# MMP-8 Deficiency Improves Host Responses to  Influenza Viral Infections

> **NIH NIH F32** · UNIVERSITY OF GEORGIA · 2020 · $50,301

## Abstract

Project Summary/ Abstract
Seasonal influenza causes 0.25-0.5 million deaths/year world-wide and mortality increases substantially in
pandemic years. Although influenza vaccines are developed annually, only 49% of the US population was
vaccinated in 2010-2011, and not all subjects develop robust protective immune responses to these vaccines.
Current anti-viral drugs (e.g. oseltamivir) target only the virus and do not prevent influenza-associated mortality
in all individuals. Thus, there is an urgent need to develop more effective therapies that limit the mortality and
high health care burden that are associated with influenza A viral (IAV) infections. MMP-8 cleaves pro-
inflammatory mediators to regulate inflammatory responses to various stimuli, but its contributions to the
pathogenesis of IAV disease have not been evaluated. My novel preliminary data strongly link Matrix
metalloproteinase-8 (Mmp-8) to adverse outcomes in animals infected with IAV. Plasma MMP-8 levels are
significantly upregulated in patients diagnosed with pandemic H1N1 and seasonal IAV infections, and levels
correlate inversely with the PaO2/FiO2 ratio. Mmp-8 lung levels are also increased in the lungs of H1N1-
infected WT mice and localized to airway epithelial cells and airway macrophages. Compared with WT mice,
Mmp-8-/- mice have reduced H1N1 IAV-induced mortality; lower lung viral burdens; increased lung levels of
type I interferons (IFNs) and products of activated M1 macrophages, and increased necroptosis of virally-
infected epithelial cells. Thus, our data identifying MMP-8 for the first time as a novel therapeutic target during
serious IAV infections. The goal of this postdoctoral fellowship is to test the central hypotheses: Mmp-8
deficiency in leukocytes (macrophages) reduces lung viral burdens and improves outcomes in IAV-infected
mice by increasing: 1) M1 macrophage polarization to induce a more effective (Th1) adaptive immune
response to IAV; 2) the lung macrophage type I IFN response; and 3) type I IFN induced-necroptosis of IAV-
infected epithelial cells to limit IAV viral replication and spreading. Small molecule MMP-8 inhibitors are not
selective and have off-target toxic effects. Our studies will also determine the extent to which a novel nanobody
inhibitor (Nb14_NbAlb) that selectively inhibits this host protein has therapeutic efficacy in a pre-clinical model of
IAV infection. Successful completion of these studies will pave the way for future 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 infections.

## Key facts

- **NIH application ID:** 10260933
- **Project number:** 7F32HL147437-03
- **Recipient organization:** UNIVERSITY OF GEORGIA
- **Principal Investigator:** Xiaoyun Wang
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $50,301
- **Award type:** 7
- **Project period:** 2019-05-15 → 2022-05-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10260933

## Citation

> US National Institutes of Health, RePORTER application 10260933, MMP-8 Deficiency Improves Host Responses to  Influenza Viral Infections (7F32HL147437-03). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10260933. Licensed CC0.

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