Autophagy and microbial pathogenesis

Abstract

Autophagy is a cell biological process that promotes resilience in the face of environmental perturbations. Given that infectious agents represent a major type of environmental threat, it follows that the autophagy pathway is central to the outcome of host–microbe interactions. Detailed molecular studies have revealed intricate ways in which autophagy suppresses or enhances the fitness of infectious agents, particularly intracellular pathogens such as viruses that require the host cell machinery for replication. Findings in animal models have reinforced the importance of these events that occur within individual cells and have extended the role of autophagy to extracellular microbes and immunity at the whole organism level. These functions impact adaptation to bacteria that are part of the gut microbiota, which has implications for the etiology of chronic disorders such as inflammatory bowel disease. Despite major advances in how autophagy regulates inflammatory reactions toward microbes, many challenges remain, including distinguishing autophagy from closely related pathways such as LC3-associated phagocytosis. Here, we review the role of autophagy in microbial pathogenesis at the level of organismal biology. In addition to providing an overview of the prominent function of autophagy proteins in host–microbe interactions, we highlight how observations at the cellular level are informing pathogenesis studies and offer our perspective on the future directions of the field.

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Fig. 1: Overview of the autophagy pathway. Autophagy is initiated when the preinitiation complex (ULK1 or ULK2, FIP200, ATG13, and ATG101) mediates the phosphorylation of Beclin-1 to activate the class 3 phosphatidylinositol kinase (PI3KC3) complex (VPS34, VPS15, Beclin-1, and ATG14L) to generate PI3Ps at the ER-Golgi intermediate compartment (ERGIC) and ER-mitochondria contact regions.
Fig. 2: The ATG16L1 complex defends the plasma membrane from pore-forming molecules during infections.
Fig. 3: Non-autophagy functions of ATGs mediate cell autonomous defense against eukaryotic pathogens.

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Acknowledgements

We apologize for omitting many great studies in this review due to lack of space. The selected studies are used as examples of the great complexity and breadth of autophagy studies. The authors laboratories are supported by US National Institute of Health grants R01 AI121244 (KC and VJT), R01 HL123340 (KC), R01 DK093668 (KC), R01 DK103788 (KC), R01 AI130945 (KC), R01 HL125816 (KC), R01AI099394 (VJT) and R01AI105129 (VJT), T32AI007180 and F31HL137304 (MDK) and pilot awards from the NYU CTSA grant UL1TR001445 from the National Center for Advancing Translational Sciences (KC) and NYU Cancer Center grant P30CA016087 (KC). The laboratories have also received recent support from the Faculty Scholar grant from the Howard Hughes Medical Institute (KC), Merieux Institute (KC), Kenneth Rainin Foundation (KC), Crohn’s & Colitis Foundation, and Stony Wold-Herbert Fund (KC). KC and VJT are Burroughs Wellcome Fund Investigators in the Pathogenesis of Infectious Diseases.

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Correspondence to Ken Cadwell.

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VJT is an inventor on patents and patent applications filed by New York University, which are currently under commercial license to Janssen Biotech Inc. KC has consulted for or received an honorarium from Puretech Health, Genentech, and AbbVie, Inc., has received research support from Puretech Health and Pfizer, Inc, and has a provisional patent, US Patent Appln. No. 15/625,934.

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Keller, M.D., Torres, V.J. & Cadwell, K. Autophagy and microbial pathogenesis. Cell Death Differ 27, 872–886 (2020). https://doi.org/10.1038/s41418-019-0481-8

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