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

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.

Activation of A 1 -Adenosine Receptors Promotes Leukocyte Recruitment to the Lung and Attenuates Acute Lung Injury in Mice Infected with Influenza A/WSN/33 (H1N1) Virus

“…These results are in agreement with those of several previous studies in which neutrophil depletion did not alter viral replication or body weight loss (39)(40)(41)(42). However, macrophage depletion studies (including our own) have generally shown that macrophage depletion increases viral replication, which contrasts with our current findings (24,(43)(44)(45)(46). The underlying reason for this discrepancy is unclear, although it may indicate that, despite being attenuated, the macrophage response to infection in A 1 -KO mice may nevertheless be sufficient to control viral replication.…”

Influenza virus replication in macrophages: balancing protection and pathogenesis

“…Thus, the response of these cells to IAV infection is likely to be of critical importance to disease outcome. The importance of macrophages for protection against IAV infection is well established, as ablation of macrophages enhances IAV-associated immunopathology and mortality [8][9][10][11][12]. The importance of macrophages during IAV infection goes beyond protection from virus-induced pneumonia.…”

Respiratory syncytial virus-like nanoparticle vaccination induces long-term protection without pulmonary disease by modulating cytokines and T-cells partially through alveolar macrophages

“…11,12 AMs are known to be required to induce protective immune responses against bacteria, fungi, and viruses. 13 Dendritic cells (DCs) together with AMs are major antigen-presenting cells in the lungs. Respiratory DCs play a crucial role in inducing adaptive immune responses.…”