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

作者：Schneider Christoph^*; Nobs Samuel P; Heer Alex K; Kurrer Michael; Klinke Glynis; van Rooijen Nico; Vogel Johannes; Kopf Manfred

来源：PLoS Pathogens, 2014, 10(4): e1004053.

DOI：10.1371/journal.ppat.1004053

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 CD8(+) 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.
Author Summary Acute respiratory viral infections can cause severe morbidity and pneumonia in infected individuals. Alveolar macrophages and various subsets of dendritic cells have been implicated in innate immunity and induction of anti-viral T cell responses that contribute to host defense against influenza virus infection. However, their relative importance in protection from pathology and disease severity has never been compared side by side. In this report, we demonstrate that mice lacking alveolar macrophages succumb to infection with low dose influenza virus and vaccinia virus infection due to respiratory failure. In contrast, mice lacking lymphoid CD8(+) and lung CD103(+) DCs survived and showed little if any differences in disease severity compared to infected wild-type mice. These results indicate that therapies supporting AM and lung function may be beneficial during severe respiratory viral infection.

• 出版日期2014-4