# Molecular and cellular mechanism regulating innate immunity and inflammation during pattern recognition receptor activation and respiratory virus infection

> **NIH NIH R01** · WASHINGTON STATE UNIVERSITY · 2020 · $375,233

## Abstract

Innate immunity constitutes pro-inflammatory response to initiate inflammation for adaptive immune response
required for virus clearance. Pro-inflammatory (and inflammation) response need to be “tightly” regulated
during virus infection since exaggerated inflammation contributes to inflammatory diseases. Activation of
Pattern Recognition Receptors (PRRs) is critical for triggering innate immunity and inflammation during
infection with human respiratory syncytial virus (RSV) and influenza A virus (IAV). Therefore, it is important to
study the underlying cellular/molecular mechanism involved in transducing optimal innate immunity and
inflammatory (and pro-inflammatory) response upon PRR activation. We have surprisingly identified a novel
signaling network that is required for optimal pro-inflammatory response following PRR activation. Our
preliminary result suggested that an oxysterol (a bioactive lipid) 25-hydroxycholesterol (25HC) play an
important role in magnifying and intensifying pro-inflammatory response following activation of PRRs and
during virus (RSV, IAV) infection. Surprisingly we observed interaction of 25HC with cell surface integrins and
further preliminary studies suggested a possible mechanism. Mechanistically, we postulate that 25HC released
from PRR activated (and virus infected) cells act as an extracellular soluble mediator to activate 25HC---
integrin (51, V3 integrins)---FAK (focal adhesion kinase)---NFB pathway for optimal pro-inflammatory
response. Thus, we envision that extracellular 25HC serve as a “linker” (via autocrine/paracine mechanism) to
bridge PRR pathway with integrin pathway for optimal pro-inflammatory response. We hypothesize that - a)
extracellular 25HC links PRR pathway with integrin pathway; b) PRR---25HC---integrin---FAK---NFB signaling
network magnifies pro-inflammatory response and inflammation; and c) 25HC--- integrin---FAK signaling
pathway contributes to exaggerated inflammation during RSV and IAV infection, thus leading to development
of exacerbated airway diseases like pneumonia and bronchiolitis. In the current proposal we have selected a
membrane bound PRR (i.e. toll-like receptor 3 or TLR3) and a cytosolic PRR (i.e. Nod2) along with two
clinically important respiratory viruses (RSV, IAV) to elucidate the role of 25HC---integrin---FAK---NFB
pathway in promoting optimal and maximal pro-inflammatory response. In aim-1 we will investigate interaction
of 25HC with integrins leading to activation of integrin---FAK---NFB pathway and subsequent pro-
inflammatory response in macrophages. In aim-2 we will examine the role of 25HC---integrin---FAK---NFB
pathway in triggering optimal pro-inflammatory response in macrophages following PRR (TLR3, Nod2)
activation and virus (RSV, IAV) infection. Finally, in aim-3 we will utilize knockout mice to study physiological in
vivo role of 25HC---integrin---FAK pathway during PRR (Nod2, TLR3) activation and virus (RSV, IAV) infection.
Significance –Our current...

## Key facts

- **NIH application ID:** 9987429
- **Project number:** 5R01AI083387-09
- **Recipient organization:** WASHINGTON STATE UNIVERSITY
- **Principal Investigator:** Santanu Bose
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $375,233
- **Award type:** 5
- **Project period:** 2010-06-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9987429

## Citation

> US National Institutes of Health, RePORTER application 9987429, Molecular and cellular mechanism regulating innate immunity and inflammation during pattern recognition receptor activation and respiratory virus infection (5R01AI083387-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9987429. Licensed CC0.

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