Impaired autophagy in myeloid cell disrupts pulmonary B cell follicles and exacerbates chronic tuberculosis 2340

Abstract Description Mycobacterium tuberculosis (Mtb) is the leading cause of death from an infectious disease. Transmitted via respiratory aerosols, Mtb infects various lung macrophage populations, each with distinct abilities to restrict Mtb. What enables Mtb survival in certain macrophage populations is not well understood. In our recent study (Mittal E. et al., Nature Microbiology 2024) we demonstrated how Mtb phthiocerol dimycocerosate (PDIM), a virulence lipid present in the outer envelope of Mtb, inhibits the NADPH oxidase and antagonizes autophagy, key host defense mechanisms against intracellular pathogens. Notably, we found that PDIM is dispensable for Mtb survival in alveolar macrophages; however, it is required for Mtb to survive in interstitial and recruited macrophage populations in the lungs. Furthermore, we show that the ability of these macrophages to restrict growth of Mtb lacking PDIM relies on autophagy. Mice with autophagy-defective myeloid cells succumb to infection with both PDIM mutants and wild-type (WT) Mtb. This increased susceptibility is accompanied by a failure to develop B cell follicles in the lungs during chronic infection. Here, we present a concise summary of our recent publication, along with our new findings that underscore the importance of autophagy in myeloid cells for the development of B cell follicles during chronic infection, providing new insights into the long-term immune response to Mtb. Funding Sources This work was supported by Washington University School of Medicine, NIH AI087682, and AI130454 to Jennifer A. Philips. Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)