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

Abstract

Summary Paragraph 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 degradation1. 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 LC32–6, stimulation of autophagy increases bacterial killing6–8, and inhibition of autophagy allows for increased bacterial survival1,2,4,6,7. Notably, these studies reveal modest (e.g. 1.5- to 3-fold change) effects on Mtb replication. In contrast, Atg5fl/fl-LysM-Cre mice lacking ATG5 in monocyte-derived cells and neutrophils (polymorphic mononuclear cells, PMN) succumb to Mtb within 30 days4,9, an extremely severe phenotype similar to mice lacking IFN-γ signaling10,11. Importantly, ATG5 is the only ATG factor that has been studied during Mtb infection in vivo and autophagy-independent functions of ATG5 have been described12–18. 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.

Polymorphisms in autophagy genes and active pulmonary tuberculosis susceptibility in Romania

“…However, we were not able to identify any association between NOD2 rs2066844 (c.2104C>T) polymorphism and the increased risk to develop active TB. This observation, coupled with absence of effects of ATG5 genetic variants, suggest that autophagy and Mtb have a complex interaction, and that the autophagy process may be redundant for host defense against tuberculosis, as recently suggested (2).…”

PPAR-α Activation Mediates Innate Host Defense through Induction of TFEB and Lipid Catabolism

“…Atgs exert a concerted effect in autophagy, i.e., autophagosome initiation and elongation and lysosomal functions (28). Various Atgs play diverse roles in innate and inflammatory responses, such as the eradication of intracellular pathogens, murine gammaherpesvirus 68 reactivation from latency, Ag presentation, and innate immune signaling in a cell type-specific manner (28,35,36). Despite these findings, research on the molecular mechanisms of Atg regulation in macrophages during infection is in its infancy.…”

Autophagy in Pulmonary Diseases

“…Myeloid cell-specific ATG5 deficiency increases Mtb replication and reduces the survival in mice infected with Mtb; however, such phenotypes are not observed when other autophagy genes, such as ATG3, ATG7, ATG12, and ATG16, are knocked down (68). In addition, ATG5 plays a unique role in protection against Mtb by preventing polymorphonuclear cell-mediated immunopathology (68).…”