# A Multifaceted Approach to Study Tissue and Cell Type Specific Molecular Mechanisms of the Host Response to Acute/Chronic Viral Infection.

> **NIH NIH R35** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2020 · $9,974

## Abstract

Very few viruses are able to manifest as chronic infections or symptomatic acute infections in humans. Once
intrinsic innate immune responses are ineffective at controlling virus replication, chronic viral infections are
established or humans may die from a subsequent cytokine storm. In most organs, the first line of defense
against invading viruses is the epithelial cell which provides initial immune response and subsequent immune
control. Previous research on innate immune responses, specifically antiviral responses, have primarily focused
on the characterization of pattern recognition receptors (PRRs), associated signaling molecules, and interferon
(IFN) signaling pathways while also defining antiviral functions of interferon stimulated genes (ISGs). Recent
studies of stem cell differentiation to hepatocytes have revealed differential regulation of ISG expression which
contributes to host cell susceptibility to viral infection. Interestingly, epithelial cells predominantly produce type
III interferons (IFNs) in response to viral infection whereas immune cells produce Type II IFNs (γ) and Type I
IFNs (α/β) are produced by most cells in the body. The mechanism underlying cell type and tissue specific
expression of the type III IFNs are unknown and likely involve regulation of epigenetics modifications, gene
expression of pattern recognition receptors and associated signaling molecules. We have developed novel and
exciting in vitro models that utilize primary epithelial cells from several organs that have intact innate immune
responses when compared to immortalized or transformed cell lines. We and others have shown that these cell
types are of critical importance in the development of disease since they directly detect components of viral
pathogens. We therefore assert that primary cells are the optimal model to use for studies on innate immunity
and we propose a novel approach to study innate immunity based on the innate immune pathways that we have
demonstrated to be important for microbial pathogenesis. In addition, we are developing novel physiologic
models incorporating primary epithelial cells, stem cell-derived epithelial cells, 3-dimensional chip and
microfluidic-based platforms. The use of stem cell-derived cells would facilitate the identification of changes in
gene expression, which occur during differentiation, that contribute to the unique innate immune system in
epithelial cells. The specific goal of this summer research supplement for David Barr is to support model
development to further interrogate these organ specific host defense responses. Completion of these studies
would offer the most in depth characterization of innate immunity in epithelial and other cell- types while
improving our understanding of its contribution to human disease in multiple organs including those involving
coronaviruses.

## Key facts

- **NIH application ID:** 10152086
- **Project number:** 3R35GM124915-03S2
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** Emmanuel Thomas
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $9,974
- **Award type:** 3
- **Project period:** 2017-09-10 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10152086

## Citation

> US National Institutes of Health, RePORTER application 10152086, A Multifaceted Approach to Study Tissue and Cell Type Specific Molecular Mechanisms of the Host Response to Acute/Chronic Viral Infection. (3R35GM124915-03S2). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10152086. Licensed CC0.

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