# Mechanisms of hepatic innate immune activation by HCV

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2020 · $523,114

## Abstract

Our proposal is focused on defining the molecular mechanisms by which hepatitis C virus (HCV)
triggers inflammasome activation and signaling crosstalk from interleukin (IL)-1β to drive hepatic
inflammation, innate immune activation, and therapeutic outcome of infection and immunity. HCV
is a major cause of liver disease worldwide, wherein disease is marked by hepatic
inflammation/chronic hepatitis that eventually compromises liver function. However, the molecular
mechanisms by which HCV triggers hepatic inflammation to impart immune activation and
disease are not known nor has the outcome of the new direct acting antiviral (DAA) therapy on
these processes defined. Our studies reveal a central role for hepatic macrophages or “Kupffer
cells” in responding to HCV to trigger hepatic inflammation through activation of the NLRP3
inflammasome, and show that IL-1 receptor signaling imparts novel cytokine crosstalk that
promotes an innate immune/inflammatory circuit driving hepatic innate immune activation
underscoring liver disease. Importantly, our preliminary studies suggest that the acute drop of
HCV load by DAA therapy in HCV patients can abrogate this circuit for possible resolution of
innate immune activation and inflammatory signaling. Our study design comprises two Aims to
investigate the hypothesis that HCV activation of the NLRP3 inflammasome in liver macrophages
drives hepatic inflammation, innate immune activation, and chronic hepatitis through a virion-
induced inflammasome-cytokine loop that underlies immune activation and liver disease.

## Key facts

- **NIH application ID:** 9828766
- **Project number:** 5R01AI127463-04
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Michael Gale
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $523,114
- **Award type:** 5
- **Project period:** 2016-12-15 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9828766

## Citation

> US National Institutes of Health, RePORTER application 9828766, Mechanisms of hepatic innate immune activation by HCV (5R01AI127463-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9828766. Licensed CC0.

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