Influenza A infection decrease the population of tissue resident alveolar macrophages

Rationale Influenza A pneumonia is the most common cause of death from an infectious agent and can become an important contributor to overall mortality during pandemics. Severe influenza A pneumonia results in the development of the acute respiratory distress syndrome, which is the proximal cause of death in most of these patients. It is now recognized that alveolar macrophages represent a heterogeneous population of cells. Tissue resident alveolar macrophages are long lived, self‐renewing cells with developmental origins outside of the bone marrow. During infection, monocytes are recruited to the lung where they differentiate into alveolar macrophages. The role and fate of these different macrophage populations during the course of influenza A pneumonia is not known. Hypothesis Influenza A infection results in the replacement of tissue resident alveolar macrophages with monocyte derived cells that persist after injury. Methods We infected ten to twelve week old C57Bl/6 mice intratracheally with lethal and sublethal doses of influenza A/WSN/33. We analyzed inflammatory cell populations in lung digests at different time points after the influenza A infection using multi‐color flow cytometry. We developed a shielded bone marrow chimera system to unambiguously identify tissue resident and alveolar macrophage populations during the development and resolution of influenza A infection. Results In the early stages of influenza A infection, tissue‐resident alveolar macrophages could be readily distinguished from monocyte‐derived cells using flow cytometry. Tissue‐resident alveolar macrophages were rapidly depleted during influenza A infection accompanied by an influx of monocyte derived cells into the lung. Using bone marrow chimeric mice generated with lung protection followed by myeloablation, we observed that monocyte derived cells persisted in the lung after the resolution of infection for as long as 10 months but could no longer be distinguished from tissue resident cells on the basis of flow cytometry. Conclusions Influenza A infection results in the dose‐dependent depletion of tissue resident alveolar macrophages in the lung. Whether this results from direct infection by the influenza A virus or secondary effects related to lung tissue destruction and inflammation is not clear. Monocytes recruited to the lung during influenza A infection differentiate into alveolar macrophages in the local microenvironment of the lung and persist long after the resolution of infection. Our results suggest that severe influenza infection results in permanent changes in tissue resident alveolar macrophage ontogeny.