Ifn-γ drives tnf-α hyperproduction and lethal lung inflammation during antibiotic treatment of postinfluenza staphylococcus aureus pneumonia

Atul K. Verma, Christopher Bauer, Sunil Palani, Dennis W. Metzger, Keer Sun

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Inflammatory cytokine storm is a known cause for acute respiratory distress syndrome. In this study, we have investigated the role of IFN-γ in lethal lung inflammation using a mouse model of postinfluenza methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. To mimic the clinical scenario, animals were treated with antibiotics for effective bacterial control following MRSA superinfection. However, antibiotic therapy alone is not sufficient to improve survival of wild-type animals in this lethal acute respiratory distress syndrome model. In contrast, antibiotics induce effective protection in mice deficient in IFN-γ response. Mechanistically, we show that rather than inhibiting bacterial clearance, IFN-γ promotes proinflammatory cytokine response to cause lethal lung damage. Neutralization of IFN-γ after influenza prevents hyperproduction of TNF-α, and thereby protects against inflammatory lung damage and animal mortality. Taken together, the current study demonstrates that influenza-induced IFN-γ drives a stepwise propagation of inflammatory cytokine response, which ultimately results in fatal lung damage during secondary MRSA pneumonia, despite of antibiotic therapy.

Original languageEnglish (US)
Pages (from-to)1371-1376
Number of pages6
JournalJournal of Immunology
Volume207
Issue number5
DOIs
StatePublished - Sep 1 2021

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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