# Oxidative Burst in Influenza and MRSA Co-infection

> **NIH NIH R01** · UNIVERSITY OF TEXAS MED BR GALVESTON · 2021 · $511,461

## Abstract

PROJECT SUMMARY
Methicillin-resistant S. aureus (MRSA) infection complicated by influenza emerges as a leading cause of death
during recent influenza pandemics and epidemics. Defective bacterial control and exaggerated lung
inflammation are believed to be responsible for high mortality in patients and animals. However, a hitherto
incomplete understanding of coinfection pathophysiology has hampered the development of effective
treatments.
NADPH oxidase 2 (NOX2) is an enzyme complex predominantly expressed by phagocytes. The generation of
reactive oxygen species (ROS) through NOX2, a process called oxidative burst, is required for lung S. aureus
clearance. During the initial funding period, the work from PI's laboratory has established that intracellular ROS
in phagocytes decrease at the recovery stage of influenza infection, thereby leading to defective killing of S.
aureus. However, although intracellular ROS are reduced per cell, there are excessive inflammatory cells that
release oxidants during coinfection. This event eventually culminates in lethal oxidative lung damage.
Furthermore, preliminary studies in PI's laboratory reveal that type I IFN (IFN-I) signaling facilitates monocyte
recruitment as it inhibits lung bacterial clearance, whereas IFN-γ signaling promotes lung inflammation and
lethal lung damage after influenza and S. aureus coinfection. Therefore, it is hypothesized that influenza-
induced IFN responses disrupt the balance between oxidative burst-associated antibacterial immunity and
inflammation, and results in not only susceptibility to secondary S. aureus infection but also lethal lung injury
thereafter.
The approaches to test the hypothesis include: 1) to determine whether influenza-induced IFN-I impairs
antibacterial immunity by promoting monocyte recruitment. Specifically, the cellular and signaling mechanisms
for IFN-I-suppressed bacterial killing will be examined in mouse coinfection models; 2) to elucidate how IFN-γ
promotes an inflammatory cytokine storm and lethal lung injury during influenza and S. aureus coinfection.
Specifically, the contribution of the IFN-γ-driven destructive inflammation cascade to lethal lung damage will be
determined in a clinical-relevant coinfection mouse model; and 3) refine combination treatment strategies that
target both intracellular bacteria and lung inflammation. It has been reported by PI's laboratory that
combination treatment with antibiotic and NOX2 inhibitor significantly improves animal survival from influenza
and MRSA coinfection. Specific aim 3 is to optimize this combination therapeutic approach based on the
findings from studies proposed in aim 1 &2. The ultimate goal of this project is to establish the treatment
strategy to restore antimicrobial defense while limiting inflammatory lung damage during influenza and MRSA
coinfection.

## Key facts

- **NIH application ID:** 10075296
- **Project number:** 7R01HL118408-09
- **Recipient organization:** UNIVERSITY OF TEXAS MED BR GALVESTON
- **Principal Investigator:** Keer Sun
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $511,461
- **Award type:** 7
- **Project period:** 2013-05-22 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10075296

## Citation

> US National Institutes of Health, RePORTER application 10075296, Oxidative Burst in Influenza and MRSA Co-infection (7R01HL118408-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10075296. Licensed CC0.

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