Alveolar Macrophages Are Essential for Protection from Respiratory Failure and Associated Morbidity following Influenza Virus Infection

Christoph Schneider,Samuel P Nobs,Manfred Kopf,Alex K Heer,Johannes Vogel,Michael Kurrer,Glynis Klinke,Nico Van Rooijen,Andrew Pekosz

doi:10.1371/journal.ppat.1004053

Christoph Schneider, Samuel P Nobs + Show 7 more

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https://doi.org/10.1371/journal.ppat.1004053

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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/Pparg fl/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.

Highlights

Alveolar macrophages (AM) are lung-resident macrophages important for the maintenance of surfactant homeostasis in the alveolar space [1]. Their importance for lung physiology becomes evident in a rare human syndrome termed ‘‘pulmonary alveolar proteinosis’’ (PAP), which is characterized by the accumulation of surfactant material and a varying degree of respiratory insufficiency [2]
Alveolar macrophages and various subsets of dendritic cells have been implicated in innate immunity and induction of antiviral T cell responses that contribute to host defense against influenza virus infection
We demonstrate that mice lacking alveolar macrophages succumb to infection with low dose influenza virus and vaccinia virus infection due to respiratory failure

Summary

Introduction

Alveolar macrophages (AM) are lung-resident macrophages important for the maintenance of surfactant homeostasis in the alveolar space [1]. PAP typically occurs in patients that spontaneously develop GM-CSF autoantibodies [4] or carrying mutations in the GM-CSF receptor a chain [5] associated with impaired function and/or reduced numbers of AM. Mice lacking GM-CSF (Csf22/2) or the receptor b chain (Csf2rb2/2) develop PAP [6,7,8,9] and display increased susceptibility to a range of bacterial and fungal infections, which is associated with impaired innate functions of AM [10,11,12,13,14]. AM were described to have anti-inflammatory properties based on direct inhibition of the antigen-presenting function of lung DCs [15] and production of immunosuppressive mediators such as IL-10 and nitric oxide [16]

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