# MAVS-Mediated Pulmonary Inflammation and Injury Response During Cigarette Smoke Exposure and Influenza Viral Infection and in COPD

> **NIH VA I01** · VA CONNECTICUT HEALTHCARE SYSTEM · 2021 · —

## Abstract

Viral infections have more severe consequences in individuals who have been exposed to cigarette smoke (CS)
than in those not exposed to CS. Acute exacerbations of COPD contributes toward rapid lung function decline.
Surprisingly, the mechanisms that underlie the exaggerated virus-induced responses in CS-exposed individuals
have not been adequately addressed. Our studies demonstrated that viruses cause increased levels of
inflammation, tissue destruction and lung fibrosis in CS exposed mice. We first reported adverse effects of CS
exposure were eliminated by null mutations of mitochondrial antiviral signaling molecule (MAVS), a key adapter
molecule that is bound to the mitochondrial outer membrane and essential for antiviral signaling. To further define
the mechanisms of these responses, on the premise that CS causes alteration of MAVS-mediated signaling, we
have focused on the dysregulation of MAVS-mediated signaling and its regulatory mechanisms in CS-exposed
and CS + virus exposed mice.
 Our studies highlight the following novel insights: (1) CS exposure leads to persistent macrophage
inflammation and increased fibrotic lung changes after influenza virus (Flu); (2) Lung macrophages show
increased MAVS levels which were associated with excessive inflammatory, injury and fibrotic responses during
CS+Flu; (3) Ex vivo lung-derived fibroblasts from CS+Flu have increased proliferation, expression of alpha-
smooth muscle actin stained stress fibers, growth factor expression with pro-fibrotic and pro-proliferative
transcriptomic signature; (4) The prion-like multimeric aggregation of MAVS, a key event in MAVS-mediated
antiviral signaling, is markedly enhanced in mouse lungs exposed to CS+Flu; (5) Lungs from COPD patients
have increased MAVS aggregation; (6) Inflammasomes activation, inflammatory and tissue damage responses
are exaggerated in CS+Flu lungs and involves MAVS; and (7) Phosphatase and tensin homologue (PTEN)-
induced putative kinase 1 (PINK1), an important regulator of mitochondrial health, plays a critical inhibitory role
in regulating MAVS-mediated inflammasomes and pathology.
 Based on these observations, we hypothesize that CS-induced dysregulation of MAVS homeostasis on
mitochondria has a critical functional role in the exaggerated pulmonary inflammation and tissue damage
responses observed in the lungs during viral infection. In Aim 1, we will characterize the dysregulation of
homeostatic regulation of MAVS on mitochondria, the MAVS prion-like aggregation and MAVS- and PINK1-
mediated signaling after CS and influenza virus co-exposure. In Aim 2, we will define the consequences of
PINK1-mediated regulation of MAVS aggregation on pathological pulmonary outcomes in smoke exacerbated
influenza pathology and PINK1 augmentation as a possible therapeutic approach. In Aim 3, we will characterize
MAVS aggregation pathway in patients with smoking exposure and respiratory viral infection.
 These proposed studies will provide new insights into h...

## Key facts

- **NIH application ID:** 10045508
- **Project number:** 5I01BX004661-02
- **Recipient organization:** VA CONNECTICUT HEALTHCARE SYSTEM
- **Principal Investigator:** Charles S Dela Cruz
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-10-01 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10045508

## Citation

> US National Institutes of Health, RePORTER application 10045508, MAVS-Mediated Pulmonary Inflammation and Injury Response During Cigarette Smoke Exposure and Influenza Viral Infection and in COPD (5I01BX004661-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10045508. Licensed CC0.

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