# Inhibition of PAR2 as therapeutic approach to enhance anti-viral immune responses

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $388,750

## Abstract

Viral infections cause considerable morbidity and mortality worldwide. Viruses induce tissue factor (TF)
expression in various cell types and this leads to activation of coagulation as part of the innate immune
response. Coagulation proteases activate cells by cleavage of protease-activated receptors (PARs). For
instance, the TF:FVIIa:FXa activates PAR2 on a variety of cell types. Besides this, other proteases such as
trypsin or tryptase can activate PAR2. Toll-like receptors (TLRs) play a central role in host defense. It has been
proposed that TLRs and PARs act as a dual-receptor system to detect pathogens. Viral myocarditis causes up
to 20% of sudden death in adults less than 40 years of age. Coxsackievirus B3 (CVB3) is considered to be one
of the dominant etiological agents of myocarditis. Influenza A and B virus causes the flu. Influenza virus infects
epithelial cells in the lung and in severe cases causes viral pneumonia. The elderly are particularly susceptible
to the flu. At present, treatment of myocarditis remains nonspecific and only supportive. Furthermore, optimal
IAV treatments are still under development. PAR2 is known to play a major role in multiple inflammatory
disorder. In addition, expression and activity of PAR2 activating proteases, such as tryptase and trypsin, has
been linked to CVB3 myocarditis and influenza virus infection susceptibility. Recently, we discovered that the
PAR2 pathway dampens the innate immune response to CVB3 in mice leading to more pronounced
myocarditis. Furthermore, we and others found that PAR2 deficiency was associated with reduced influenza
virus infection. At present little is known about the underlying pathologic mechanism of PAR2 in CVB3-induced
myocarditis and influenza virus infection. The proposal will elucidate the mechanisms by which PAR2
enhances viral infection using mouse models of CVB3 myocarditis and H1N1 influenza A virus infection. More
important, we will test a therapeutic approach by inhibiting FXa or PAR2 to improve the outcome after CVB3 or
H1N1 infection. The proposed studies are highly significant because they may elucidate new pathways and
treatments to treat viral myocarditis, H1N1 influenza A virus infection and viral infections in general.

## Key facts

- **NIH application ID:** 9948744
- **Project number:** 5R01HL142799-03
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Silvio Antoniak
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $388,750
- **Award type:** 5
- **Project period:** 2018-08-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9948744

## Citation

> US National Institutes of Health, RePORTER application 9948744, Inhibition of PAR2 as therapeutic approach to enhance anti-viral immune responses (5R01HL142799-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9948744. Licensed CC0.

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