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Principal Investigator: Diane Bimczok
Organization: MONTANA STATE UNIVERSITY - BOZEMAN
Fiscal Year: 2024
Award: $181,250
Funding agency: National Institute of Allergy and Infectious Diseases
Summary
The gastrointestinal (GI) tract is a major target organ for viral infection in bats, but infections rarely cause
typical symptoms of viral enteritis such as diarrhea. The long-term goal of our project is to understand the
specific innate immune response mechanisms of the intestinal epithelium that enable bats to sustain viral
infection without experiencing cytopathic effects and intestinal barrier dysfunction. We hypothesize that
protective type I and type III interferon (IFN) responses in Jamaican Fruit Bats (Artibeus jamaicensis, JFBs)
enable persistent, asymptomatic viral infection of the gastrointestinal epithelium. To test our hypothesis, we will
utilize a novel in vitro model of the JFB intestine, 3-D enteroids, which are complex long-term cultures of
primary intestinal epithelial cells generated from adult tissue-derived stem cells. Responses in the gut
epithelium of JFBs will be compared to those induced in human enteroids. In Aim 1, we will define type I/III IFN
responses of JFB enteroids to viral infection. In Aim 2, we will determine to what extent type I/III IFNs impact
viral replication and barrier function in the gastrointestinal epithelium of JFBs. We will analyze intestinal
epithelial cell responses to three single-stranded RNA viruses that can infect JFB cells: H18N11 influenza
virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and Cedar virus, a non-pathogenic
henipavirus. Specifically, we will analyze the kinetics of viral replication and type I/III IFN activation in the
enteroids and will also perform a comprehensive proteomics analysis of virus-infected intestinal epithelial cells.
To assess the role of virus-induced type I/III IFNs for gastrointestinal epithelial pathology, IFN signaling will be
induced or inhibited, and the impact on enteroid susceptibility to viral infection will be analyzed. We also will
measure epithelial cell viability, barrier and repair functions that are commonly disrupted during viral enteritis.
Our project is technologically innovative, because we will, for the first time, analyze viral infection in enteroid
cultures derived from JFBs and because we also will perform a complete proteome analysis of the JFB
intestinal epithelium. The proposed work is conceptually innovative, because it will define how virus-induced
type I/III IFNs impact intestinal epithelial function and integrity. Our proposed work is significant, because it will
provide novel insights in the epithelial cell-intrinsic innate immune mechanisms involved in asymptomatic
infection of the bat intestine with viral pathogens, which has important implications for potential pathogen
spillover events.
Terms: <(IFN) α><(IFN)-α><(IFN)α><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><21+ years old><3-D><3-Dimensional><3D><Adult><Adult Human><Alferon><Alimentary Canal><Anti-viral Response><Bats><Biological Response Modifiers><Biomodulators><Black Flies><Blackflies><COVID-19 virus><COVID19 virus><Cell Body><Cell Communication and Signaling><Cell Function><Cell Physiology><Cell Process><Cell Signaling><Cell Survival><Cell Viability><Cells><Cellular Function><Cellular Physiology><Cellular Process><Characteristics><Chiroptera><CoV-2><CoV2><Complex><Coronaviridae><Coronavirus><Diarrhea><Diet><Differential Gene Expression><Digestive Tract><Disease><Disorder><Dysfunction><Endogenous Interferon Beta><Enteritis><Epithelial Cells><Epithelium><Expression Signature><Family Pteropodidae><Feces><Fibroblast Interferon><Filoviridae><Filovirus><Flying Foxes><Fruit><Functional disorder><GI Tract><Gastrointestinal Tract><Gastrointestinal tract structure><Gene Expression><Gene Expression Monitoring><Gene Expression Pattern Analysis><Gene Expression Profile><Gene Expression Profiling><Goals><Grippe><Gut Epithelium><Henipavirus><Human><IFN><IFN Alpha><IFN activation><IFN α><IFN-Beta><IFN-α><IFN-β><IFNa><IFNb><IFNα><Immune Mediators><Immune Mediators/Modulators><Immune Regulators><Immune system><Immunochemical Immunologic><Immunologic><Immunological><Immunologically><Immunologics><Immunology><Individual><Infection><Infectious Diseases / Laboratory><Infectious Diseases Research><Influenza><Influenza Virus><Innate Immune Response><Interferon Activation><Interferon Alfa-n3><Interferon alpha><Interferon-beta><Interferon-α><Interferon-β><Interferons><Intestinal><Intestines><Intracellular Communication and Signaling><Jamaican><Kinetics><Leukocyte Interferon><Lymphoblast Interferon><Lymphoblastoid Interferon><Lytotoxicity><MERS corona virus><MERS coronavirus><MERS virus><MERS-CoV><Maintenance><Mammalia><Mammals><Measures><Middle East Respiratory Syndrome Corona Virus><Middle East Respiratory Syndrome Coronavirus><Middle East Respiratory Syndrome Virus><Middle East Respiratory Syndrome-CoV><Middle East Respiratory Virus><Middle East Respiratory coronavirus><Middle Eastern Respiratory Syndrome Corona virus><Middle Eastern Respiratory Syndrome Coronavirus><Middle Eastern Respiratory Syndrome Virus><Middle Eastern Respiratory Syndrome-CoV><Modeling><Modern Man><Natural Interferon Beta><Natural human interferon beta><Network Analysis><Organ><Organoids><Outcome><Pathogen detection><Pathogenicity><Pathology><Pathway Analysis><Pathway interactions><Pattern><Pattern recognition receptor><Physiopathology><Predisposition><Proteome><Proteomics><Pteropodidae><Purified Lymphoblastoid Interferon><RNA Viruses><Recombinant Interferon Alfa><Rectum><Resistance><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome related corona virus 2><Short interfering RNA><Signal Transduction><Signal Transduction Systems><Signaling><Simuliidae><Small Interfering RNA><Small Intestines><Subcellular Process><Susceptibility><Swab><Symptoms><System><Tacaribe virus><Testing><Time><Tissue-Specific Differential Gene Expression><Tissue-Specific Gene Expression><Transcript Expression Analyses><Transcript Expression Analysis><Viral><Viral Diseases><Virus><Virus Diseases><Virus Replication><Work><Wuhan coronavirus><ZIKV><Zika Virus><Zoonoses><Zoonotic><Zoonotic Infection><adulthood><alimentary tract><analyze gene expression><anti-viral immunity><antiviral immunity><biological signal transduction><bowel><chronic infection><corona virus><coronavirus disease 2019 virus><coronavirus disease-19 virus><cytotoxicity><dietary fruit><diets><digestive canal><enteral pathogen><enteric pathogen><enteropathogen><experience><experiment><experimental research><experimental study><experiments><gastrointestinal epithelium><gene expression analysis><gene expression assay><gene expression pattern><gene expression signature><genome annotation><hCoV19><human tissue><immunomodulatory biologics><in vitro Model><influenzavirus><innate immune mechanisms><innovate><innovation><innovative><innovative technologies><insight><intestinal barrier><intestinal epithelium><intestinal mucosal barrier><intestinal pathogen><intestine pathogen><model organism><nCoV2><novel><pathogen><pathogen spillover><pathogenic virus><pathophysiology><pathway><persistent infection><protection pathway><protective pathway><repair function><reparative function><resistant><response><siRNA><small bowel><small molecular inhibitor><small molecule inhibitor><social role><spillover event><stool><three dimensional><tissue derived stem cell><transcriptional profile><transcriptional profiling><transcriptional signature><transcriptomics><viral infection><viral multiplication><viral pathogen><viral replication><virus infection><virus multiplication><virus pathogen><virus-induced disease><zikav>