Flagellin-modulated inflammasome pathways characterize the human alveolar macrophage response to , a lung-tropic pathogen.

Melioidosis is an emerging tropical infection caused by inhalation, inoculation, or ingestion of the flagellated, facultatively intracellular pathogen . The melioidosis case fatality rate is often high, and pneumonia, the most common presentation, doubles the risk of death. The alveolar macrophage is a sentinel pulmonary host defense cell, but the human alveolar macrophage in infection has never been studied. The objective of this study was to investigate the host-pathogen interaction of infection with the human alveolar macrophage and to determine the role of flagellin in modulating inflammasome-mediated pathways. We found that infects primary human alveolar macrophages but is gradually restricted in the setting of concurrent cell death. Electron microscopy revealed cytosolic bacteria undergoing division, indicating that likely escapes the alveolar macrophage phagosome and may replicate in the cytosol, where it triggers immune responses. In paired human blood monocytes, uptake and intracellular restriction of are similar to those observed in alveolar macrophages, but cell death is reduced. The alveolar macrophage cytokine response to is characterized by marked interleukin (IL)-18 secretion compared to monocytes. Both cytotoxicity and IL-18 secretion in alveolar macrophages are partially flagellin dependent. However, the proportion of IL-18 release that is driven by flagellin is greater in alveolar macrophages than in monocytes. These findings suggest differential flagellin-mediated inflammasome pathway activation in the human alveolar macrophage response to infection and expand our understanding of intracellular pathogen recognition by this unique innate immune lung cell.