Type I IFN Signaling Is Essential for Preventing IFN-γ Hyperproduction and Subsequent Deterioration of Antibacterial Immunity during Postinfluenza Pneumococcal Infection

Sunil Palani, Shruti Bansal, Atul K. Verma, Christopher Bauer, Shengjun Shao, Md Bashir Uddin, Keer Sun

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Postinfluenza bacterial pneumonia is a significant cause of hospitalization and death in humans. The mechanisms underlying this viral and bacterial synergy remain incompletely understood. Recent evidence indicates that influenza-induced IFNs, particularly type I IFN (IFN-I) and IFN-γ, suppress antibacterial defenses. In this study, we have investigated the relative importance and interplay of IFN-I and IFN-γ pathways in influenza-induced susceptibility to Streptococcus pneumoniae infection. Using genedeficient mouse models, as well as in vivo blocking Abs, we show that both IFN-I and IFN-γ signaling pathways contribute to the initial suppression of antibacterial immunity; however, IFN-γ plays a dominant role in the disease deterioration, in association with increased TNF-α production and alveolar macrophage (AM) depletion. We have previously shown that IFN-γ impairs AM antibacterial function and thereby acute bacterial clearance. The findings in this study indicate that IFN-γ signaling also impairs AM viability and αβ T cell recruitment during the progression of influenza/S. pneumoniae coinfection. Macrophages insensitive to IFN-γ mice express a dominant-negative mutant IFN-γR in mononuclear phagocytes. Interestingly, macrophages insensitive to IFN-γ mice exhibited significantly improved recovery and survival from coinfection, despite delayed bacterial clearance. Importantly, we demonstrate that IFN-I receptor signaling is essential for preventing IFN-γ hyperproduction and animal death during the progression of postinfluenza pneumococcal pneumonia.

Original languageEnglish (US)
Pages (from-to)128-135
Number of pages8
JournalJournal of Immunology
Volume209
Issue number1
DOIs
StatePublished - Jul 1 2022

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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