GM-CSF modulates pulmonary resistance to influenza A infection

Zvjezdana Sever-Chroneos, Aditi Murthy, Jeremy Davis, Jon Matthew Florence, Anna Kurdowska, Agnieszka Krupa, Jay W. Tichelaar, Mitchell R. White, Kevan L. Hartshorn, Lester Kobzik, Jeffrey A. Whitsett, Zissis C. Chroneos

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

Alveolar type II epithelial or other pulmonary cells secrete GM-CSF that regulates surfactant catabolism and mucosal host defense through its capacity to modulate the maturation and activation of alveolar macrophages. GM-CSF enhances expression of scavenger receptors MARCO and SR-A. The alveolar macrophage SP-R210 receptor binds the surfactant collectin SP-A mediating clearance of respiratory pathogens. The current study determined the effects of epithelial-derived GM-CSF in host resistance to influenza A pneumonia. The results demonstrate that GM-CSF enhanced resistance to infection with 1.9×10 4ffc of the mouse-adapted influenza A/Puerto Rico/8/34 (PR8) H1N1 strain, as indicated by significant differences in mortality and mean survival of GM-CSF-deficient (GM -/-) mice compared to GM -/- mice in which GM-CSF is expressed at increased levels. Protective effects of GM-CSF were observed both in mice with constitutive and inducible GM-CSF expression under the control of the pulmonary-specific SFTPC or SCGB1A1 promoters, respectively. Mice that continuously secrete high levels of GM-CSF developed desquamative interstitial pneumonia that impaired long-term recovery from influenza. Conditional expression of optimal GM-CSF levels at the time of infection, however, resulted in alveolar macrophage proliferation and focal lymphocytic inflammation of distal airways. GM-CSF enhanced alveolar macrophage activity as indicated by increased expression of SP-R210 and CD11c. Infection of mice lacking the GM-CSF-regulated SR-A and MARCO receptors revealed that MARCO decreases resistance to influenza in association with increased levels of SP-R210 in MARCO -/- alveolar macrophages. In conclusion, GM-CSF enhances early host resistance to influenza. Targeting of MARCO may reinforce GM-CSF-mediated host defense against pathogenic influenza.

Original languageEnglish (US)
Pages (from-to)319-328
Number of pages10
JournalAntiviral Research
Volume92
Issue number2
DOIs
StatePublished - Nov 2011

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Virology

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