β-glucan-induced monocyte-derived alveolar macrophages confer protection against Mycobacterium tuberculosis 4395

Abstract Description Lung alveolar macrophages (AMs) originate from yolk sac and fetal liver monocytes during embryogenesis. AMs function as sentinels to airway pathogens and can be replaced by the infiltration of monocyte-derived-AMs (Mo-AMs) during inflammation. During Mycobacterium tuberculosis (Mtb) infection, AMs act as an early permissive niche to promote Mtb growth. However, the fate of AMs during long-term Mtb infection and how ontogeny impacts the permissiveness of AMs to Mtb remains to be elucidated. Combining single-cell RNA-seq with a fate-mapping approach, we revealed that long-term Mtb infection results in replenishment of embryonic-derived-AMs by Mo-AMs with a higher proinflammatory status, which implicates an enhanced capacity to control Mtb infection in those cells. To investigate the impact of ontogeny on AM responses to Mtb, we utilized a β-glucan intranasal inoculation model in which β-glucan induces highly glycolytic, phagocytic and proinflammatory Mo-AMs in the airway. Moreover, using single cell ATAC-seq and chemical inhibition, we demonstrated the requirement of the SWItch/Sucrose Non-Fermentable complexes in regulating inflammatory responses in Mo-AMs upon stimulation. Lastly, β-glucan-induced Mo-AMs produced higher levels of protective cytokines and limited pulmonary Mtb burden in mice. Collectively, these findings assert that monocytes contribute to the AM pool during Mtb infection and implicate ontogeny as an intrinsic determinant for AM responses to Mtb infection. Funding Sources Supported by NIH/NIAID R01AI184960; R21AI175738. Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)