Autophagy promotes efficient T cell responses to restrict high-dose Mycobacterium tuberculosis infection in mice

Siwei Feng, Michael E. McNehlan, Rachel L. Kinsella, Chanchal Sur Chowdhury, Sthefany M. Chavez, Sumanta K. Naik, Samuel R. McKee, Jacob A. Van Winkle, Neha Dubey, Amanda Samuels, Amanda Swain, Xiaoyan Cui, Skyler V. Hendrix, Reilly Woodson, Darren Kreamalmeyer, Asya Smirnov, Maxim N. Artyomov, Herbert W. Virgin, Ya Ting Wang, Christina L. Stallings

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Although autophagy sequesters Mycobacterium tuberculosis (Mtb) in in vitro cultured macrophages, loss of autophagy in macrophages in vivo does not result in susceptibility to a standard low-dose Mtb infection until late during infection, leaving open questions regarding the protective role of autophagy during Mtb infection. Here we report that loss of autophagy in lung macrophages and dendritic cells results in acute susceptibility of mice to high-dose Mtb infection, a model mimicking active tuberculosis. Rather than observing a role for autophagy in controlling Mtb replication in macrophages, we find that autophagy suppresses macrophage responses to Mtb that otherwise result in accumulation of myeloid-derived suppressor cells and subsequent defects in T cell responses. Our finding that the pathogen-plus-susceptibility gene interaction is dependent on dose has important implications both for understanding how Mtb infections in humans lead to a spectrum of outcomes and for the potential use of autophagy modulators in clinical medicine.

Original languageEnglish
Pages (from-to)684-697
Number of pages14
JournalNature microbiology
Volume9
Issue number3
DOIs
StatePublished - Mar 2024

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