# 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 · $43,582

## Abstract

Very few viruses are able to manifest as chronic infections in humans. The intrinsic innate immune response
provides a first line of defense against invading viruses; however, in the case of chronic viral infections, these
initial responses that were ineffective at controlling virus replication can then cause disease over many years
due to chronic activation. In most organs, epithelial cells are some of the first cells to encounter viruses in the
human body and innate immune responses in these cells are paramount to driving subsequent immune
control. 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. In drosophila, the fat body is the primary innate immune organ producing
antimicrobial peptides in response to pathogens. The human liver, equivalent to the drosophila fat body in
terms of function, utilizes Type III IFN responses to fight viral infection and likely possesses other unique
properties with respect to innate immunity when compared to other organs. 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 goals of this program are to functionally characterize the innate immune
response, including the production of Type III IFNs, to multiple viral pathogen associated patterns, including
both DNA and RNA sensing pathways, and to elucidate the underlying molecular mechanisms through which
innate immunity manifests in epithelial cells using sophisticated in vitro models. In addition, tissue specific and
developmental expression of specific innate immune signaling components including, TLR3, STING and IRF7,
will be addressed as a mechanism underlying tissue specific respons...

## Key facts

- **NIH application ID:** 9974884
- **Project number:** 3R35GM124915-03S1
- **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:** $43,582
- **Award type:** 3
- **Project period:** 2017-09-10 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9974884

## Citation

> US National Institutes of Health, RePORTER application 9974884, A Multifaceted Approach to Study Tissue and Cell Type Specific Molecular Mechanisms of the Host Response to Acute/Chronic Viral Infection (3R35GM124915-03S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9974884. Licensed CC0.

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