Autophagy protects against high-dose Mycobacterium tuberculosis infection

Host autophagy had been associated with the control of Mycobacterium tuberculosis (Mtb) infection due to its ability to sequesters microorganisms through a process termed "xenophagy" (1-4). Xenophagy purportedly limits Mtb replication within infected macrophages (1-4). However, studies in mice using a standard low-dose infection model demonstrated that xenophagy in infected phagocytes is not required to control Mtb pathogenesis (5,6). Instead, an autophagy-independent function of ATG5 in myeloid cells controls low-dose Mtb infection through limiting neutrophilic inflammation5. Hitherto, an in vivo role for autophagy during Mtb infection remained to be elucidated. We report herein that autophagy in myeloid cells mediates protection against high-dose Mtb infection, providing the first evidence for a role for autophagy in myeloid cells during Mtb infection in vivo. With the exception of ATG5, the autophagy proteins required to control high-dose Mtb infection are dispensable for host defense against a standard low-dose Mtb infection. Specifically, autophagy is required in CD11c+ cells, but is dispensable in neutrophils, to control a high-dose Mtb infection in the lung. The role for autophagy is not to directly degrade Mtb in macrophages through xenophagy, but mainly to limit myeloid-derived suppressor cell accumulation and to promote sustained protective T cell responses. Together, our data highlight a novel role for autophagy in controlling Mtb infection, distinct from that of Atg5 during low-dose Mtb infection, or any previously reported roles for autophagy. In addition, our finding that the result of a pathogen-plus-susceptibility gene interaction is dependent on pathogen burden has important implications on our understanding of how Mtb infection in humans can lead to a spectrum of outcomes, the variables that contribute to autophagy gene function during infection and inflammation, and the potential use of autophagy modulators in clinical medicine. ### Competing Interest Statement Dr. Virgin is a founder of Casma Therapeutics and PierianDx. The work reported here was not funded by either company. Dr. Virgin was employed by and holds stock in Vir Biotechnology, which did not fund this work.