# Reversing Cigarette Smoke-Induced Antiviral Immunosuppression

> **NIH VA I01** · OKLAHOMA CITY VA MEDICAL CENTER · 2021 · —

## Abstract

The long-term goal of our work is to understand how the human innate immune system responds to
Influenza A virus (IAV) infection and to find novel methods to control the infection. Cigarette smoking is a
significant public health problem, particularly among veterans. Exposure to cigarette smoke (CS) significantly
increases the risk for respiratory viral infections. Influenza infection is seven times more common and is much
more severe in smokers than nonsmokers. The goal of our proposed studies is to determine the severity and
mechanisms of CS-mediated innate immune suppression. Induction of interferon (IFN) is a critical component
of the host response to influenza infection. IFNs are further divided into type I (mainly IFN-α and β), II (IFN-γ)
and III (IFN-λ) subtypes, based in part on the differential use of unique receptors through which they mediate
signal transduction to induce antiviral activity. Retinoic acid-inducible protein I (RIG-I) plays an important role in
the recognition of, and IFN induction by, IAV. Our previous studies have shown that CS and cigarette smoke
extract (CSE) suppress antiviral innate immune responses in IAV-infected human and mouse lung, especially
immunosuppression due to RIG-I inhibition. This immunosuppressive effect of CS may play a critical role in the
enhanced susceptibility of smokers to serious influenza infection. We have also shown that reversing the RIG-I
defect prevents CS induced immunosuppression, restores all three types of IFN responses, and reduces
mortality. We have also discovered a new mechanism whereby IAV and CS decreases barrier function and
increases lung injury during infection through induction of cytochrome P450 family 1 subfamily B member 1
(CYP1B1). We have new preliminary data that demonstrates this effect, and that RIG-I activation appears to
suppress CYP1B1 induction, and that partial loss of CYP1B1 decreases lung injury during infection. These
novel findings support the idea that understanding the mechanisms of CS-induced immunosuppression may
have significant therapeutic potential.
 Our overall hypothesis is that CS increases lung injury by suppressing RIG-I and upregulating CYP1B1.
We further hypothesize that RIG-I overexpression or chemical RIG-I activation using SLR10 suppresses
CYP1B1, decreases lung injury and mortality during IAV infection. We will use an in vitro human model and an
in vivo mouse model to test these concepts to evaluate the role of CYP1B1-mediated lung injury and RIG-I-
mediated immune restoration in smokers during IAV infection.
We will test these hypotheses using the following integrated Specific Aims:
 AIM 1: Determine whether chemical activation of RIG-I alleviates CS-induced mortality and
immunosuppression during IAV infection.
 AIM 2: Determine whether CYP1B1 induction by CS enhances lung injury and mortality during IAV
infection.
 This proposal is conceptually innovative, as it addresses unanswered questions regarding whether specific
stimulation of RIG...

## Key facts

- **NIH application ID:** 10125418
- **Project number:** 1I01BX005023-01A2
- **Recipient organization:** OKLAHOMA CITY VA MEDICAL CENTER
- **Principal Investigator:** JORDAN PATRICK METCALF
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2020-10-01 → 2024-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10125418

## Citation

> US National Institutes of Health, RePORTER application 10125418, Reversing Cigarette Smoke-Induced Antiviral Immunosuppression (1I01BX005023-01A2). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10125418. Licensed CC0.

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