as powerful tools for studying gut development and modeling the pathogenesis of intestinal diseases. This review provides an in-depth exploration of technological advancements and applications of gut organoids, with a focus on their construction methods. Additionally, the potential applications of gut organoids in disease modeling, microenvironmental simulation, and personalized medicine are summarized. This review aims to offer perspectives and directions for understanding the mechanisms of intestinal health and disease as well as for developing innovative therapeutic strategies.
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Affiliation(s)
- Xiaoting Xu
- School of Life Science and Technology, Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing 210031, China
| | - Yuping Zhang
- School of Life Science and Technology, Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing 210031, China
| | - Guoxin Huang
- Clinical Research Center, Shantou Key Laboratory of Basic and Translational Research of Malignant Tumor, Shantou Central Hospital, Shantou 515041, China
| | - Ansu Perekatt
- Department of Chemistry and Chemical Biology, Stevens Institute of Technology, Hoboken, NJ 07030, United States
| | - Yan Wang
- Center for Translation Medicine Research and Development, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
| | - Lei Chen
- School of Life Science and Technology, Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing 210031, China
- Institute of Microphysiological Systems, Southeast University, Nanjing 211189, China
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Chaimongkol N, Kim DY, Matsushima Y, Durkee-Shock J, Barton K, Ahorrio CN, Fahle GA, Bok K, Behrle-Yardley A, Johnson JA, de Jesús-Díaz DA, Parra GI, Levenson EA, Maeda FY, Sosnovtsev SV, Green KY. A Decade of Chronic Norovirus Infection Surveillance at the National Institutes of Health Clinical Research Center: Clinical Characteristics, Molecular Epidemiology, and Replication. J Infect Dis 2025; 231:784-794. [PMID: 39207021 PMCID: PMC11911794 DOI: 10.1093/infdis/jiae440] [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: 06/05/2024] [Revised: 08/14/2024] [Accepted: 08/27/2024] [Indexed: 09/04/2024] Open
Abstract
BACKGROUND Noroviruses are an important viral cause of chronic diarrhea in immunocompromised individuals. METHODS We collected norovirus-positive stool samples (n = 448) from immunocompromised patients (n = 88) at the National Institutes of Health (NIH) Clinical Research Center from 2010 to 2022. We assessed norovirus molecular epidemiology and infectivity in human intestinal enteroid (HIE) monolayers and clinical characteristics of the cohort. RESULTS Noroviruses were genetically diverse: both genogroup I (GI.2, GI.5 and GI.6) and genogroup II (GII.1-GII.4, GII.6, GII.7, GII.12, GII.14, and GII.17) genotypes were detected, with GII.4 variants (Osaka, Apeldoorn, Den Haag, New Orleans, and Sydney) predominant (51/88 [57.9%]). Viruses belonging to the GII.4 Sydney variant group that replicated in HIEs (n = 9) showed a higher fold-increase in RNA genome copies compared to others that replicated. Chronic norovirus infection was documented in thirty-nine patients with shedding levels ranging from 104 to 1011 genome copies/g of stool. The majority (32/39 [82%]) had clinical evidence of an inborn error of immunity (13 identified monogenic diseases), most with combined immunodeficiency (15 of 32) or common variable immunodeficiency (11 of 32). CONCLUSIONS Genetically and biologically diverse noroviruses established chronic infection in NIH patients with both inborn and acquired immunologic defects.
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Affiliation(s)
| | | | | | - Jessica Durkee-Shock
- Medical Virology Section, Laboratory of Infectious Diseases, Division of Intramural Research, National Institute of Allergy and Infectious Diseases
| | - Karenna Barton
- Medical Virology Section, Laboratory of Infectious Diseases, Division of Intramural Research, National Institute of Allergy and Infectious Diseases
| | | | - Gary A Fahle
- Department of Laboratory Medicine, Clinical Research Center, National Institutes of Health, Bethesda, Maryland
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Al-Qadami G, Raposo A, Chien CC, Ma C, Priebe I, Hor M, Fung K. Intestinal organoid coculture systems: current approaches, challenges, and future directions. Am J Physiol Gastrointest Liver Physiol 2025; 328:G252-G276. [PMID: 39716040 DOI: 10.1152/ajpgi.00203.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 12/12/2024] [Accepted: 12/12/2024] [Indexed: 12/25/2024]
Abstract
The intestinal microenvironment represents a complex and dynamic ecosystem, comprising a diverse range of epithelial and nonepithelial cells, a protective mucus layer, and a diverse community of gut microbiota. Understanding the intricate interplay between these components is essential for uncovering the mechanisms underlying intestinal health and disease. The development of intestinal organoids, three-dimensional (3-D) mini-intestines that closely mimic the architecture, cellular diversity, and functionality of the intestine, offers a powerful platform for investigating different aspects of intestinal physiology and pathology. However, current intestinal organoid models, mainly adult stem cell-derived organoids, lack the nonepithelial and microbial components of the intestinal microenvironment. As such, several coculture systems have been developed to coculture intestinal organoids with other intestinal elements including microbes (bacteria and viruses) and immune, stromal, and neural cells. These coculture models allow researchers to recreate the complex intestinal environment and study the intricate cross talk between different components of the intestinal ecosystem under healthy and pathological conditions. Currently, there are several approaches and methodologies to establish intestinal organoid cocultures, and each approach has its own strengths and limitations. This review discusses the existing methods for coculturing intestinal organoids with different intestinal elements, focusing on the methodological approaches, strengths and limitations, and future directions.
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Affiliation(s)
| | - Anita Raposo
- Health and Biosecurity, CSIRO, Sydney, New South Wales, Australia
| | - Chia-Chi Chien
- Australian Animal Health Laboratory, Australian Centre for Disease Preparedness, CSIRO, Geelong, Victoria, Australia
| | - Chenkai Ma
- Health and Biosecurity, CSIRO, Sydney, New South Wales, Australia
| | - Ilka Priebe
- Health and Biosecurity, CSIRO, Adelaide, South Australia, Australia
| | - Maryam Hor
- Health and Biosecurity, CSIRO, Adelaide, South Australia, Australia
| | - Kim Fung
- Health and Biosecurity, CSIRO, Sydney, New South Wales, Australia
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Cheng C, Cai X, Li J, Zhang X, Xie Y, Zhang J. In Vitro Culture of Human Norovirus in the Last 20 Years. Biomedicines 2024; 12:2442. [PMID: 39595008 PMCID: PMC11592199 DOI: 10.3390/biomedicines12112442] [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: 09/14/2024] [Revised: 10/12/2024] [Accepted: 10/21/2024] [Indexed: 11/28/2024] Open
Abstract
Human noroviruses (HuNoVs) are the main pathogens that cause acute gastroenteritis and lead to huge economic losses annually. Due to the lack of suitable culture systems, the pathogenesis of HuNoVs and the development of vaccines and drugs have progressed slowly. Although researchers have employed various methods to culture HuNoVs in vitro in the last century, problems relating to the irreducibility, low viral titer, and non-infectiousness of the progeny virus should not be ignored. In 2016, researchers achieved the cultivation and successive passaging of some HuNoV genotypes using human intestinal enteroids, initially demonstrating the potential use of organoids in overcoming this challenge. This paper reviews the efforts made in the last 20 years to culture HuNoVs in vitro and discusses the superiority and limitations of employing human intestinal enteroids/organoids as an in vitro culture model for HuNoVs.
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Affiliation(s)
- Chao Cheng
- MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, Shanghai Institute of Infectious Disease and Biosecurity, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China; (C.C.); (J.L.); (X.Z.)
| | - Xia Cai
- Biosafety Level 3 Laboratory, Shanghai Medical College, Fudan University, Shanghai 200032, China;
| | - Jingjing Li
- MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, Shanghai Institute of Infectious Disease and Biosecurity, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China; (C.C.); (J.L.); (X.Z.)
| | - Xiaomeng Zhang
- MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, Shanghai Institute of Infectious Disease and Biosecurity, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China; (C.C.); (J.L.); (X.Z.)
| | - Youhua Xie
- MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, Shanghai Institute of Infectious Disease and Biosecurity, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China; (C.C.); (J.L.); (X.Z.)
| | - Junqi Zhang
- MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, Shanghai Institute of Infectious Disease and Biosecurity, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China; (C.C.); (J.L.); (X.Z.)
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5
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Wang X, Zhu Y, Cheng Z, Zhang C, Liao Y, Liu B, Zhang D, Li Z, Fang Y. Emerging microfluidic gut-on-a-chip systems for drug development. Acta Biomater 2024; 188:48-64. [PMID: 39299625 DOI: 10.1016/j.actbio.2024.09.012] [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: 05/16/2024] [Revised: 08/29/2024] [Accepted: 09/10/2024] [Indexed: 09/22/2024]
Abstract
The gut is a vital organ that is central to the absorption and metabolic processing of orally administered drugs. While there have been many models developed with the goal of studying the absorption of drugs in the gut, these models fail to adequately recapitulate the diverse, complex gastrointestinal microenvironment. The recent emergence of microfluidic organ-on-a-chip technologies has provided a novel means of modeling the gut, yielding radical new insights into the structure of the gut and the mechanisms through which it shapes disease, with key implications for biomedical developmental efforts. Such organ-on-a-chip technologies have been demonstrated to exhibit greater cost-effectiveness, fewer ethical concerns, and a better ability to address inter-species differences in traditional animal models in the context of drug development. The present review offers an overview of recent developments in the reconstruction of gut structure and function in vitro using microfluidic gut-on-a-chip (GOC) systems, together with a discussion of the potential applications of these platforms in the context of drug development and the challenges and future prospects associated with this technology. STATEMENT OF SIGNIFICANCE: This paper outlines the characteristics of the different cell types most frequently used to construct microfluidic gut-on-a-chip models and the microfluidic devices employed for the study of drug absorption. And the applications of gut-related multichip coupling and disease modelling in the context of drug development is systematically reviewed. With the detailed summarization of microfluidic chip-based gut models and discussion of the prospective directions for practical application, this review will provide insights to the innovative design and application of microfluidic gut-on-a-chip for drug development.
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Affiliation(s)
- Xueqi Wang
- College of Pharmaceutical Engineering of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China; State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China; Tianjin Key Laboratory of Intelligent and Green Pharmaceuticals for Traditional Chinese Medicine, Tianjin 301617, PR China; State Key Laboratory of Chinese Medicine Modernization, Tianjin 301617, PR China
| | - Yuzhuo Zhu
- Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China; State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China; Tianjin Key Laboratory of Intelligent and Green Pharmaceuticals for Traditional Chinese Medicine, Tianjin 301617, PR China; State Key Laboratory of Chinese Medicine Modernization, Tianjin 301617, PR China
| | - Zhaoming Cheng
- College of Pharmaceutical Engineering of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China; State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China; Tianjin Key Laboratory of Intelligent and Green Pharmaceuticals for Traditional Chinese Medicine, Tianjin 301617, PR China; State Key Laboratory of Chinese Medicine Modernization, Tianjin 301617, PR China
| | - Chuanjun Zhang
- College of Pharmaceutical Engineering of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China; State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China; Tianjin Key Laboratory of Intelligent and Green Pharmaceuticals for Traditional Chinese Medicine, Tianjin 301617, PR China; State Key Laboratory of Chinese Medicine Modernization, Tianjin 301617, PR China
| | - Yumeng Liao
- College of Pharmaceutical Engineering of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China; State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China; Tianjin Key Laboratory of Intelligent and Green Pharmaceuticals for Traditional Chinese Medicine, Tianjin 301617, PR China
| | - Boshi Liu
- College of Pharmaceutical Engineering of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China; State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China; Tianjin Key Laboratory of Intelligent and Green Pharmaceuticals for Traditional Chinese Medicine, Tianjin 301617, PR China
| | - Di Zhang
- College of Pharmaceutical Engineering of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China; State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China; Tianjin Key Laboratory of Intelligent and Green Pharmaceuticals for Traditional Chinese Medicine, Tianjin 301617, PR China; State Key Laboratory of Chinese Medicine Modernization, Tianjin 301617, PR China; Haihe Laboratory of Modern Chinese Medicine, Tianjin 301617, PR China.
| | - Zheng Li
- College of Pharmaceutical Engineering of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China; State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China; Tianjin Key Laboratory of Intelligent and Green Pharmaceuticals for Traditional Chinese Medicine, Tianjin 301617, PR China; State Key Laboratory of Chinese Medicine Modernization, Tianjin 301617, PR China; Haihe Laboratory of Modern Chinese Medicine, Tianjin 301617, PR China.
| | - Yuxin Fang
- State Key Laboratory of Chinese Medicine Modernization, Tianjin 301617, PR China; Research Center of Experimental Acupuncture Science, College of Acumox and Tuina, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China.
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Lulla V, Sridhar A. Understanding neurotropic enteric viruses: routes of infection and mechanisms of attenuation. Cell Mol Life Sci 2024; 81:413. [PMID: 39365457 PMCID: PMC11452578 DOI: 10.1007/s00018-024-05450-6] [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: 07/10/2024] [Revised: 09/03/2024] [Accepted: 09/12/2024] [Indexed: 10/05/2024]
Abstract
The intricate connection between the gut and the brain involves multiple routes. Several viral families begin their infection cycle in the intestinal tract. However, amongst the long list of viral intestinal pathogens, picornaviruses, and astroviruses stand out for their ability to transition from the intestinal epithelia to central or peripheral nervous system cells. In immunocompromised, neonates and young children, these viral infections can manifest as severe diseases, such as encephalitis, meningitis, and acute flaccid paralysis. What confers this remarkable plasticity and makes them efficient in infecting cells of the gut and the brain axes? Here, we review the current understanding of the virus infection along the gut-brain axis for some enteric viruses and discuss the molecular mechanisms of their attenuation.
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Affiliation(s)
- Valeria Lulla
- Division of Virology, Department of Pathology, Addenbrooke's Hospital, University of Cambridge, Hills Road, Cambridge, CB2 0QQ, UK.
| | - Adithya Sridhar
- OrganoVIR Labs, Department of Pediatric Infectious Diseases, Amsterdam UMC, location Academic Medical Center, Amsterdam Institute for Reproduction and Development, University of Amsterdam, Meibergdreef 9, 1100 AZ, Amsterdam, The Netherlands
- OrganoVIR Labs, Department of Medical Microbiology, Amsterdam UMC, location Academic Medical Center, Amsterdam Institute for Infection and Immunity, University of Amsterdam, Meibergdreef 9, 1100 AZ, Amsterdam, The Netherlands
- Emma Center for Personalized Medicine, Amsterdam UMC, Amsterdam, The Netherlands
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7
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Huang CY, Su SB, Chen KT. A review of enterovirus-associated hand-foot and mouth disease: preventive strategies and the need for a global enterovirus surveillance network. Pathog Glob Health 2024; 118:538-548. [PMID: 39229797 PMCID: PMC11892072 DOI: 10.1080/20477724.2024.2400424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/05/2024] Open
Abstract
Enterovirus (EV)-associated hand, foot, and mouth disease (HFMD) is a significant public health issue worldwide, commonly occurring in children five years of age or younger. The leading causes of most HFMD cases are EVs, which are members of the Picornaviridae family. The typical clinical manifestations of EV-associated HFMD are febrile presentations with mucosal herpangina, oral ulcerations, and skin rashes on the hands and feet. The majority of HFMD cases resolve without consequence; however, a subset progresses to severe neurological and cardiopulmonary complications, which can be fatal. In the past two decades, EV-associated HFMD has received significant attention. In this review, we organize published papers and provide updates on epidemiology, pathogenesis, surveillance, and vaccine developments for EV-associated HFMD. The impact of EV-associated HFMD is increasing globally. Developing efficacious vaccines has become a priority for preventing EV infections without adequate treatment. Simultaneously, emerging EV infections (including EV-D68, EV-A71, Coxsackieviruses, and echoviruses) are increasing, highlighting the need to create a vigilant surveillance system for EV infections worldwide.
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Affiliation(s)
- Chien-Yuan Huang
- Division of Occupational Medicine, Chi-Mei Medical Center, Tainan, Taiwan
| | - Shih-Bin Su
- Department of Occupational Medicine, Chi-Mei Medical Center, Tainan, Taiwan
| | - Kow-Tong Chen
- Department of Occupational Medicine, Tainan Municipal Hospital (managed by Show Chwan Medical Care Corporation), Tainan, Taiwan
- Department of Public Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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8
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Burton TD, Carrera Montoya J, Frota T, Mackenzie JM. Human norovirus cultivation models, immune response and vaccine landscape. Adv Virus Res 2024; 120:1-37. [PMID: 39455167 DOI: 10.1016/bs.aivir.2024.09.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2024]
Abstract
Norovirus infections are a leading cause of gastroenteritis worldwide. Despite the substantial global health burden and economic impact, there are currently no approved antiviral therapeutics or vaccines. Additionally, much of our knowledge of norovirus comes from experiments using surrogate viruses, such as murine norovirus and feline calicivirus. The challenge surrounding human norovirus research arises from a lack of robust cell culture systems and efficient animal models. In this review, we explore recent advances in the in vitro cultivation of human norovirus and reverse genetics systems and discuss commonly used in vivo models. We summarize the current understanding of both innate and adaptive immune responses to norovirus infection and provide an overview of vaccine strategies and the current clinical trial landscape, with a focus on the only vaccine candidate that has reached phase III clinical development stage.
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Affiliation(s)
- Thomas D Burton
- Department of Microbiology and Immunology, University of Melbourne, within the Peter Doherty Institute for Infection and Immunity, Parkville, Melbourne, VIC, Australia
| | - Julio Carrera Montoya
- Department of Microbiology and Immunology, University of Melbourne, within the Peter Doherty Institute for Infection and Immunity, Parkville, Melbourne, VIC, Australia
| | - Thalia Frota
- Department of Microbiology and Immunology, University of Melbourne, within the Peter Doherty Institute for Infection and Immunity, Parkville, Melbourne, VIC, Australia
| | - Jason M Mackenzie
- Department of Microbiology and Immunology, University of Melbourne, within the Peter Doherty Institute for Infection and Immunity, Parkville, Melbourne, VIC, Australia.
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Paužuolis M, Samperio Ventayol P, Neyazi M, Bartfeld S. Organoids as a tool to study the impact of heterogeneity in gastrointestinal epithelium on host-pathogen interactions. Clin Exp Immunol 2024; 218:16-27. [PMID: 38245816 PMCID: PMC11404121 DOI: 10.1093/cei/uxae002] [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: 09/04/2023] [Revised: 11/17/2023] [Accepted: 01/19/2024] [Indexed: 01/22/2024] Open
Abstract
The epithelium of the gastrointestinal (GI) tract has been extensively characterized using advanced histological and RNA sequencing techniques, which has revealed great cellular diversity. Pathogens, such as viruses and bacteria, are highly adapted to their host and often exhibit not only species-specificity but also a preference or tropism for specific GI segments or even cell types-some of these preferences are so specific, that these pathogens still cannot be cultured invitro. Organoid technology now provides a tool to generate human cell types, which enables the study of host cell tropism. Focussing on the GI tract, we provide an overview about cellular differentiation in vivo and in organoids and how differentiation in organoids and their derived models is used to advance our understanding of viral, bacterial, and parasitic infection. We emphasize that it is central to understand the composition of the model, as the alteration of culture conditions yields different cell types which affects infection. We examine future directions for wider application of cellular heterogeneity and potential advanced model systems for GI tract infection studies.
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Affiliation(s)
- Mindaugas Paužuolis
- Research Centre for Infectious Diseases, Institute for Molecular Infection Biology, Julius Maximilians Universität Würzburg, Würzburg, Germany
| | | | - Mastura Neyazi
- Research Centre for Infectious Diseases, Institute for Molecular Infection Biology, Julius Maximilians Universität Würzburg, Würzburg, Germany
| | - Sina Bartfeld
- Research Centre for Infectious Diseases, Institute for Molecular Infection Biology, Julius Maximilians Universität Würzburg, Würzburg, Germany
- Institute of Biotechnology, Technische Universität Berlin, Berlin, Germany
- Si-M/‘Der Simulierte Mensch’, Technische Universität Berlin and Charité–Universitätsmedizin Berlin, Berlin, Germany
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Luo W, Wang L, Chen Z, Liu M, Zhao Y, Wu Y, Huang B, Wang P. Pathoimmunological analyses of fatal E11 infection in premature infants. Front Cell Infect Microbiol 2024; 14:1391824. [PMID: 39045132 PMCID: PMC11263194 DOI: 10.3389/fcimb.2024.1391824] [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: 02/26/2024] [Accepted: 06/27/2024] [Indexed: 07/25/2024] Open
Abstract
E11 causes acute fulminant hepatitis in newborns. We investigated the pathological changes of different tissues from premature male twins who died due to E11 infection. The E11 expression level was higher in the liver than in other tissues. IP10 was upregulated in liver tissue in the patient group, and might be regulated by IFNAR and IRF7, whereas IFNα was regulated by IFNAR or IRF5.
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Affiliation(s)
- Wei Luo
- Department of Neonatology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Lixia Wang
- College of Pediatrics, Guangzhou Medical University, Guangzhou, China
| | - Zhengrong Chen
- Department of Pathology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Ming Liu
- Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Yixue Zhao
- Department of Neonatology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Yucan Wu
- Department of Neonatology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Bing Huang
- Department of Gastroenterology, Guangdong Provincial Key Laboratory of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Ping Wang
- Department of Neonatology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China
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11
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Liu Y, Wang D, Luan Y, Tao B, Li Q, Feng Q, Zhou H, Mu J, Yu J. The application of organoids in colorectal diseases. Front Pharmacol 2024; 15:1412489. [PMID: 38983913 PMCID: PMC11231380 DOI: 10.3389/fphar.2024.1412489] [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: 04/05/2024] [Accepted: 06/07/2024] [Indexed: 07/11/2024] Open
Abstract
Intestinal organoids are a three-dimensional cell culture model derived from colon or pluripotent stem cells. Intestinal organoids constructed in vitro strongly mimic the colon epithelium in cell composition, tissue architecture, and specific functions, replicating the colon epithelium in an in vitro culture environment. As an emerging biomedical technology, organoid technology has unique advantages over traditional two-dimensional culture in preserving parental gene expression and mutation, cell function, and biological characteristics. It has shown great potential in the research and treatment of colorectal diseases. Organoid technology has been widely applied in research on colorectal topics, including intestinal tumors, inflammatory bowel disease, infectious diarrhea, and intestinal injury regeneration. This review focuses on the application of organoid technology in colorectal diseases, including the basic principles and preparation methods of organoids, and explores the pathogenesis of and personalized treatment plans for various colorectal diseases to provide a valuable reference for organoid technology development and application.
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Affiliation(s)
- Yanxin Liu
- Department of Gastric and Colorectal Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, China
| | - Dongxu Wang
- Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, China
| | - Yanhong Luan
- Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, China
| | - Boqiang Tao
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
| | - Qirong Li
- Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, China
| | - Qiang Feng
- Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, China
| | - Hengzong Zhou
- Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, China
| | - Jianfeng Mu
- Department of Gastric and Colorectal Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, China
| | - Jinhai Yu
- Department of Gastric and Colorectal Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, China
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Qiao W, Richards CM, Kim Y, Zengel JR, Ding S, Greenberg HB, Carette JE. MYADM binds human parechovirus 1 and is essential for viral entry. Nat Commun 2024; 15:3469. [PMID: 38658526 PMCID: PMC11043367 DOI: 10.1038/s41467-024-47825-0] [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: 08/08/2023] [Accepted: 04/11/2024] [Indexed: 04/26/2024] Open
Abstract
Human parechoviruses (PeV-A) are increasingly being recognized as a cause of infection in neonates and young infants, leading to a spectrum of clinical manifestations ranging from mild gastrointestinal and respiratory illnesses to severe sepsis and meningitis. However, the host factors required for parechovirus entry and infection remain poorly characterized. Here, using genome-wide CRISPR/Cas9 loss-of-function screens, we identify myeloid-associated differentiation marker (MYADM) as a host factor essential for the entry of several human parechovirus genotypes including PeV-A1, PeV-A2 and PeV-A3. Genetic knockout of MYADM confers resistance to PeV-A infection in cell lines and in human gastrointestinal epithelial organoids. Using immunoprecipitation, we show that MYADM binds to PeV-A1 particles via its fourth extracellular loop, and we identify critical amino acid residues within the loop that mediate binding and infection. The demonstrated interaction between MYADM and PeV-A1, and its importance specifically for viral entry, suggest that MYADM is a virus receptor. Knockout of MYADM does not reduce PeV-A1 attachment to cells pointing to a role at the post-attachment stage. Our study suggests that MYADM is a multi-genotype receptor for human parechoviruses with potential as an antiviral target to combat disease associated with emerging parechoviruses.
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Affiliation(s)
- Wenjie Qiao
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA
| | - Christopher M Richards
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA
| | - Youlim Kim
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA
| | - James R Zengel
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA
| | - Siyuan Ding
- Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, USA
| | - Harry B Greenberg
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
- Department of Veterans Affairs, VA Palo Alto Health Care System, Palo Alto, CA, USA
| | - Jan E Carette
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.
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13
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Hayashi T, Kobayashi S, Hirano J, Murakami K. Human norovirus cultivation systems and their use in antiviral research. J Virol 2024; 98:e0166323. [PMID: 38470106 PMCID: PMC11019851 DOI: 10.1128/jvi.01663-23] [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] [Indexed: 03/13/2024] Open
Abstract
Human norovirus (HuNoV) is a major cause of acute gastroenteritis and foodborne diseases, affecting all age groups. Despite its clinical needs, no approved antiviral therapies are available. Since the discovery of HuNoV in 1972, studies on anti-norovirals, mechanism of HuNoV infection, viral inactivation, etc., have been hampered by the lack of a robust laboratory-based cultivation system for HuNoV. A recent breakthrough in the development of HuNoV cultivation systems has opened opportunities for researchers to investigate HuNoV biology in the context of de novo HuNoV infections. A tissue stem cell-derived human intestinal organoid/enteroid (HIO) culture system is one of those that supports HuNoV replication reproducibly and, to our knowledge, is most widely distributed to laboratories worldwide to study HuNoV and develop therapeutic strategies. This review summarizes recently developed HuNoV cultivation systems, including HIO, and their use in antiviral studies.
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Affiliation(s)
- Tsuyoshi Hayashi
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Sakura Kobayashi
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Junki Hirano
- Laboratory of Virus Control, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
| | - Kosuke Murakami
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
- Center for Emergency Preparedness and Response, National Institute of Infectious Diseases, Tokyo, Japan
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14
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Chen Y, Chen Z, Zhu Y, Wen Y, Zhao C, Mu W. Recent Progress in Human Milk Oligosaccharides and Its Antiviral Efficacy. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:7607-7617. [PMID: 38563422 DOI: 10.1021/acs.jafc.3c09460] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/04/2024]
Abstract
Gastrointestinal (GI)-associated viruses, including rotavirus (RV), norovirus (NV), and enterovirus, usually invade host cells, transmit, and mutate their genetic information, resulting in influenza-like symptoms, acute gastroenteritis, encephalitis, or even death. The unique structures of human milk oligosaccharides (HMOs) enable them to shape the gut microbial diversity and endogenous immune system of human infants. Growing evidence suggests that HMOs can enhance host resistance to GI-associated viruses but without a systematic summary to review the mechanism. The present review examines the lactose- and neutral-core HMOs and their antiviral effects in the host. The potential negative impacts of enterovirus 71 (EV-A71) and other GI viruses on children are extensive and include neurological sequelae, neurodevelopmental retardation, and cognitive decline. However, the differences in the binding affinity of HMOs for GI viruses are vast. Hence, elucidating the mechanisms and positive effects of HMOs against different viruses may facilitate the development of novel HMO derived oligosaccharides.
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Affiliation(s)
- Yihan Chen
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi 214122, China
| | - Zhengxin Chen
- College of Food Science, Fujian Agriculture and Forestry University, Fuzhou 350002, China
| | - Yingying Zhu
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi 214122, China
| | - Yuxi Wen
- College of Marine Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China
- Department of Analytical and Food Chemistry, Faculty of Sciences, Universidade de Vigo, 32004 Ourense Spain
| | - Chao Zhao
- College of Marine Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China
| | - Wanmeng Mu
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi 214122, China
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15
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Jungbauer-Groznica M, Wiese K, Fischer I, Markus J, Chang TH, Gösler I, Kowalski H, Blaas D, Real-Hohn A. Aichivirus A1 replicates in human intestinal epithelium and bronchial tissue: Lung-gut axis? Virus Res 2024; 342:199338. [PMID: 38373599 PMCID: PMC10901855 DOI: 10.1016/j.virusres.2024.199338] [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: 12/28/2023] [Revised: 02/08/2024] [Accepted: 02/10/2024] [Indexed: 02/21/2024]
Abstract
The role of aichivirus A1 (AiV-A1) in acute gastroenteritis remains controversial and in vitro data illustrating its pathogenesis in suitable human models are scarce. Here, we demonstrate that AiV-A1 isolate A846/88 replicates in ApoA1- (absorptive) and Ki-67-positive (proliferative) enterocytes in stem cell-derived human small intestinal epithelium (HIE) as well as in patient biopsy samples, but not in any of the tested human cell lines. The infection did not result in tissue damage and did not trigger type I and type III interferon (IFN) signalling, whereas the control, human coxsackievirus B3 (strain Nancy), triggered both IFNs. To investigate the tissue tropism, we infected a human tracheal/bronchial epithelium model (HTBE) with AiV-A1 isolates A846/88 and kvgh99012632/2010 and, as a control, with rhinovirus A2 (RV-A2). AiV-A1 isolate kvgh99012632/2010, but not isolate A846/88, replicated in HTBE and induced type III IFN and ISGs signalling. By using various pharmacological inhibitors, we elaborated that cellular entry of AiV-A1 depends on clathrin, dynamin, and lipid rafts and is strongly reliant on endosome acidification. Viral particles co-localised with Rab5a-positive endosomes and promoted leakage of endosomal content. Our data shed light on the early events of AiV-A1 infection and reveal that different isolates exhibit distinct tissue tropism. This supports its clinical importance as a human pathogen with the potential to evolve toward broader tissue specificity.
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Affiliation(s)
- Martin Jungbauer-Groznica
- Center for Medical Biochemistry, Vienna Biocenter, Max Perutz Laboratories, Medical University of Vienna, Vienna, Austria; Virus and Immunity Unit, Institute Pasteur, Université Paris Cité, Paris, France
| | - Konstantin Wiese
- Center for Medical Biochemistry, Vienna Biocenter, Max Perutz Laboratories, Medical University of Vienna, Vienna, Austria
| | - Irmgard Fischer
- Histology Facility, Vienna Biocenter, Max Perutz Laboratories, Vienna, Austria
| | - Jan Markus
- MatTek In Vitro Life Science Laboratories, Bratislava, Slovakia
| | - Tsung-Hsien Chang
- National Defense Medical Center, Department of Microbiology and Immunology, Taipei, Taiwan
| | - Irene Gösler
- Center for Medical Biochemistry, Vienna Biocenter, Max Perutz Laboratories, Medical University of Vienna, Vienna, Austria
| | - Heinrich Kowalski
- Center for Medical Biochemistry, Vienna Biocenter, Max Perutz Laboratories, Medical University of Vienna, Vienna, Austria.
| | - Dieter Blaas
- Center for Medical Biochemistry, Vienna Biocenter, Max Perutz Laboratories, Medical University of Vienna, Vienna, Austria
| | - Antonio Real-Hohn
- Center for Medical Biochemistry, Vienna Biocenter, Max Perutz Laboratories, Medical University of Vienna, Vienna, Austria.
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16
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Roodsant TJ, van der Ark KC, Schultsz C. Translocation across a human enteroid monolayer by zoonotic Streptococcus suis correlates with the presence of Gb3-positive cells. iScience 2024; 27:109178. [PMID: 38439959 PMCID: PMC10909756 DOI: 10.1016/j.isci.2024.109178] [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: 04/26/2023] [Revised: 11/14/2023] [Accepted: 02/06/2024] [Indexed: 03/06/2024] Open
Abstract
Streptococcus suis is a zoonotic pathogen that can cause meningitis and septicaemia. The consumption of undercooked pig products is an important risk factor for zoonotic infections, suggesting an oral route of infection. In a human enteroid model, we show that the zoonotic CC1 genotype has a 40% higher translocation frequency than the non-zoonotic CC16 genotype. Translocation occurred without increasing the permeability or disrupting the adherens junctions and tight junctions of the epithelial monolayer. The translocation of zoonotic S. suis was correlated with the presence of Gb3-positive cells, a human glycolipid receptor found on Paneth cells and targeted by multiple enteric pathogens. The virulence factors Streptococcal adhesin Protein and suilysin, known to interact with Gb3, were not essential for translocation in our epithelial model. Thus, the ability to translocate across an enteroid monolayer correlates with S. suis core genome composition and the presence of Gb3-positive cells in the intestinal epithelium.
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Affiliation(s)
- Thomas J. Roodsant
- Amsterdam UMC, Location University of Amsterdam, Department of Global Health, Amsterdam Institute for Global Health and Development, Meibergdreef 9, Amsterdam, the Netherlands
- Amsterdam UMC, Location University of Amsterdam, Department of Medical Microbiology and Infection Prevention, Meibergdreef 9, Amsterdam, the Netherlands
| | - Kees C.H. van der Ark
- Amsterdam UMC, Location University of Amsterdam, Department of Global Health, Amsterdam Institute for Global Health and Development, Meibergdreef 9, Amsterdam, the Netherlands
- Amsterdam UMC, Location University of Amsterdam, Department of Medical Microbiology and Infection Prevention, Meibergdreef 9, Amsterdam, the Netherlands
| | - Constance Schultsz
- Amsterdam UMC, Location University of Amsterdam, Department of Global Health, Amsterdam Institute for Global Health and Development, Meibergdreef 9, Amsterdam, the Netherlands
- Amsterdam UMC, Location University of Amsterdam, Department of Medical Microbiology and Infection Prevention, Meibergdreef 9, Amsterdam, the Netherlands
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17
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Chu JTS, Lamers MM. Organoids in virology. NPJ VIRUSES 2024; 2:5. [PMID: 40295690 PMCID: PMC11721363 DOI: 10.1038/s44298-024-00017-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Accepted: 01/04/2024] [Indexed: 04/30/2025]
Abstract
To adequately prepare against imminent disease outbreaks from diverse and ever-changing viral pathogens, improved experimental models that can accurately recapitulate host-virus responses and disease pathogenesis in human are essential. Organoid platforms have emerged in recent years as amenable in vitro tools that can bridge the limitations of traditional 2D cell lines and animal models for viral disease research. We highlight in this review the key insights that have contributed by organoid models to virus research, the limitations that exist in current platforms, and outline novel approaches that are being applied to address these shortcomings.
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Affiliation(s)
- Julie T S Chu
- Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore, Singapore
| | - Mart M Lamers
- Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore, Singapore.
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18
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Torii S, David SC, Larivé O, Cariti F, Kohn T. Observed Kinetics of Enterovirus Inactivation by Free Chlorine Are Host Cell-Dependent. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2023; 57:18483-18490. [PMID: 36649532 DOI: 10.1021/acs.est.2c07048] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/17/2023]
Abstract
Virucidal efficacies of disinfectants are typically assessed by infectivity assay utilizing a single type of host cell. Enteroviruses infect multiple host cells via various entry routes, and each entry route may be impaired differently by a given disinfectant. Yet, it is unknown how the choice of host cells affects the observed inactivation kinetics. Here, we evaluated the inactivation kinetics of echovirus 11 (E11) by free chlorine, ultraviolet (UV) irradiation, and heat, using three different host cells (BGMK, RD, and A549). Inactivation rates were independent of the host cell for treatment of E11 by UV or heat. Conversely, E11 inactivation by free chlorine occurred 2-fold faster when enumerated on BGMK cells compared with RD and A549 cells. Host cell-dependent inactivation kinetics by free chlorine were also observed for echovirus 7, 9, and 13, and coxsackievirus A9. E11 inactivation by free chlorine was partly caused by a loss in host cell attachment, which was most pronounced for BGMK cells. BGMK cells lack the attachment receptor CD55 and a key subunit of the uncoating receptor β2M, which may contribute to the differential inactivation kinetics for this cell type. Consequently, inactivation kinetics of enteroviruses should be assessed using host cells with different receptor profiles.
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Affiliation(s)
- Shotaro Torii
- Laboratory of Environmental Chemistry, School of Architecture, Civil and Environmental Engineering (ENAC), École Polytechnique Fédérale de Lausanne (EPFL), CH-1015Lausanne, Switzerland
| | - Shannon Christa David
- Laboratory of Environmental Chemistry, School of Architecture, Civil and Environmental Engineering (ENAC), École Polytechnique Fédérale de Lausanne (EPFL), CH-1015Lausanne, Switzerland
| | - Odile Larivé
- Laboratory of Environmental Chemistry, School of Architecture, Civil and Environmental Engineering (ENAC), École Polytechnique Fédérale de Lausanne (EPFL), CH-1015Lausanne, Switzerland
| | - Federica Cariti
- Laboratory of Environmental Chemistry, School of Architecture, Civil and Environmental Engineering (ENAC), École Polytechnique Fédérale de Lausanne (EPFL), CH-1015Lausanne, Switzerland
| | - Tamar Kohn
- Laboratory of Environmental Chemistry, School of Architecture, Civil and Environmental Engineering (ENAC), École Polytechnique Fédérale de Lausanne (EPFL), CH-1015Lausanne, Switzerland
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19
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Adeniyi-Ipadeola G, Nwanosike H, Ramani S. Human intestinal organoids as models to study enteric bacteria and viruses. Curr Opin Microbiol 2023; 75:102362. [PMID: 37536261 PMCID: PMC10529792 DOI: 10.1016/j.mib.2023.102362] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 07/03/2023] [Accepted: 07/04/2023] [Indexed: 08/05/2023]
Abstract
Laboratory studies of host-microbe interactions have historically been carried out using transformed cell lines and animal models. Although much has been learned from these models, recent advances in the development of multicellular, physiologically active, human intestinal organoid (HIO) cultures are allowing unprecedented discoveries of host-microbe interactions. Here, we review recent literature using HIOs as models to investigate the pathogenesis of clinically important enteric bacteria and viruses and study commensal intestinal microbes. We also discuss limitations of current HIO culture systems and how technical advances and innovative engineering approaches are providing new directions to improve the model. The studies discussed here highlight the potential of HIOs for studying microbial pathogenesis, host-microbe interactions, and for preclinical development of therapeutics and vaccines.
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Affiliation(s)
- Grace Adeniyi-Ipadeola
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA
| | - Hephzibah Nwanosike
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA
| | - Sasirekha Ramani
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA.
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20
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Moreni G, van Eijk H, Koen G, Johannesson N, Calitz C, Benschop K, Cremer J, Pajkrt D, Sridhar A, Wolthers K. Non-Polio Enterovirus C Replicate in Both Airway and Intestine Organotypic Cultures. Viruses 2023; 15:1823. [PMID: 37766230 PMCID: PMC10537321 DOI: 10.3390/v15091823] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Revised: 08/22/2023] [Accepted: 08/25/2023] [Indexed: 09/29/2023] Open
Abstract
Non-polio enteroviruses (EV) belonging to species C, which are highly prevalent in Africa, mainly among children, are poorly characterized, and their pathogenesis is mostly unknown as they are difficult to culture. In this study, human airway and intestinal organotypic models were used to investigate tissue and cellular tropism of three EV-C genotypes, EV-C99, CVA-13, and CVA-20. Clinical isolates were obtained within the two passages of culture on Caco2 cells, and all three viruses were replicated in both the human airway and intestinal organotypic cultures. We did not observe differences in viral replication between fetal and adult tissue that could potentially explain the preferential infection of infants by EV-C genotypes. Infection of the airway and the intestinal cultures indicates that they both can serve as entry sites for non-polio EV-C. Ciliated airway cells and enterocytes are the target of infection for all three viruses, as well as enteroendocrine cells for EV-C99.
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Affiliation(s)
- Giulia Moreni
- OrganoVIR Labs, Department of Medical Microbiology, Amsterdam UMC, Location AMC, Amsterdam Institute for Infection and Immunity, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; (H.v.E.); (G.K.); (N.J.); (C.C.); (A.S.); (K.W.)
- OrganoVIR Labs, Department of Pediatric Infectious Diseases, Emma Children’s Hospital, Amsterdam UMC, Location AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands;
| | - Hetty van Eijk
- OrganoVIR Labs, Department of Medical Microbiology, Amsterdam UMC, Location AMC, Amsterdam Institute for Infection and Immunity, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; (H.v.E.); (G.K.); (N.J.); (C.C.); (A.S.); (K.W.)
| | - Gerrit Koen
- OrganoVIR Labs, Department of Medical Microbiology, Amsterdam UMC, Location AMC, Amsterdam Institute for Infection and Immunity, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; (H.v.E.); (G.K.); (N.J.); (C.C.); (A.S.); (K.W.)
| | - Nina Johannesson
- OrganoVIR Labs, Department of Medical Microbiology, Amsterdam UMC, Location AMC, Amsterdam Institute for Infection and Immunity, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; (H.v.E.); (G.K.); (N.J.); (C.C.); (A.S.); (K.W.)
- OrganoVIR Labs, Department of Pediatric Infectious Diseases, Emma Children’s Hospital, Amsterdam UMC, Location AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands;
| | - Carlemi Calitz
- OrganoVIR Labs, Department of Medical Microbiology, Amsterdam UMC, Location AMC, Amsterdam Institute for Infection and Immunity, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; (H.v.E.); (G.K.); (N.J.); (C.C.); (A.S.); (K.W.)
- OrganoVIR Labs, Department of Pediatric Infectious Diseases, Emma Children’s Hospital, Amsterdam UMC, Location AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands;
| | - Kimberley Benschop
- National Institute for Public Health and Environment, RIVM, 3721 MA Bilthoven, The Netherlands; (K.B.); (J.C.)
| | - Jeroen Cremer
- National Institute for Public Health and Environment, RIVM, 3721 MA Bilthoven, The Netherlands; (K.B.); (J.C.)
| | - Dasja Pajkrt
- OrganoVIR Labs, Department of Pediatric Infectious Diseases, Emma Children’s Hospital, Amsterdam UMC, Location AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands;
| | - Adithya Sridhar
- OrganoVIR Labs, Department of Medical Microbiology, Amsterdam UMC, Location AMC, Amsterdam Institute for Infection and Immunity, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; (H.v.E.); (G.K.); (N.J.); (C.C.); (A.S.); (K.W.)
- OrganoVIR Labs, Department of Pediatric Infectious Diseases, Emma Children’s Hospital, Amsterdam UMC, Location AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands;
| | - Katja Wolthers
- OrganoVIR Labs, Department of Medical Microbiology, Amsterdam UMC, Location AMC, Amsterdam Institute for Infection and Immunity, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; (H.v.E.); (G.K.); (N.J.); (C.C.); (A.S.); (K.W.)
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21
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de Oliveira LF, Filho DM, Marques BL, Maciel GF, Parreira RC, do Carmo Neto JR, Da Silva PEF, Guerra RO, da Silva MV, Santiago HDC, Birbrair A, Kihara AH, Dias da Silva VJ, Glaser T, Resende RR, Ulrich H. Organoids as a novel tool in modelling infectious diseases. Semin Cell Dev Biol 2023; 144:87-96. [PMID: 36182613 DOI: 10.1016/j.semcdb.2022.09.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Accepted: 09/04/2022] [Indexed: 11/23/2022]
Abstract
Infectious diseases worldwide affect human health and have important societal impacts. A better understanding of infectious diseases is urgently needed. In vitro and in vivo infection models have brought notable contributions to the current knowledge of these diseases. Organoids are multicellular culture systems resembling tissue architecture and function, recapitulating many characteristics of human disease and elucidating mechanisms of host-infectious agent interactions in the respiratory and gastrointestinal systems, the central nervous system and the skin. Here, we discuss the applicability of the organoid technology for modeling pathogenesis, host response and features, which can be explored for the development of preventive and therapeutic treatments.
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Affiliation(s)
- Lucas Felipe de Oliveira
- Departamento de Fisiologia, Instituto de Ciências Biológicas e Naturais, Universidade Federal do Triângulo Mineiro, Uberaba, MG, Brazil; Instituto Nacional de Ciência e Tecnologia de Medicina Regenerativa, Rio de Janeiro, RJ, Brazil
| | - Daniel Mendes Filho
- Departamento de Fisiologia, Escola Médica de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil
| | - Bruno Lemes Marques
- Departamento de Farmacologia, Instituto de Ciências Biológicas, Universidade Federal deGoiás, Goiânia, GO, Brazil
| | | | | | - José Rodrigues do Carmo Neto
- Departamento de Biociência e Tecnologia, Instituto de Patologia Tropical e Saúde Pública, Universidade Federal de Goiás, Goiânia, GO, Brazil
| | | | - Rhanoica Oliveira Guerra
- Departamento de Microbiologia, Imunologia eParasitologia, Instituto de Ciências Naturais e Biológicas, Universidade Federal do Triângulo Mineiro, Uberaba, MG, Brazil
| | - Marcos Vinicius da Silva
- Departamento de Microbiologia, Imunologia eParasitologia, Instituto de Ciências Naturais e Biológicas, Universidade Federal do Triângulo Mineiro, Uberaba, MG, Brazil
| | - Helton da Costa Santiago
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Belo Horizonte, MG, Brazil
| | - Alexander Birbrair
- Department of Dermatology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA; Department of Radiology, Columbia University Medical Center, New York, NY, USA; Departamento de Patologia, Instituto de Ciências Biológicas, Universidade Federal de Belo Horizonte, MG, Brazil
| | - Alexandre H Kihara
- Laboratório de Neurogenética, Universidade Federal do ABC, São Bernardo do Campo, SP, Brazil
| | - Valdo José Dias da Silva
- Departamento de Fisiologia, Instituto de Ciências Biológicas e Naturais, Universidade Federal do Triângulo Mineiro, Uberaba, MG, Brazil; Instituto Nacional de Ciência e Tecnologia de Medicina Regenerativa, Rio de Janeiro, RJ, Brazil
| | - Talita Glaser
- Departmento de Bioquímica, Instituto de Química, Universidade de São Paulo, SP, Brazil
| | - Rodrigo R Resende
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Belo Horizonte, MG, Brazil
| | - Henning Ulrich
- Instituto Nacional de Ciência e Tecnologia de Medicina Regenerativa, Rio de Janeiro, RJ, Brazil; Departmento de Bioquímica, Instituto de Química, Universidade de São Paulo, SP, Brazil.
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22
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Andres SF, Zhang Y, Kuhn M, Scottoline B. Building better barriers: how nutrition and undernutrition impact pediatric intestinal health. Front Immunol 2023; 14:1192936. [PMID: 37545496 PMCID: PMC10401430 DOI: 10.3389/fimmu.2023.1192936] [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: 03/24/2023] [Accepted: 06/26/2023] [Indexed: 08/08/2023] Open
Abstract
Chronic undernutrition is a major cause of death for children under five, leaving survivors at risk for adverse long-term consequences. This review focuses on the role of nutrients in normal intestinal development and function, from the intestinal epithelium, to the closely-associated mucosal immune system and intestinal microbiota. We examine what is known about the impacts of undernutrition on intestinal physiology, with focus again on the same systems. We provide a discussion of existing animal models of undernutrition, and review the evidence demonstrating that correcting undernutrition alone does not fully ameliorate effects on intestinal function, the microbiome, or growth. We review efforts to treat undernutrition that incorporate data indicating that improved recovery is possible with interventions focused not only on delivery of sufficient energy, macronutrients, and micronutrients, but also on efforts to correct the abnormal intestinal microbiome that is a consequence of undernutrition. Understanding of the role of the intestinal microbiome in the undernourished state and correction of the phenotype is both complex and a subject that holds great potential to improve recovery. We conclude with critical unanswered questions in the field, including the need for greater mechanistic research, improved models for the impacts of undernourishment, and new interventions that incorporate recent research gains. This review highlights the importance of understanding the mechanistic effects of undernutrition on the intestinal ecosystem to better treat and improve long-term outcomes for survivors.
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Affiliation(s)
- Sarah F. Andres
- Division of Pediatric Gastroenterology, Department of Pediatrics, Oregon Health and Science University, Portland, OR, United States
| | - Yang Zhang
- Division of Pediatric Gastroenterology, Department of Pediatrics, Oregon Health and Science University, Portland, OR, United States
| | - Madeline Kuhn
- Division of Pediatric Gastroenterology, Department of Pediatrics, Oregon Health and Science University, Portland, OR, United States
| | - Brian Scottoline
- Division of Neonatology, Department of Pediatrics, Oregon Health and Science University, Portland, OR, United States
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Liang Y, Chen J, Wang C, Yu B, Zhang Y, Liu Z. Investigating the mechanism of Echovirus 30 cell invasion. Front Microbiol 2023; 14:1174410. [PMID: 37485505 PMCID: PMC10359910 DOI: 10.3389/fmicb.2023.1174410] [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: 02/26/2023] [Accepted: 06/23/2023] [Indexed: 07/25/2023] Open
Abstract
Viruses invade susceptible cells through a complex mechanism before injecting their genetic material into them. This causes direct damage to the host cell, as well as resulting in disease in the corresponding system. Echovirus type 30 (E30) is a member of the Enterovirus B group and has recently been reported to cause central nervous system (CNS) disorders, leading to viral encephalitis and viral meningitis in children. In this review, we aim to help in improving the understanding of the mechanisms of CNS diseases caused by E30 for the subsequent development of relevant drugs and vaccines.
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Affiliation(s)
- Yucai Liang
- Department of Microbiology, Weifang Medical University, Weifang, China
| | - Junbing Chen
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, Beijing, China
| | - Congcong Wang
- Department of Microbiology, Weifang Medical University, Weifang, China
| | - Bowen Yu
- Department of Immunology, Weifang Medical University, Weifang, China
| | - Yong Zhang
- National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Zhijun Liu
- Department of Microbiology, Weifang Medical University, Weifang, China
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Toprak K, Inanır M, Memioğlu T, Kaplangoray M, Palice A, Tascanov MB. Could Zonulin and Presepsin Be Biomarkers and Therapeutic Targets for Acute Myocarditis? Arq Bras Cardiol 2023; 120:e20230017. [PMID: 37556677 PMCID: PMC10464857 DOI: 10.36660/abc.20230017] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 04/28/2023] [Accepted: 05/17/2023] [Indexed: 08/11/2023] Open
Abstract
BACKGROUND The diagnosis of acute myocarditis is usually made with clinical and laboratory parameters. This can sometimes be mixed up with diseases that have similar clinical features, making the diagnosis difficult. Therefore, the use of more specific biomarkers, in addition to the classically used biomarkers such as troponin, will accelerate the diagnosis. In addition, these biomarkers may help us to understand the mechanism of myocarditis development and thus predict unpredictable clinical outcomes. OBJECTIVE This study aims to reveal the possible relationship between intestinal permeability and acute myocarditis. METHODS In this study, we wanted to evaluate serum levels of zonulin and presepsin in 138 consecutive subjects, including 68 patients with myocarditis and another 70 as the control group, matched for age, gender, and cardiovascular risk factors. P-values <0.05 were considered to be statistically significant. RESULTS Compared to the control group, zonulin and presepsin were significantly higher in the patient group with myocarditis (p < 0.001, for all). Zonulin levels were positively correlated with presepsin, peak CK-MB, and peak troponin levels (r = 0.461, p < 0.001; r = 0.744, p < 0.001; r = 0.627, p < 0.001; respectively). In regression analysis, presepsin and zonulin were determined as independent predictors for myocarditis (OR 1.002, 95% CI 1.001-1.003, p = 0.025; OR 12.331, 95% CI 4.261-35.689; p < 0.001; respectively). The predictive value of acute myocarditis of presepsin and zonulin in ROC curve analysis was statistically significant (p < 0.001, for both). CONCLUSION This study showed that zonulin and presepsin could be biomarkers that can be used in the diagnosis of myocarditis, and they can also be therapeutic targets by shedding light on the developmental mechanism of myocarditis.
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Affiliation(s)
- Kenan Toprak
- Harran UniversityFaculty of MedicineDepartment of CardiologySanliurfaTurquiaHarran University Faculty of Medicine – Department of Cardiology, Sanliurfa – Turquia
| | - Mehmet Inanır
- Abant Izzet Baysal University HospitalBoluTurquiaAbant Izzet Baysal University Hospital – Cardiology, Bolu – Turquia
| | - Tolga Memioğlu
- Abant Izzet Baysal University HospitalBoluTurquiaAbant Izzet Baysal University Hospital – Cardiology, Bolu – Turquia
| | - Mustafa Kaplangoray
- Sanliurfa Mehmet Akif Inan Training and ResearchSanliurfaTurquiaSanliurfa Mehmet Akif Inan Training and Research – Cardiology, Sanliurfa – Turquia
| | - Ali Palice
- Sanliurfa Mehmet Akif Inan Training and ResearchSanliurfaTurquiaSanliurfa Mehmet Akif Inan Training and Research – Cardiology, Sanliurfa – Turquia
| | - Mustafa Begenc Tascanov
- Harran UniversityFaculty of MedicineDepartment of CardiologySanliurfaTurquiaHarran University Faculty of Medicine – Department of Cardiology, Sanliurfa – Turquia
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25
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Masmoudi F, Santos-Ferreira N, Pajkrt D, Wolthers KC, DeGroot J, Vlaming MLH, Rocha-Pereira J, Buti L. Evaluation of 3D Human Intestinal Organoids as a Platform for EV-A71 Antiviral Drug Discovery. Cells 2023; 12:cells12081138. [PMID: 37190047 DOI: 10.3390/cells12081138] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 03/24/2023] [Accepted: 04/07/2023] [Indexed: 05/17/2023] Open
Abstract
Enteroviruses are a leading cause of upper respiratory tract, gastrointestinal, and neurological infections. Management of enterovirus-related diseases has been hindered by the lack of specific antiviral treatment. The pre-clinical and clinical development of such antivirals has been challenging, calling for novel model systems and strategies to identify suitable pre-clinical candidates. Organoids represent a new and outstanding opportunity to test antiviral agents in a more physiologically relevant system. However, dedicated studies addressing the validation and direct comparison of organoids versus commonly used cell lines are lacking. Here, we described the use of human small intestinal organoids (HIOs) as a model to study antiviral treatment against human enterovirus 71 (EV-A71) infection and compared this model to EV-A71-infected RD cells. We used reference antiviral compounds such as enviroxime, rupintrivir, and 2'-C-methylcytidine (2'CMC) to assess their effects on cell viability, virus-induced cytopathic effect, and viral RNA yield in EV-A71-infected HIOs and cell line. The results indicated a difference in the activity of the tested compounds between the two models, with HIOs being more sensitive to infection and drug treatment. In conclusion, the outcome reveals the value added by using the organoid model in virus and antiviral studies.
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Affiliation(s)
- Fatma Masmoudi
- Charles River Laboratories, 2333 CR Leiden, The Netherlands
- OrganoVIR Labs, Department of Medical Microbiology, Amsterdam UMC Location Academic Medical Center, Amsterdam Institute for Infection and Immunity, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
| | - Nanci Santos-Ferreira
- Laboratory of Virology and Chemotherapy, KU Leuven-Department of Microbiology, Immunology and Transplantation, Rega Institute, 3000 Leuven, Belgium
| | - Dasja Pajkrt
- OrganoVIR Labs, Pediatric Infectious Diseases, Emma Children's Hospital, Amsterdam UMC Location University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
| | - Katja C Wolthers
- OrganoVIR Labs, Department of Medical Microbiology, Amsterdam UMC Location Academic Medical Center, Amsterdam Institute for Infection and Immunity, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
| | - Jeroen DeGroot
- Charles River Laboratories, 2333 CR Leiden, The Netherlands
| | | | - Joana Rocha-Pereira
- Laboratory of Virology and Chemotherapy, KU Leuven-Department of Microbiology, Immunology and Transplantation, Rega Institute, 3000 Leuven, Belgium
| | - Ludovico Buti
- Charles River Laboratories, 2333 CR Leiden, The Netherlands
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26
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Wang P, Xu Y, Liu M, Li H, Wang H, Liu Y, Wang B, Xia S, Su H, Wei M, Tao L, Chen X, Lu B, Gu X, Lyu H, Zhou W, Zhang H, Gong S. Risk factors and early markers for echovirus type 11 associated haemorrhage-hepatitis syndrome in neonates, a retrospective cohort study. Front Pediatr 2023; 11:1063558. [PMID: 37090924 PMCID: PMC10117901 DOI: 10.3389/fped.2023.1063558] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Accepted: 03/14/2023] [Indexed: 04/25/2023] Open
Abstract
Background Echovirus type 11(E-11) can cause fatal haemorrhage-hepatitis syndrome in neonates. This study aims to investigate clinical risk factors and early markers of E-11 associated neonatal haemorrhage-hepatitis syndrome. Methods This is a multicentre retrospective cohort study of 105 neonates with E-11 infection in China. Patients with haemorrhage-hepatitis syndrome (the severe group) were compared with those with mild disease. Clinical risk factors and early markers of haemorrhage-hepatitis syndrome were analysed. In addition, cytokine analysis were performed in selective patients to explore the immune responses. Results In addition to prematurity, low birth weight, premature rupture of fetal membrane, total parenteral nutrition (PN) (OR, 28.7; 95% CI, 2.8-295.1) and partial PN (OR, 12.9; 95% CI, 2.2-77.5) prior to the onset of disease were identified as risk factors of developing haemorrhage-hepatitis syndrome. Progressive decrease in haemoglobin levels (per 10 g/L; OR, 1.5; 95% CI, 1.1-2.0) and platelet (PLT) < 140 × 10⁹/L at early stage of illness (OR, 17.7; 95% CI, 1.4-221.5) were associated with the development of haemorrhage-hepatitis syndrome. Immunological workup revealed significantly increased interferon-inducible protein-10(IP-10) (P < 0.0005) but decreased IFN-α (P < 0.05) in peripheral blood in severe patients compared with the mild cases. Conclusions PN may potentiate the development of E-11 associated haemorrhage-hepatitis syndrome. Early onset of thrombocytopenia and decreased haemoglobin could be helpful in early identification of neonates with the disease. The low level of IFN-α and elevated expression of IP-10 may promote the progression of haemorrhage-hepatitis syndrome.
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Affiliation(s)
- Ping Wang
- Division of Neonatology and Center for Newborn Care, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Yi Xu
- Division of Infectious Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Ming Liu
- Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Huixian Li
- Data Center, Guangdong Provincial People's Hospital, Guangzhou, China
| | - Hui Wang
- Division of Neonatology, Tongji Medical College, Maternal and Child Health Hospital of Hubei Province, Huazhong University of Science and Technology, Wuhan, China
| | - Yumei Liu
- Division of Neonatology, Guangdong Provincial People's Hospital, Guangzhou, China
| | - Bin Wang
- Division of Neonatology, Zhujiang Hospital of Southern Medical University, Guangzhou, China
| | - Shiwen Xia
- Division of Neonatology, Tongji Medical College, Maternal and Child Health Hospital of Hubei Province, Huazhong University of Science and Technology, Wuhan, China
| | - Heng Su
- Division of Neonatology and Center for Newborn Care, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Mou Wei
- Division of Neonatology and Center for Newborn Care, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Li Tao
- Division of Neonatology and Center for Newborn Care, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Xiaowen Chen
- Division of Neonatology and Center for Newborn Care, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Bingtai Lu
- Medical Research Center of Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Xiaoqiong Gu
- Department of Clinical Laboratory, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Hui Lyu
- Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Wei Zhou
- Division of Neonatology and Center for Newborn Care, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Huayan Zhang
- Division of Neonatology and Center for Newborn Care, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
- Division of Neonatology, Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, United States
| | - Sitang Gong
- Division of Gestroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
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Moshiri J, Craven AR, Mixon SB, Amieva MR, Kirkegaard K. Mechanosensitive extrusion of Enterovirus A71-infected cells from colonic organoids. Nat Microbiol 2023; 8:629-639. [PMID: 36914754 PMCID: PMC10066035 DOI: 10.1038/s41564-023-01339-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Accepted: 02/10/2023] [Indexed: 03/16/2023]
Abstract
Enterovirus A71 causes severe disease upon systemic infection, sometimes leading to life-threatening neurological dysfunction. However, in most cases infection is asymptomatic and limited to the gastrointestinal tract, where virus is amplified for transmission. Picornaviruses have previously been shown to exit infected cells via either cell lysis or secretion of vesicles. Here we report that entire Enterovirus A71-infected cells are specifically extruded from the apical surface of differentiated human colon organoids, as observed by confocal microscopy. Differential sensitivity to chemical and peptide inhibitors demonstrated that extrusion of virus-infected cells is dependent on force sensing via mechanosensitive ion channels rather than apoptotic cell death. When isolated and used as inoculum, intact virus-containing extruded cells can initiate new infections. In contrast, when mechanical force sensing is inhibited, large amounts of free virus are released. Thus, extrusion of live, virus-infected cells from intact epithelial tissue is likely to benefit both the integrity of host tissues and the protected spread of this faecal-oral pathogen within and between hosts.
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Affiliation(s)
- Jasmine Moshiri
- Department of Microbiology and Immunology, Stanford University, Stanford, CA, USA
| | - Ailsa R Craven
- Department of Genetics, Stanford University, Stanford, CA, USA
| | - Sara B Mixon
- Department of Genetics, Stanford University, Stanford, CA, USA
| | - Manuel R Amieva
- Department of Microbiology and Immunology, Stanford University, Stanford, CA, USA
- Department of Pediatrics, Stanford University, Stanford, CA, USA
| | - Karla Kirkegaard
- Department of Microbiology and Immunology, Stanford University, Stanford, CA, USA.
- Department of Genetics, Stanford University, Stanford, CA, USA.
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28
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Shakya R, Jiménez-Meléndez A, Robertson LJ, Myrmel M. Bovine Enteroids as an In Vitro Model for Infection with Bovine Coronavirus. Viruses 2023; 15:635. [PMID: 36992344 PMCID: PMC10054012 DOI: 10.3390/v15030635] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 02/24/2023] [Accepted: 02/24/2023] [Indexed: 03/02/2023] Open
Abstract
Bovine coronavirus (BCoV) is one of the major viral pathogens of cattle, responsible for economic losses and causing a substantial impact on animal welfare. Several in vitro 2D models have been used to investigate BCoV infection and its pathogenesis. However, 3D enteroids are likely to be a better model with which to investigate host-pathogen interactions. This study established bovine enteroids as an in vitro replication system for BCoV, and we compared the expression of selected genes during the BCoV infection of the enteroids with the expression previously described in HCT-8 cells. The enteroids were successfully established from bovine ileum and permissive to BCoV, as shown by a seven-fold increase in viral RNA after 72 h. Immunostaining of differentiation markers showed a mixed population of differentiated cells. Gene expression ratios at 72 h showed that pro-inflammatory responses such as IL-8 and IL-1A remained unchanged in response to BCoV infection. Expression of other immune genes, including CXCL-3, MMP13, and TNF-α, was significantly downregulated. This study shows that the bovine enteroids had a differentiated cell population and were permissive to BCoV. Further studies are necessary for a comparative analysis to determine whether enteroids are suitable in vitro models to study host responses during BCoV infection.
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Affiliation(s)
| | | | | | - Mette Myrmel
- Department of Paraclinical Sciences, Faculty of Veterinary Medicine, Norwegian University of Life Sciences (NMBU), 1430 Ås, Norway
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29
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Zhu P, Ji W, Li D, Li Z, Chen Y, Dai B, Han S, Chen S, Jin Y, Duan G. Current status of hand-foot-and-mouth disease. J Biomed Sci 2023; 30:15. [PMID: 36829162 PMCID: PMC9951172 DOI: 10.1186/s12929-023-00908-4] [Citation(s) in RCA: 85] [Impact Index Per Article: 42.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Accepted: 02/16/2023] [Indexed: 02/26/2023] Open
Abstract
Hand-foot-and-mouth disease (HFMD) is a viral illness commonly seen in young children under 5 years of age, characterized by typical manifestations such as oral herpes and rashes on the hands and feet. These symptoms typically resolve spontaneously within a few days without complications. Over the past two decades, our understanding of HFMD has greatly improved and it has received significant attention. A variety of research studies, including epidemiological, animal, and in vitro studies, suggest that the disease may be associated with potentially fatal neurological complications. These findings reveal clinical, epidemiological, pathological, and etiological characteristics that are quite different from initial understandings of the illness. It is important to note that HFMD has been linked to severe cardiopulmonary complications, as well as severe neurological sequelae that can be observed during follow-up. At present, there is no specific pharmaceutical intervention for HFMD. An inactivated Enterovirus A71 (EV-A71) vaccine that has been approved by the China Food and Drug Administration (CFDA) has been shown to provide a high level of protection against EV-A71-related HFMD. However, the simultaneous circulation of multiple pathogens and the evolution of the molecular epidemiology of infectious agents make interventions based solely on a single agent comparatively inadequate. Enteroviruses are highly contagious and have a predilection for the nervous system, particularly in child populations, which contributes to the ongoing outbreak. Given the substantial impact of HFMD around the world, this Review synthesizes the current knowledge of the virology, epidemiology, pathogenesis, therapy, sequelae, and vaccine development of HFMD to improve clinical practices and public health efforts.
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Affiliation(s)
- Peiyu Zhu
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou, 450001, China
| | - Wangquan Ji
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou, 450001, China
| | - Dong Li
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou, 450001, China
| | - Zijie Li
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou, 450001, China
| | - Yu Chen
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou, 450001, China
| | - Bowen Dai
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou, 450001, China
| | - Shujie Han
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou, 450001, China
| | - Shuaiyin Chen
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou, 450001, China
| | - Yuefei Jin
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou, 450001, China.
| | - Guangcai Duan
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou, 450001, China.
- Academy of Medical Science, Zhengzhou University, Zhengzhou, 450001, Henan, China.
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Gebert JT, Scribano F, Engevik KA, Perry JL, Hyser JM. Gastrointestinal organoids in the study of viral infections. Am J Physiol Gastrointest Liver Physiol 2023; 324:G51-G59. [PMID: 36414538 PMCID: PMC9799139 DOI: 10.1152/ajpgi.00152.2022] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 11/04/2022] [Accepted: 11/14/2022] [Indexed: 11/24/2022]
Abstract
Viruses are among the most prevalent enteric pathogens. Although virologists historically relied on cell lines and animal models, human intestinal organoids (HIOs) continue to grow in popularity. HIOs are nontransformed, stem cell-derived, ex vivo cell cultures that maintain the cell type diversity of the intestinal epithelium. They offer higher throughput than standard animal models while more accurately mimicking the native tissue of infection than transformed cell lines. Here, we review recent literature that highlights virological advances facilitated by HIOs. We discuss the variations and limitations of HIOs, how HIOs have allowed for the cultivation of previously uncultivatable viruses, and how they have offered insight into tropism, entry, replication kinetics, and host-pathogen interactions. In each case, we discuss exemplary viruses and archetypal studies. We discuss how the speed and flexibility of HIO-based studies contributed to our knowledge of SARS-CoV-2 and antiviral therapeutics. Finally, we discuss the current limitations of HIOs and future directions to overcome these.
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Affiliation(s)
- J Thomas Gebert
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas
| | - Francesca Scribano
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas
| | - Kristen A Engevik
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas
| | - Jacob L Perry
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas
| | - Joseph M Hyser
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas
- Center for Metagenomics and Microbiome Research, Baylor College of Medicine, Houston, Texas
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Identification and Characterization of Cell Lines HepG2, Hep3B217 and SNU387 as Models for Porcine Epidemic Diarrhea Coronavirus Infection. Viruses 2022; 14:v14122754. [PMID: 36560758 PMCID: PMC9785011 DOI: 10.3390/v14122754] [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: 11/15/2022] [Revised: 12/01/2022] [Accepted: 12/06/2022] [Indexed: 12/14/2022] Open
Abstract
Porcine epidemic diarrhea virus (PEDV), a member of the genera alphacoronavirus, causes acute watery diarrhea and dehydration in suckling piglets and results in enormous economic losses in the swine industry worldwide. Identification and characterization of different cell lines are not only invaluable for PEDV entry and replication studies but also important for the development of various types of biological pharmaceuticals against PEDV. In this study, we present an approach to identify suitable permissive cell lines for PEDV research. Human cell lines were screened for a high correlation coefficient with the established PEDV infection model Huh7 based on RNA-seq data from the Cancer Cell Line Encyclopedia (CCLE). Experimentally testing permissiveness towards PEDV infection, three highly permissive human cell lines, HepG2, Hep3B217, and SNU387 were identified. The replication kinetics of PEDV in HepG2, Hep3B217, and SNU387 cells were similar to that in Vero and Huh7 cells. Additionally, the transcriptomes analysis showed robust induction of transcripts associated with the innate immune in response to PEDV infection in all three cell lines, including hundreds of inflammatory cytokine and interferon genes. Moreover, the expression of inflammatory cytokines and interferons were confirmed by qPCR assay. Our findings indicate that HepG2, Hep3B217, and SNU387 are suitable cell lines for PEDV replication and innate immune response studies.
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Organoid Technologies for SARS-CoV-2 Research. CURRENT STEM CELL REPORTS 2022; 8:151-163. [PMID: 36313938 PMCID: PMC9589566 DOI: 10.1007/s40778-022-00220-1] [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] [Accepted: 10/07/2022] [Indexed: 12/05/2022]
Abstract
Purpose of Review Organoids are an emerging technology utilizing three-dimensional (3D), multi-cellular in vitro models to represent the function and physiological responses of tissues and organs. By using physiologically relevant models, more accurate tissue responses to viral infection can be observed, and effective treatments and preventive strategies can be identified. Animals and two-dimensional (2D) cell culture models occasionally result in inaccurate disease modeling outcomes. Organoids have been developed to better represent human organ and tissue systems, and accurately model tissue function and disease responses. By using organoids to study SARS-Cov-2 infection, researchers have now evaluated the viral effects on different organs and evaluate efficacy of potential treatments. The purpose of this review is to highlight organoid technologies and their ability to model SARS-Cov-2 infection and tissue responses. Recent Findings Lung, cardiac, kidney, and small intestine organoids have been examined as potential models of SARS-CoV-2 infection. Lung organoid research has highlighted that SARS-CoV-2 shows preferential infection of club cells and have shown value for the rapid screening and evaluations of multiple anti-viral drugs. Kidney organoid research suggests human recombinant soluble ACE2 as a preventative measure during early-stage infection. Using small intestine organoids, fecal to oral transmission has been evaluated as a transmission route for the virus. Lastly in cardiac organoids drug evaluation studies have found that drugs such as bromodomain, external family inhibitors, BETi, and apabetalone may be effective treatments for SARs-CoV-2 cardiac injury. Summary Organoids are an effective tool to study the effects of viral infections and for drug screening and evaluation studies. By using organoids, more accurate disease modeling can be performed, and physiological effects of infection and treatment can be better understood.
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Nolan LS, Baldridge MT. Advances in understanding interferon-mediated immune responses to enteric viruses in intestinal organoids. Front Immunol 2022; 13:943334. [PMID: 35935957 PMCID: PMC9354881 DOI: 10.3389/fimmu.2022.943334] [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: 05/13/2022] [Accepted: 06/30/2022] [Indexed: 11/16/2022] Open
Abstract
Interferons (IFN) are antiviral cytokines with critical roles in regulating pathogens at epithelial barriers, but their capacity to restrict human enteric viruses has been incompletely characterized in part due to challenges in cultivating some viruses in vitro, particularly human norovirus. Accordingly, advancements in the development of antiviral therapies and vaccine strategies for enteric viral infections have been similarly constrained. Currently emerging is the use of human intestinal enteroids (HIEs) to investigate mechanisms of human enteric viral pathogenesis. HIEs provide a unique opportunity to investigate host-virus interactions using an in vitro system that recapitulates the cellular complexity of the in vivo gastrointestinal epithelium. This approach permits the exploration of intestinal epithelial cell interactions with enteric viruses as well as the innate immune responses mediated by IFNs and IFN-stimulated genes. Here, we describe recent findings related to the production, signaling, and function of IFNs in the response to enteric viral infections, which will ultimately help to reveal important aspects of pathogenesis and facilitate the future development of therapeutics and vaccines.
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Affiliation(s)
- Lila S. Nolan
- Department of Pediatrics, Division of Newborn Medicine, Washington University School of Medicine, St. Louis Children’s Hospital, St. Louis, MO, United States
- Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO, United States
| | - Megan T. Baldridge
- Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO, United States
- Department of Medicine, Division of Infectious Diseases, Washington University School of Medicine, St. Louis, MO, United States
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Wells AI, Coyne CB. An In Vivo Model of Echovirus-Induced Meningitis Defines the Differential Roles of Type I and Type III Interferon Signaling in Central Nervous System Infection. J Virol 2022; 96:e0033022. [PMID: 35699446 PMCID: PMC9278148 DOI: 10.1128/jvi.00330-22] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Accepted: 04/20/2022] [Indexed: 11/20/2022] Open
Abstract
Echoviruses are among the most common worldwide causes of aseptic meningitis, which can cause long-term sequelae and death, particularly in neonates. However, the mechanisms by which these viruses induce meningeal inflammation are poorly understood, owing at least in part to the lack of in vivo models that recapitulate this aspect of echovirus pathogenesis. Here, we developed an in vivo neonatal mouse model that recapitulates key aspects of echovirus-induced meningitis. We show that expression of the human homologue of the primary echovirus receptor, the neonatal Fc receptor (FcRn), is not sufficient for infection of the brains of neonatal mice. However, ablation of type I, but not III, interferon (IFN) signaling in mice expressing human FcRn permitted high levels of echovirus replication in the brain, with corresponding clinical symptoms, including delayed motor skills and hind-limb weakness. Using this model, we defined the immunological response of the brain to echovirus infection and identified key cytokines, such as granulocyte colony-stimulating factor (G-CSF) and interleukin 6 (IL-6), that were induced by this infection. Lastly, we showed that echoviruses specifically replicate in the leptomeninges, where they induce profound inflammation and cell death. Together, this work establishes an in vivo model of aseptic meningitis associated with echovirus infections that delineates the differential roles of type I and type III IFNs in echovirus-associated neuronal disease and defines the specificity of echoviral infections within the meninges. IMPORTANCE Echoviruses are among the most common worldwide causes of aseptic meningitis, which can cause long-term sequelae or even death. The mechanisms by which echoviruses infect the brain are poorly understood, largely owing to the lack of robust in vivo models that recapitulate this aspect of echovirus pathogenesis. Here, we establish a neonatal mouse model of echovirus-induced aseptic meningitis and show that expression of the human homologue of the FcRn, the primary receptor for echoviruses, and ablation of type I IFN signaling are required to recapitulate echovirus-induced meningitis and clinical disease. These findings provide key insights into the host factors that control echovirus-induced meningitis and a model that could be used to test anti-echovirus therapeutics.
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Affiliation(s)
- Alexandra I. Wells
- Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina, USA
| | - Carolyn B. Coyne
- Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina, USA
- Duke Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, USA
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35
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Filipe IC, Tee HK, Prados J, Piuz I, Constant S, Huang S, Tapparel C. Comparison of tissue tropism and host response to enteric and respiratory enteroviruses. PLoS Pathog 2022; 18:e1010632. [PMID: 35789345 PMCID: PMC9286751 DOI: 10.1371/journal.ppat.1010632] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 07/15/2022] [Accepted: 06/01/2022] [Indexed: 11/21/2022] Open
Abstract
Enteroviruses (EVs) are among the most prevalent viruses worldwide. They are characterized by a high genetic and phenotypic diversity, being able to cause a plethora of symptoms. EV-D68, a respiratory EV, and EV-D94, an enteric EV, represent an interesting paradigm of EV tropism heterogeneity. They belong to the same species, but display distinct phenotypic characteristics and in vivo tropism. Here, we used these two viruses as well as relevant 3D respiratory, intestinal and neural tissue culture models, to highlight key distinctive features of enteric and respiratory EVs. We emphasize the critical role of temperature in restricting EV-D68 tissue tropism. Using transcriptomic analysis, we underscore fundamental differences between intestinal and respiratory tissues, both in the steady-state and in response to infection. Intestinal tissues present higher cell proliferation rate and are more immunotolerant than respiratory tissues. Importantly, we highlight the different strategies applied by EV-D94 and EV-D68 towards the host antiviral response of intestinal and respiratory tissues. EV-D68 strongly activates antiviral pathways while EV-D94, on the contrary, barely induces any host defense mechanisms. In summary, our study provides an insightful characterization of the differential pathogenesis of EV-D68 and EV-D94 and the interplay with their main target tissues. Enteroviruses (EVs) are important human pathogens, associated with more than 20 clinical presentations. They replicate predominantly in the intestinal and/or respiratory mucosae. The respiratory EV-D68 can be considered an emerging virus because it caused an unprecedent outbreak in 2014, and contemporary isolates display increased virulence and novel neurotropic potential. The genetically related enteric EV-D94 is less common and its pathogenesis remains poorly defined, however, its infection has also been associated with neurological symptoms such as acute flaccid paralysis. To decipher the pathogenic mechanisms of these two viruses, we investigated their tropism and innate immunity induction in relevant human respiratory, intestinal and neural tissue culture models. Our results highlight the critical role of temperature in restricting EV-D68 tropism. Furthermore, using transcriptomic analysis, we identified key differences between respiratory and intestinal tissues, with the latter exhibiting higher cell proliferation and being more immunotolerant. More importantly, we could demonstrate the different strategies applied by EV-D94 and EV-D68 towards the host antiviral response, with EV-D68 strongly activating antiviral pathways and EV-D94, in contrast, inducing few host antiviral transcripts. This work identifies key differences in the pathogenesis of these representative respiratory and enteric EVs, which may contribute to the development of targeted antiviral therapies.
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Affiliation(s)
- Ines Cordeiro Filipe
- Department of Microbiology and Molecular Medicine, University of Geneva, Geneva, Switzerland
| | - Han Kang Tee
- Department of Microbiology and Molecular Medicine, University of Geneva, Geneva, Switzerland
| | - Julien Prados
- Bioinformatics Support Platform, University of Geneva, Geneva, Switzerland
| | - Isabelle Piuz
- Department of Microbiology and Molecular Medicine, University of Geneva, Geneva, Switzerland
| | | | - Song Huang
- Epithelix SAS Geneva, Geneva, Switzerland
| | - Caroline Tapparel
- Department of Microbiology and Molecular Medicine, University of Geneva, Geneva, Switzerland
- * E-mail:
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36
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Enterovirus Replication and Dissemination Are Differentially Controlled by Type I and III Interferons in the Gastrointestinal Tract. mBio 2022; 13:e0044322. [PMID: 35604122 PMCID: PMC9239134 DOI: 10.1128/mbio.00443-22] [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] [Indexed: 12/23/2022] Open
Abstract
Echovirus infections are associated with a broad spectrum of illness, particularly in neonates, and are primarily transmitted through the fecal-oral route. Little is known regarding how echoviruses infect the gastrointestinal tract and how the intestinal epithelium controls echoviral replication.
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Wang J, Hu Y, Zheng M. Enterovirus A71 antivirals: Past, present, and future. Acta Pharm Sin B 2022; 12:1542-1566. [PMID: 35847514 PMCID: PMC9279511 DOI: 10.1016/j.apsb.2021.08.017] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 07/28/2021] [Accepted: 08/12/2021] [Indexed: 02/07/2023] Open
Abstract
Enterovirus A71 (EV-A71) is a significant human pathogen, especially in children. EV-A71 infection is one of the leading causes of hand, foot, and mouth diseases (HFMD), and can lead to neurological complications such as acute flaccid myelitis (AFM) in severe cases. Although three EV-A71 vaccines are available in China, they are not broadly protective and have reduced efficacy against emerging strains. There is currently no approved antiviral for EV-A71. Significant progress has been made in developing antivirals against EV-A71 by targeting both viral proteins and host factors. However, viral capsid inhibitors and protease inhibitors failed in clinical trials of human rhinovirus infection due to limited efficacy or side effects. This review discusses major discoveries in EV-A71 antiviral development, analyzes the advantages and limitations of each drug target, and highlights the knowledge gaps that need to be addressed to advance the field forward.
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Affiliation(s)
- Jun Wang
- Department of Pharmacology and Toxicology, College of Pharmacy, the University of Arizona, Tucson, AZ 85721, USA
| | - Yanmei Hu
- Department of Pharmacology and Toxicology, College of Pharmacy, the University of Arizona, Tucson, AZ 85721, USA
| | - Madeleine Zheng
- Department of Pharmacology and Toxicology, College of Pharmacy, the University of Arizona, Tucson, AZ 85721, USA
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38
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Goldstein ME, Scull MA. Modeling Innate Antiviral Immunity in Physiological Context. J Mol Biol 2022; 434:167374. [PMID: 34863779 PMCID: PMC8940657 DOI: 10.1016/j.jmb.2021.167374] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 11/14/2021] [Accepted: 11/15/2021] [Indexed: 12/16/2022]
Abstract
An effective innate antiviral response is critical for the mitigation of severe disease and host survival following infection. In vivo, the innate antiviral response is triggered by cells that detect the invading pathogen and then communicate through autocrine and paracrine signaling to stimulate the expression of genes that inhibit viral replication, curtail cell proliferation, or modulate the immune response. In other words, the innate antiviral response is complex and dynamic. Notably, in the laboratory, culturing viruses and assaying viral life cycles frequently utilizes cells that are derived from tissues other than those that support viral replication during natural infection, while the study of viral pathogenesis often employs animal models. In recapitulating the human antiviral response, it is important to consider that variation in the expression and function of innate immune sensors and antiviral effectors exists across species, cell types, and cell differentiation states, as well as when cells are placed in different contexts. Thus, to gain novel insight into the dynamics of the host response and how specific sensors and effectors impact infection kinetics by a particular virus, the model system must be selected carefully. In this review, we briefly introduce key signaling pathways involved in the innate antiviral response and highlight how these differ between systems. We then review the application of tissue-engineered or 3D models for studying the antiviral response, and suggest how these in vitro culture systems could be further utilized to assay physiologically-relevant host responses and reveal novel insight into virus-host interactions.
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Affiliation(s)
- Monty E Goldstein
- Department of Cell Biology and Molecular Genetics, Maryland Pathogen Research Institute, 3134 Bioscience Research Building, University of Maryland, College Park, MD 20742, USA
| | - Margaret A Scull
- Department of Cell Biology and Molecular Genetics, Maryland Pathogen Research Institute, 3134 Bioscience Research Building, University of Maryland, College Park, MD 20742, USA.
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39
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Zhang M, Lv L, Cai H, Li Y, Gao F, Yu L, Jiang Y, Tong W, Li L, Li G, Tong G, Liu C. Long-Term Expansion of Porcine Intestinal Organoids Serves as an in vitro Model for Swine Enteric Coronavirus Infection. Front Microbiol 2022; 13:865336. [PMID: 35369438 PMCID: PMC8967161 DOI: 10.3389/fmicb.2022.865336] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Accepted: 02/21/2022] [Indexed: 01/22/2023] Open
Abstract
A reliable and reproducible model in vitro for swine enteric coronaviruses infection would be intestinal models that support virus replication and can be long-term cultured and manipulated experimentally. Here, we designed a robust long-term culture system for porcine intestinal organoids from the intestinal crypt or single LGR5+ stem cell by combining previously defined insights into the growth requirements of the intestinal epithelium of humans. We showed that long-term cultured swine intestinal organoids were expanded in vitro for more than 6 months and maintained the potential to differentiate into different types of cells. These organoids were successfully infected with porcine enteric coronavirus, including porcine epidemic diarrhea virus (PEDV) and transmissible gastroenteritis virus (TGEV), and were capable of supporting virus replication and progeny release. RNA-seq analysis showed robust induction of transcripts associated with antiviral signaling in response to enteric coronavirus infection, including hundreds of interferon-stimulated genes and cytokines. Moreover, gene set enrichment analysis indicated that PEDV infection could suppress the immune response in organoids. This 3D intestinal organoid model offers a long-term, renewable resource for investigating porcine intestinal infections with various pathogens.
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Affiliation(s)
- Min Zhang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
| | - Lilei Lv
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
| | - Hongming Cai
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
- Key Laboratory of Fujian-Taiwan Animal Pathogen Biology, College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou, China
| | - Yanhua Li
- College of Veterinary Medicine, Yangzhou University, Yangzhou, China
| | - Fei Gao
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
- Jiangsu Co-innovation Center for the Prevention and Control of Important Animal Infectious Disease and Zoonosis, Yangzhou University, Yangzhou, China
| | - Lingxue Yu
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
- Jiangsu Co-innovation Center for the Prevention and Control of Important Animal Infectious Disease and Zoonosis, Yangzhou University, Yangzhou, China
| | - Yifeng Jiang
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
- Jiangsu Co-innovation Center for the Prevention and Control of Important Animal Infectious Disease and Zoonosis, Yangzhou University, Yangzhou, China
| | - Wu Tong
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
- Jiangsu Co-innovation Center for the Prevention and Control of Important Animal Infectious Disease and Zoonosis, Yangzhou University, Yangzhou, China
| | - Liwei Li
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
- Jiangsu Co-innovation Center for the Prevention and Control of Important Animal Infectious Disease and Zoonosis, Yangzhou University, Yangzhou, China
| | - Guoxin Li
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
- Jiangsu Co-innovation Center for the Prevention and Control of Important Animal Infectious Disease and Zoonosis, Yangzhou University, Yangzhou, China
| | - Guangzhi Tong
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
- Jiangsu Co-innovation Center for the Prevention and Control of Important Animal Infectious Disease and Zoonosis, Yangzhou University, Yangzhou, China
- *Correspondence: Guangzhi Tong,
| | - Changlong Liu
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
- Jiangsu Co-innovation Center for the Prevention and Control of Important Animal Infectious Disease and Zoonosis, Yangzhou University, Yangzhou, China
- Changlong Liu,
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40
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Wirusanti NI, Baldridge MT, Harris VC. Microbiota regulation of viral infections through interferon signaling. Trends Microbiol 2022; 30:778-792. [PMID: 35135717 PMCID: PMC9344482 DOI: 10.1016/j.tim.2022.01.007] [Citation(s) in RCA: 53] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2021] [Revised: 01/10/2022] [Accepted: 01/12/2022] [Indexed: 12/22/2022]
Abstract
The interferon (IFN) response is the major early innate immune response against invading viral pathogens and is even capable of mediating sterilizing antiviral immunity without the support of the adaptive immune system. Cumulative evidence suggests that the gut microbiota can modulate IFN responses, indirectly determining virological outcomes. This review outlines our current knowledge of the interactions between the gut microbiota and IFN responses and dissects the different mechanisms by which the gut microbiota may alter IFN expression to diverse viral infections. This knowledge offers a basis for translating experimental evidence from animal studies into the human context and identifies avenues for leveraging the gut microbiota–IFN–virus axis to improve control of viral infections and performance of viral vaccines.
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41
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Heckenberg E, Steppe JT, Coyne CB. Enteroviruses: The role of receptors in viral pathogenesis. Adv Virus Res 2022; 113:89-110. [DOI: 10.1016/bs.aivir.2022.09.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
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42
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Zhu H, Xu R, Zang H, Feng J, Shen G, Liu P. Metabolomic characteristics of hand-foot-mouth disease facilitate discovery and diagnosis of pathogeny. Pediatr Int 2022; 64:e14927. [PMID: 34273220 DOI: 10.1111/ped.14927] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 06/10/2021] [Accepted: 07/16/2021] [Indexed: 01/06/2023]
Abstract
BACKGROUND Hand-foot-mouth disease (HFMD) is a significant public health concern, especially in Asia-Pacific countries. Its diagnosis mainly depends on clinical symptoms. It is easy to miss the source of infection and best treatment period. This research aims to provide a tool for its early clinical diagnosis and for predicting the possibility of complications. METHODS The serum samples of 39 HFMD children and 36 healthy children were collected for clinical testing and 1 H-NMR spectroscopy. Metabolomic analyses were performed to obtain the metabolic differences between the HFMD and healthy children and to speculate on the pathogenesis of HFMD. RESULTS Thirty-nine children were divided into severe cases and mild cases. Severe cases demonstrated more obvious inflammatory responses, but no metabolic difference was observed between the severe and mild cases. The metabolic differences between HFMD and healthy children were noticeable. Ten differential metabolites were screened out as the potential biomarkers for HFMD, and seven disturbed metabolic pathways responsible for HFMD were affected by inflammation, impaired intestinal absorptive function, and immune response. CONCLUSIONS Our results will provide a complementary tool for the early diagnosis of HFMD and potential ideas for later treatment.
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Affiliation(s)
- Hongwei Zhu
- Department of Pediatrics, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Rui Xu
- Department of Electronic Science, Fujian Provincial Key Laboratory of Plasma and Magnetic Resonance, Xiamen University, Xiamen, China
| | - Huanhuan Zang
- Department of Pediatrics, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Jianghua Feng
- Department of Electronic Science, Fujian Provincial Key Laboratory of Plasma and Magnetic Resonance, Xiamen University, Xiamen, China
| | - Guiping Shen
- Department of Electronic Science, Fujian Provincial Key Laboratory of Plasma and Magnetic Resonance, Xiamen University, Xiamen, China
| | - Pei Liu
- Department of Pediatrics, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
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43
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Kim AH, Armah G, Dennis F, Wang L, Rodgers R, Droit L, Baldridge MT, Handley SA, Harris VC. Enteric virome negatively affects seroconversion following oral rotavirus vaccination in a longitudinally sampled cohort of Ghanaian infants. Cell Host Microbe 2021; 30:110-123.e5. [PMID: 34932985 PMCID: PMC8763403 DOI: 10.1016/j.chom.2021.12.002] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 10/22/2021] [Accepted: 11/29/2021] [Indexed: 01/04/2023]
Abstract
Rotavirus vaccines (RVVs) have substantially diminished mortality from severe rotavirus (RV) gastroenteritis but are significantly less effective in low- and middle-income countries (LMICs), limiting their life-saving potential. The etiology of RVV’s diminished effectiveness remains incompletely understood, but the enteric microbiota has been implicated in modulating immunity to RVVs. Here, we analyze the enteric microbiota in a longitudinal cohort of 122 Ghanaian infants, evaluated over the course of 3 Rotarix vaccinations between 6 and 15 weeks of age, to assess whether bacterial and viral populations are distinct between non-seroconverted and seroconverted infants. We identify bacterial taxa including Streptococcus and a poorly classified taxon in Enterobacteriaceae as positively correlating with seroconversion. In contrast, both bacteriophage diversity and detection of Enterovirus B and multiple novel cosaviruses are negatively associated with RVV seroconversion. These findings suggest that virome-RVV interference is an underappreciated cause of poor vaccine performance in LMICs.
Longitudinal analysis of microbiota of Ghanaian infants receiving rotavirus vaccine Streptococcus and Enterobacteriaceae taxa positively associate with RVV seroconversion Enterovirus B, Cosavirus A, and phage richness negatively associate with RVV serostatus
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44
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O'Farrell C, Stamatopoulos K, Simmons M, Batchelor H. In vitro models to evaluate ingestible devices: Present status and current trends. Adv Drug Deliv Rev 2021; 178:113924. [PMID: 34390774 DOI: 10.1016/j.addr.2021.113924] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 08/03/2021] [Accepted: 08/09/2021] [Indexed: 12/14/2022]
Abstract
Orally ingestible medical devices offer significant opportunity in the diagnosis and treatment of gastrointestinal conditions. Their development necessitates the use of models that simulate the gastrointestinal environment on both a macro and micro scale. An evolution in scientific technology has enabled a wide range of in vitro, ex vivo and in vivo models to be developed that replicate the gastrointestinal tract. This review describes the landscape of the existing range of in vitro tools that are available to characterize ingestible devices. Models are presented with details on their benefits and limitations with regards to the evaluation of ingestible devices and examples of their use in the evaluation of such devices is presented where available. The multitude of models available provides a suite of tools that can be used in the evaluation of ingestible devices that should be selected on the functionality of the device and the mechanism of its function.
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Affiliation(s)
- Connor O'Farrell
- School of Chemical Engineering, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
| | - Konstantinos Stamatopoulos
- School of Chemical Engineering, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK; Biopharmaceutics, Pharmaceutical Development, PDS, MST, RD Platform Technology & Science, GSK, David Jack Centre, Park Road, Ware, Hertfordshire SG12 0DP, UK
| | - Mark Simmons
- School of Chemical Engineering, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
| | - Hannah Batchelor
- Strathclyde Institute of Pharmacy and Biomedical Sciences, 161 Cathedral Street, Glasgow G4 0RE, UK.
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45
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Palmu T, Lehtonen J, Korhonen L, Virtanen SM, Niemelä O, Toppari J, Ilonen J, Veijola R, Knip M, Laitinen OH, Lönnrot M, Hyöty H. Association of different enteroviruses with atopy and allergic diseases in early childhood. Pediatr Allergy Immunol 2021; 32:1629-1636. [PMID: 34219290 DOI: 10.1111/pai.13577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 05/24/2021] [Accepted: 05/31/2021] [Indexed: 11/30/2022]
Abstract
BACKGROUND Enterovirus (EV) infections, being among the most prevalent viruses worldwide, have been associated with reduced risk of allergic diseases. We sought to determine the association between EVs and allergic sensitization and disease in early childhood. METHODS The study was carried out in a nested case-control setting within a prospective birth cohort in Finland. We included 138 case children who had specific IgE (s-IgE) sensitization at the age of 5 years and 138 control children without s-IgE sensitization. Allergic disease was recorded at study visits and identified with the ISAAC questionnaire. We screened for the presence of serotype-specific antibodies against 41 EVs at 1-5 years of age and assessed their association with allergic sensitization and disease. RESULTS The overall number of EV infections did not differ between s-IgE-sensitized children and non-sensitized control children. However, there was a tendency of case children with an allergic disease having less EV infections than their controls. This observation was statistically significant for species A EVs in case children with atopic dermatitis vs. control children: OR 0.6 (95% CI 0.36-0.99), p = .048. CONCLUSION This study supports the evidence that EV exposure and development of allergic disease are inversely associated. Interestingly, the inverse association was not observed for bare atopic IgE sensitization, but for IgE sensitization coupled with clinical atopic disease. This suggests that environmental factors influencing IgE sensitization may differ from those influencing progression to clinical allergic disease.
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Affiliation(s)
- Tiina Palmu
- Department of Virology, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.,Department of Dermatology and Allergology, The Hospital District of South Ostrobothnia, Seinäjoki, Finland
| | - Jussi Lehtonen
- Department of Virology, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Laura Korhonen
- Department of Virology, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.,Department of Dermatology, Tampere University Hospital, Tampere, Finland
| | - Suvi M Virtanen
- Health and Well-Being Promotion Unit, Finnish Institute for Health and Welfare, Helsinki, Finland.,Unit of Health Sciences, Faculty of Social Sciences, Tampere University, Tampere, Finland.,Tampere University Hospital, Research, Development and Innovation Center, Tampere, Finland.,Center for Child Health Research, Tampere University and Tampere University Hospital, Tampere, Finland
| | - Onni Niemelä
- Department of Laboratory Medicine and Medical Research Unit, Seinäjoki Central Hospital and Tampere University, Seinäjoki/Tampere, Finland
| | - Jorma Toppari
- Institute of Biomedicine, Centre for Integrative Physiology and Pharmacology, and Centre for Population Health Research, University of Turku, Turku, Finland.,Department of Pediatrics, Turku University Hospital, Turku, Finland
| | - Jorma Ilonen
- Immunogenetics Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland
| | - Riitta Veijola
- Department of Pediatrics, University of Oulu and Oulu University Hospital, Oulu, Finland
| | - Mikael Knip
- Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland.,Department of Pediatrics, Tampere University Hospital, Tampere, Finland
| | - Olli H Laitinen
- Department of Virology, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Maria Lönnrot
- Department of Virology, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.,Department of Dermatology, Tampere University Hospital, Tampere, Finland
| | - Heikki Hyöty
- Department of Virology, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.,Fimlab Laboratories, Pirkanmaa Hospital District, Tampere, Finland
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Abstract
Infectious diseases affect individual health and have widespread societal impacts. New ex vivo models are critical to understand pathogenesis, host response, and features necessary to develop preventive and therapeutic treatments. Pluripotent and tissue stem cell-derived organoids provide new tools for the study of human infections. Organoid models recapitulate many characteristics of in vivo disease and are providing new insights into human respiratory, gastrointestinal, and neuronal host-microbe interactions. Increasing culture complexity by adding the stroma, interorgan communication, and the microbiome will improve the use of organoids as models for infection. Organoid cultures provide a platform with the capability to improve human health related to infectious diseases. Expected final online publication date for the Annual Review of Medicine, Volume 73 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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Affiliation(s)
- Sarah E Blutt
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas 77030, USA; .,Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA
| | - Mary K Estes
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas 77030, USA; .,Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA
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47
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Genetic and commensal induction of IL-18 drive intestinal epithelial MHCII via IFNγ. Mucosal Immunol 2021; 14:1100-1112. [PMID: 34103660 PMCID: PMC8562907 DOI: 10.1038/s41385-021-00419-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 05/03/2021] [Accepted: 05/19/2021] [Indexed: 02/04/2023]
Abstract
Major histocompatibility complex class II (MHCII) is dynamically expressed on intestinal epithelial cells (IECs) throughout the intestine, but its regulation remains poorly understood. We observed that spontaneous upregulation of IEC MHCII in locally bred Rag1-/- mice correlated with serum Interleukin (IL)-18, was transferrable via co-housing to commercially bred immunodeficient mice and could be inhibited by both IL-12 and IL-18 blockade. Overproduction of intestinal IL-18 due to an activating Nlrc4 mutation upregulated IEC MHCII via classical inflammasome machinery independently of immunodeficiency or dysbiosis. Immunodeficient dysbiosis increased Il-18 transcription, which synergized with NLRC4 inflammasome activity to drive elevations in serum IL-18. This IL-18-MHCII axis was confirmed in several other models of intestinal and systemic inflammation. Elevated IL-18 reliably preceded MHCII upregulation, suggesting an indirect effect on IECs, and mice with IL-18 overproduction showed activation or expansion of type 1 lymphocytes. Interferon gamma (IFNg) was uniquely able to upregulate IEC MHCII in enteroid cultures and was required for MHCII upregulation in several in vivo systems. Thus, we have linked intestinal dysbiosis, systemic inflammation, and inflammasome activity to IEC MHCII upregulation via an intestinal IL-18-IFNg axis. Understanding this process may be crucial for determining the contribution of IEC MHCII to intestinal homeostasis, host defense, and tolerance.
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Zhang MM, Yang KL, Cui YC, Zhou YS, Zhang HR, Wang Q, Ye YJ, Wang S, Jiang KW. Current Trends and Research Topics Regarding Intestinal Organoids: An Overview Based on Bibliometrics. Front Cell Dev Biol 2021; 9:609452. [PMID: 34414174 PMCID: PMC8369504 DOI: 10.3389/fcell.2021.609452] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Accepted: 06/08/2021] [Indexed: 01/10/2023] Open
Abstract
Currently, research on intestinal diseases is mainly based on animal models and cell lines in monolayers. However, these models have drawbacks that limit scientific advances in this field. Three-dimensional (3D) culture systems named organoids are emerging as a reliable research tool for recapitulating the human intestinal epithelium and represent a unique platform for patient-specific drug testing. Intestinal organoids (IOs) are crypt–villus structures that can be derived from adult intestinal stem cells (ISCs), embryonic stem cells (ESCs), or induced pluripotent stem cells (iPSCs) and have the potential to serve as a platform for individualized medicine and research. However, this emerging field has not been bibliometric summarized to date. Here, we performed a bibliometric analysis of the Web of Science Core Collection (WoSCC) database to evaluate 5,379 publications concerning the use of organoids; the studies were divided into four clusters associated with the current situation and future directions for the application of IOs. Based on the results of our bibliometric analysis of IO applications, we systematically summarized the latest advances and analyzed the limitations and prospects.
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Affiliation(s)
- Meng-Meng Zhang
- Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing, China.,Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, Beijing, China
| | - Ke-Lu Yang
- Evidence-Based Nursing Center, School of Nursing, Lanzhou University, Lanzhou, China
| | - Yan-Cheng Cui
- Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing, China
| | - Yu-Shi Zhou
- Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing, China
| | - Hao-Ran Zhang
- Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing, China
| | - Quan Wang
- Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing, China.,Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, Beijing, China
| | - Ying-Jiang Ye
- Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing, China.,Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, Beijing, China
| | - Shan Wang
- Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing, China.,Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, Beijing, China
| | - Ke-Wei Jiang
- Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing, China.,Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, Beijing, China
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Caballol B, Gudiño V, Panes J, Salas A. Ulcerative colitis: shedding light on emerging agents and strategies in preclinical and early clinical development. Expert Opin Investig Drugs 2021; 30:931-946. [PMID: 34365869 DOI: 10.1080/13543784.2021.1965122] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
INTRODUCTION Ulcerative colitis (UC) is an inflammatory disease of the large intestine. Progress in preclinical therapeutic target discovery and clinical trial design has resulted in the approval of new therapies. Nonetheless, remission rates remain below 30% thus underlining the need for novel, more effective therapies. AREAS COVERED This paper reviews current experimental techniques available for drug testing in intestinal inflammation and examines new therapies in clinical development for the treatment of UC. The authors searched the literature for 'ulcerative colitis' AND 'preclinical' OR 'drug target/drug name' (i.e. infliximab, vedolizumab, IL-12, IL-23, JAK, etc.). Studies that included preclinical in vivo or in vitro experiments are discussed. The clinicaltrial.gov site was searched for 'ulcerative colitis' AND 'Recruiting' OR 'Active, not recruiting' AND 'Interventional (Clinical Trial)' AND 'early phase 1' OR 'phase 1' OR 'phase 2' OR 'phase 3.' EXPERT OPINION Using in vivo, ex vivo, and/or in vitro models could increase the success rates of drugs moving to clinical trials, and hence increase the efficiency of this costly process. Selective JAK1 inhibitors, S1P modulators, and anti-p19 antibodies are the most promising options to improve treatment effectiveness. The development of drugs with gut-restricted exposure may provide increased efficacy and an improved safety.
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Affiliation(s)
- Berta Caballol
- Inflammatory Bowel Disease Unit, Department of Gastroenterology, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigaciones Biomédicas en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
| | - Victoria Gudiño
- Inflammatory Bowel Disease Unit, Department of Gastroenterology, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigaciones Biomédicas en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
| | - Julian Panes
- Inflammatory Bowel Disease Unit, Department of Gastroenterology, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigaciones Biomédicas en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
| | - Azucena Salas
- Inflammatory Bowel Disease Unit, Department of Gastroenterology, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigaciones Biomédicas en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
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Johnson SD, Olwenyi OA, Bhyravbhatla N, Thurman M, Pandey K, Klug EA, Johnston M, Dyavar SR, Acharya A, Podany AT, Fletcher CV, Mohan M, Singh K, Byrareddy SN. Therapeutic implications of SARS-CoV-2 dysregulation of the gut-brain-lung axis. World J Gastroenterol 2021; 27:4763-4783. [PMID: 34447225 PMCID: PMC8371510 DOI: 10.3748/wjg.v27.i29.4763] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 05/10/2021] [Accepted: 07/20/2021] [Indexed: 02/06/2023] Open
Abstract
The emergence and rapid spread of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused over 180 million confirmed cases resulting in over 4 million deaths worldwide with no clear end in sight for the coronavirus disease 19 (COVID-19) pandemic. Most SARS-CoV-2 exposed individuals experience mild to moderate symptoms, including fever, cough, fatigue, and loss of smell and taste. However, many individuals develop pneumonia, acute respiratory distress syndrome, septic shock, and multiorgan dysfunction. In addition to these primarily respiratory symptoms, SARS-CoV-2 can also infiltrate the central nervous system, which may damage the blood-brain barrier and the neuron's synapses. Resultant inflammation and neurodegeneration in the brain stem can further prevent efferent signaling to cranial nerves, leading to the loss of anti-inflammatory signaling and normal respiratory and gastrointestinal functions. Additionally, SARS-CoV-2 can infect enterocytes resulting in gut damage followed by microbial dysbiosis and translocation of bacteria and their byproducts across the damaged epithelial barrier. As a result, this exacerbates pro-inflammatory responses both locally and systemically, resulting in impaired clinical outcomes. Recent evidence has highlighted the complex interactions that mutually modulate respiratory, neurological, and gastrointestinal function. In this review, we discuss the ways SARS-CoV-2 potentially disrupts the gut-brain-lung axis. We further highlight targeting specific responses to SARS-CoV-2 for the development of novel, urgently needed therapeutic interventions. Finally, we propose a prospective related to the individuals from Low- and Middle-Income countries. Here, the underlying propensity for heightened gut damage/microbial translocation is likely to result in worse clinical outcomes during this COVID-19 pandemic.
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Affiliation(s)
- Samuel D Johnson
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, United States
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Omalla A Olwenyi
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, United States
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Namita Bhyravbhatla
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Michellie Thurman
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Kabita Pandey
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, United States
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Elizabeth A Klug
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, United States
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Morgan Johnston
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Shetty Ravi Dyavar
- Antiviral Pharmacology Laboratory, University of Nebraska Medical Center (UNMC) Center for Drug Discovery, Omaha, NE 68198, United States
| | - Arpan Acharya
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Anthony T Podany
- Antiviral Pharmacology Laboratory, University of Nebraska Medical Center (UNMC) Center for Drug Discovery, Omaha, NE 68198, United States
| | - Courtney V Fletcher
- Antiviral Pharmacology Laboratory, University of Nebraska Medical Center (UNMC) Center for Drug Discovery, Omaha, NE 68198, United States
| | - Mahesh Mohan
- Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, TX 78227, United States
| | - Kamal Singh
- Department of Molecular Microbiology and Immunology and Bond Life Sciences Center, University of Missouri, Columbia, MO 65212, United States
| | - Siddappa N Byrareddy
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States
- Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, United States
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, United States
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