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Principal Investigator: Siyuan Ding
Organization: WASHINGTON UNIVERSITY
Fiscal Year: 2023
Award: $272,125
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary
Small bowel intestinal epithelial cells (IECs) are the first line of defense against human enteric viruses, the
most common and leading causes of diarrhea and death in infants and young children. How IECs
communicate with intraepithelial lymphocytes (IELs) in the small intestine and orchestrate antiviral responses
is heavily understudied. Our overall objectives are to better define the host immune signaling pathways in the
gastrointestinal tract during infections and to use that information to develop therapeutic interventions to
alleviate diarrhea and sequelae.
Our preliminary results contrasted our expectation and demonstrated that the numbers of two IEL subsets
are significantly reduced during early rotavirus infection in vivo. We also found that rotavirus infection alters the
expression of several pro-inflammatory chemokines in infected human and mouse IECs. Based on these data
and prior publications, we hypothesize that the IELs are important mediators of host defense against
rotavirus infection and that rotavirus-encoded factors antagonize the antiviral activity of IELs in the
host small intestine via inhibition of chemokine expression.
Testing these hypotheses is currently hampered by the lack of suitable model systems. Accordingly, we
have developed a highly tractable murine rotavirus reverse genetics method, a pathologically relevant neonatal
mouse model, and several innovative primary human and murine small bowel organoid culturing systems,
which will provide an unprecedented resolution of understanding of IEC-IEL crosstalk in the context of enteric
viral infections.
In Aim 1, we will define a functional antiviral role of IELs in rotavirus infection in vivo using immunological
approaches and gene knockout mice. In Aim 2, we will identify the potential mechanism by which viral factors
dampen chemokine expression in infected IECs. Collectively, we expect these studies to establish a new
paradigm of mucosal antiviral immunity, especially early in life when most enteric infections occur. We also
expect to identify novel rotavirus immune evasion strategies, which will inform new strategies to develop host-
based broad-spectrum antiviral therapeutics and next-generation vaccine candidates.
Terms: <0-11 years old><2,3,7,8-Tetrachlorodibenzo-p-dioxin Receptors><ABCD-3><AH Receptors><Ablation><Alimentary Canal><Anatomic Sites><Anatomic structures><Anatomy><Animal Model><Animal Models and Related Studies><Anti-Viral Response><Antiviral Agents><Antiviral Drugs><Antiviral Response><Antivirals><Aryl Hydrocarbon Receptor><Assay><Attenuated><Bioassay><Biologic Assays><Biologic Models><Biological Assay><Biological Models><C3Xkine><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CX3CL1><CX3CL1 gene><CXC3><CXC3C><Causality><Cell Body><Cell Communication><Cell Interaction><Cell-to-Cell Interaction><Cells><Cellular biology><Cessation of life><Chemotactic Cytokines><Child><Child Youth><Children (0-21)><Co-culture><Cocultivation><Coculture><Coculture Techniques><Country><Cryosectioning><Cryoultramicrotomy><Data><Death><Development><Diarrhea><Digestive Tract><Dioxin Receptors><Disease><Disorder><ELISA><Enteral><Enteric><Enzyme-Linked Immunosorbent Assay><Epithelial Cells><Epithelium><Etiology><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Foundations><GI Tract><Gastrointestinal Tract><Gastrointestinal tract structure><Goals><Homologous Chemotactic Cytokines><Host Defense><Hour><Human><Image><Immune Evasion><Immune signaling><Immunity><Immunochemical Immunologic><Immunofluorescence><Immunofluorescence Immunologic><Immunologic><Immunological><Immunologically><Immunologics><Infant><Infection><Inflammatory><Intercrines><Intestinal><Intestines><KO mice><Knock-out><Knock-out Mice><Knockout><Knockout Mice><Knowledge><Life><LoxP-flanked allele><Lymphatic cell><Lymphocyte><Lymphocyte Function><Lymphocyte Subpopulations><Lymphocyte Subset><Lymphocytic><Maintenance><Measures><Mediating><Mediator><Methods><Mice><Mice Mammals><Model System><Modern Man><Mucosa><Mucosal Tissue><Mucous Membrane><Murine><Mus><Neonatal><Non-structural Protein><Nonstructural Protein><Nuclear Translocator><Null Mouse><Organoids><Outcome><Pathologic><Play><Polyaromatic Hydrocarbon Receptors><Population><Primary Infection><Production><Publications><Recombinants><Resolution><Role><Rotavirus><Rotavirus Infections><Rotavirus Vaccines><SCYD1><SCmRNAseq><SIS cytokines><Scientific Publication><Signal Pathway><Small Intestines><System><T-Cell Depletion><T-Cell Subsets><T-Lymphocyte Subsets><T-cell depletion therapy><T-lymphocyte depletion therapy><T4 Cells><T4 Lymphocytes><TCDD Receptors><Testing><Therapeutic><Therapeutic Intervention><Transcript><Vaccine Design><Validation><Viral><Viral Activity><Viral Function><Viral Genome><Viral Pathogenesis><Viral Physiology><Viral Shedding><Virus><Virus Shedding><alimentary tract><antagonism><antagonist><anti-viral agents><anti-viral compound><anti-viral drugs><anti-viral immunity><anti-viral medication><anti-viral therapeutic><anti-virals><antiviral compound><antiviral immunity><antiviral medication><antiviral therapeutic><attenuate><attenuates><bowel><bowel inflammation><causation><cell biology><chemoattractant cytokine><chemokine><conditional knock-out><conditional knockout><design><designing><developmental><digestive canal><disease causation><enteral infection><enteric infection><enteric pathogen infection><enteric viral infection><enteric virus infection><enteropathogen infection><enteropathogenic infection><enzyme linked immunoassay><expectation><experiment><experimental research><experimental study><experiments><flow cytophotometry><floxed><floxed allele><functional outcomes><gut inflammation><imaging><immune evasive><improved><in vivo><infancy><infantile><infected with enteropathogen><inflamed bowel><inflamed gut><inflamed intestine><innovate><innovation><innovative><intervention therapy><intestinal epithelium><intestinal infection><intestinal inflammation><intestine infection><intraepithelial><kids><knockout gene><lymph cell><model of animal><monolayer><mortality><mouse model><murine model><neonatal mice><new approaches><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><new vaccines><next generation therapeutics><next generation vaccines><novel><novel approaches><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel strategies><novel strategy><novel therapeutics><novel therapy><novel vaccines><pathogen><pathogenic virus><prevent><preventing><pup><rational design><recruit><resolutions><response><reverse genetics><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell mRNA sequencing><single cell transcriptomic profiling><single-cell RNA sequencing><small bowel><social role><vaccine candidate><vaccine efficacy><validations><viral pathogen><virus genome><virus pathogen><virus pathogenesis><youngster>