Unique role for ATG5 in PMN-mediated immunopathology during M. tuberculosis infection

Mycobacterium tuberculosis (Mtb), a major global health threat, replicates in macrophages (MΦ) in part by inhibiting phagosome-lysosome fusion, until IFN-γ activates the MΦ to traffic Mtb to the lysosome. How IFN-γ elicits this effect is unknown, but many studies suggest a role for macroautophagy (autophagy herein), a cellular process by which cytoplasmic contents are sequestered into an autophagosome and targeted for lysosomal degradation(1). The involvement of autophagy has been defined based on studies in cultured MΦ or dendritic cells (DC) where Mtb colocalizes with autophagy (ATG) factors ATG5, ATG12, ATG16L1, p62, NDP52, Beclin1 and LC3(2–6), stimulation of autophagy increases bacterial killing(6–8), and inhibition of autophagy allows for increased bacterial survival(1,2,4,6,7). Notably, these studies reveal modest (e.g. 1.5- to 3-fold change) effects on Mtb replication. In contrast, Atg5(fl/fl)-LysM-Cre mice lacking ATG5 in monocyte-derived cells and neutrophils (polymorphic mononuclear cells, PMN) succumb to Mtb within 30 days(4,9), an extremely severe phenotype similar to mice lacking IFN-γ signaling(10,11). Importantly, ATG5 is the only ATG factor that has been studied during Mtb infection in vivo and autophagy-independent functions of ATG5 have been described(12–18). For this reason, we used a genetic approach to elucidate the role for multiple ATG genes and the requirement for autophagy in resistance to Mtb infection in vivo. We have discovered that, contrary to expectation, autophagic capacity does not correlate with the outcome of Mtb infection. Instead, ATG5 plays a unique role in protection against Mtb by preventing PMN-mediated immunopathology. Furthermore, while ATG5 is dispensable in alveolar MΦ during Mtb infection, loss of Atg5 in PMN can sensitize mice to Mtb. These findings shift our understanding of the role of ATG5 during Mtb infection, reveal a new outcome of ATG5 activity, and shed light on early events in innate immunity that are required to regulate tuberculosis disease pathology and Mtb replication.