Alveolar macrophages are essential for protection from respiratory failure and associated morbidity following influenza virus infection.
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.
Molecular Biomedicine, Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zurich, Switzerland.
Christoph
C
Schneider
Molecular Biomedicine, Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zurich, Switzerland.
Samuel P
SP
Nobs
Molecular Biomedicine, Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zurich, Switzerland.
Alex K
AK
Heer
Pathology Institute, Zurich, Switzerland.
Michael
M
Kurrer
Division of Clinical Chemistry and Biochemistry, University Children's Hospital Zurich, Zurich, Switzerland.
Glynis
G
Klinke
Department of Molecular Cell Biology, Free University Medical Center, Amsterdam, The Netherlands.
Nico
N
van Rooijen
Institute of Veterinary Physiology, University of Zurich, Zurich, Switzerland.
Johannes
J
Vogel
Molecular Biomedicine, Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zurich, Switzerland.
Manfred
M
Kopf
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D053648:Cytokine Receptor Common beta Subunit / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology; D007111:Immunity, Cellular; D053118:Influenza A Virus, H1N1 Subtype; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000473:pathology / Q000821:virology; D051379:Mice; D018345:Mice, Knockout; D009976:Orthomyxoviridae Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D047495:PPAR gamma / Q000235:genetics / Q000276:immunology; D012131:Respiratory Insufficiency / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000821:virology
D053648:Cytokine Receptor Common beta Subunit; D047495:PPAR gamma; C072186:Csf2rb protein, mouse