Alveolar macrophages are essential for protection from respiratory failure and associated morbidity following influenza virus infection

PLoS Pathog. 2014 Apr 3;10(4):e1004053. doi: 10.1371/journal.ppat.1004053. eCollection 2014 Apr.

Abstract

Alveolar macrophages (AM) are critical for defense against bacterial and fungal infections. However, a definitive role of AM in viral infections remains unclear. We here report that AM play a key role in survival to influenza and vaccinia virus infection by maintaining lung function and thereby protecting from asphyxiation. Absence of AM in GM-CSF-deficient (Csf2-/-) mice or selective AM depletion in wild-type mice resulted in impaired gas exchange and fatal hypoxia associated with severe morbidity to influenza virus infection, while viral clearance was affected moderately. Virus-induced morbidity was far more severe in Csf2-/- mice lacking AM, as compared to Batf3-deficient mice lacking CD8α+ and CD103+ DCs. Csf2-/- mice showed intact anti-viral CD8+ T cell responses despite slightly impaired CD103+ DC development. Importantly, selective reconstitution of AM development in Csf2rb-/- mice by neonatal transfer of wild-type AM progenitors prevented severe morbidity and mortality, demonstrating that absence of AM alone is responsible for disease severity in mice lacking GM-CSF or its receptor. In addition, CD11c-Cre/Ppargfl/fl mice with a defect in AM but normal adaptive immunity showed increased morbidity and lung failure to influenza virus. Taken together, our results suggest a superior role of AM compared to CD103+ DCs in protection from acute influenza and vaccinia virus infection-induced morbidity and mortality.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / pathology
  • Cytokine Receptor Common beta Subunit / genetics
  • Cytokine Receptor Common beta Subunit / immunology
  • Dendritic Cells / immunology
  • Dendritic Cells / pathology
  • Immunity, Cellular*
  • Influenza A Virus, H1N1 Subtype
  • Macrophages, Alveolar / immunology*
  • Macrophages, Alveolar / pathology
  • Macrophages, Alveolar / virology
  • Mice
  • Mice, Knockout
  • Orthomyxoviridae Infections / genetics
  • Orthomyxoviridae Infections / immunology*
  • Orthomyxoviridae Infections / pathology
  • PPAR gamma / genetics
  • PPAR gamma / immunology
  • Respiratory Insufficiency / genetics
  • Respiratory Insufficiency / immunology*
  • Respiratory Insufficiency / pathology
  • Respiratory Insufficiency / virology

Substances

  • Cytokine Receptor Common beta Subunit
  • PPAR gamma
  • Csf2rb protein, mouse

Grant support

This research was supported by a grant from the Swiss National Science Foundation (310030-124922/1) to MKo. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.