# Mechanistic Insights of TIMP-1 in Influenza Virus Infection

> **NIH NIH R03** · UNIVERSITY OF GEORGIA · 2022 · $75,500

## Abstract

PROJECT SUMMARY/ ABSTRACT
Influenza A virus (IAV) epidemics are associated with high morbidity and mortality. Complications such as the
development of secondary bacterial pneumonia and cytokine storm leading to multi-organ failure increase
morbidity and mortality. Although vaccines are developed annually for emerging IAV strains, not all subjects
are vaccinated or able to mount robust protective immune responses to the vaccines. Anti-viral drugs such as
oseltamivir are not fully effective at preventing mortality associated with severe IAV infections. Thus, there is
an urgent need to identify new therapeutic targets to facilitate the development of more effective antiviral
agents to limit the high global healthcare burden associated with IAV infections. TIMP-1 (tissue inhibitor of
metalloproteinases 1) controls the enzymatic activity of matrix metalloproteinases (MMPs) and is well-known
for regulating extracellular matrix (ECM) turnover, but its contributions to the pathogenesis of IAV disease have
not been deeply explored. Our novel preliminary data showed that plasma TIMP-1 levels are significantly
upregulated in patients diagnosed with pandemic H1N1 and seasonal IAV infections, and levels correlate
inversely with the PaO2/FiO2 ratio. Furthermore, our data using immunofluorescence staining suggested TIMP-
1 is dramatically induced in lipofibroblasts. Compared with WT mice, Timp-1-/- mice have reduced H1N1 IAV-
induced body weight loss; mortality; lung injury; increased adaptive immune responses and T cell and B cell
activation, and attenuated capillary leak. Based on our data, TIMP-1 might serve as a novel therapeutic target
during serious IAV infection. The experiments proposed in this application aim to 1) identify the regulation and
function of TIMP-1 during the IAV infection; 2) provide novel insights into the mechanism by which Timp-1
deficiency provides better outcomes during IAV infection. Successful completion of these studies will pave the
way for future investigational new drug (IND)-enabling studies to test the safety and efficacy of a “first in class”
therapeutic targeting the host response to reduce the morbidity and mortality associated with serious IAV
infection.

## Key facts

- **NIH application ID:** 10431082
- **Project number:** 1R03AI169063-01
- **Recipient organization:** UNIVERSITY OF GEORGIA
- **Principal Investigator:** Xiaoyun Wang
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $75,500
- **Award type:** 1
- **Project period:** 2022-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10431082

## Citation

> US National Institutes of Health, RePORTER application 10431082, Mechanistic Insights of TIMP-1 in Influenza Virus Infection (1R03AI169063-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10431082. Licensed CC0.

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