The role of pathogen-experienced macrophage subsets in mediating lung immunity and heterologous protection

ABSTRACT: Infections of the lung significantly impact health worldwide, with non-tuberculosis lower respiratory infections causing 2.7 million deaths annually and chronic infections significantly contributing to impaired lung function and morbidity. Pulmonary macrophages are critical, front-line mediators of host protection against helminth parasites, fungi, and viruses. Despite the well-defined role of lung macrophages as crucial initiators of immunity to diverse sets of pathogens, our understanding of the cellular and molecular events that regulate macrophage responses in the lung remain poorly defined. For example, the precise mechanisms that allow pulmonary macrophages to eliminate both intracellular and extracellular pathogens while simultaneously mitigating tissue injury and preserving lung function remain elusive. Further, an emerging body of literature has now revealed that macrophage populations in the lung are more heterogeneous than originally appreciated. Specifically, it is now understood that alveolar macrophages present in the lung can originate from embryonic precursors (tissue- derived alveolar macrophages-TD-AMs) or from blood monocytes (monocyte-derived alveolar macrophages- Mo-AMs). Despite this important advance, it is currently unclear whether these ontologically distinct pulmonary macrophage populations perform comparable or distinct functions in mediating protection (reduction in pathogen burdens and/or maintenance of tissue integrity). Also, whether these distinct macrophage populations initiate similar or unique effector functions in the context of helminth, fungal, or viral challenges remains unknown. Finally, our understanding of how a previous exposure to one pulmonary pathogen alters the responsiveness of lung macrophages to a subsequent challenge with a distinct pathogen is poorly understood. This important gap in knowledge has become extremely evident during the COVID-19 pandemic where individual outcomes vary dramatically and we have a poor understanding of how one’s infectious past may contribute to these differences. The leaders of this project will employ their combined expertise to address these critical questions. The central hypothesis of this application is that infection with diverse pathogens program TD-AMs and Mo-AMs to perform distinct functions against heterologous pathogens while mitigating tissue injury. We further hypothesize that the pathogen-induced response of TD-AMs and Mo-AMs is critically shaped by neutrophil-derived signals and type I and III interferons. In three distinct and complementary aims we will use a combination of discovery-based studies combined with targeted in vitro and in vivo approaches to define the overlapping and unique contributions of tissue-derived macrophages and recruited monocyte-derived cells to host protective responses following helminth, fungal or viral infections. This thorough and comprehensive approach will allow us to gain an unprecedented understanding of fundamental innate immune functions. This novel insight may inform therapeutic strategies to target lung macrophage populations in a manner that will allow for the fine tuning of inflammation and pulmonary infection outcomes.