{"doi":"10.1101/2022.11.04.515158","title":"Autophagy protects against high-dose <i>Mycobacterium tuberculosis</i> infection","abstract":"Summary 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 inflammation 5 . 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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":300579,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9592,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":987159,"name":"Eric M. Nehls","orcid":null,"position":1,"is_corresponding":false},{"id":986714,"name":"Rachel L. Kinsella","orcid":"0009-0003-4191-5047","position":2,"is_corresponding":false},{"id":986715,"name":"Sthefany M. Chavez","orcid":"0000-0001-5887-8826","position":3,"is_corresponding":false},{"id":889648,"name":"Sumanta Kumar Naik","orcid":"0000-0003-4499-0811","position":4,"is_corresponding":false},{"id":991117,"name":"Samuel R. McKee","orcid":"0009-0005-7166-2153","position":5,"is_corresponding":false},{"id":991118,"name":"Neha Dubey","orcid":"0009-0005-1581-9099","position":6,"is_corresponding":false},{"id":378155,"name":"Amanda N. Samuels","orcid":"0000-0003-1499-2453","position":7,"is_corresponding":false},{"id":246482,"name":"Amanda Swain","orcid":"0000-0003-0683-368X","position":8,"is_corresponding":false},{"id":991119,"name":"Xiaoyan Cui","orcid":"0000-0003-1395-7330","position":9,"is_corresponding":false},{"id":889647,"name":"Skyler V. Hendrix","orcid":"0000-0002-0644-6519","position":10,"is_corresponding":false},{"id":991545,"name":"Reilly Woodson","orcid":null,"position":11,"is_corresponding":false},{"id":987160,"name":"Darren Kreamalmeyer","orcid":null,"position":12,"is_corresponding":false},{"id":917727,"name":"Asya Smirnov","orcid":"0000-0003-4767-1680","position":13,"is_corresponding":false},{"id":52958,"name":"Maxim N. Artyomov","orcid":"0000-0002-1133-4212","position":14,"is_corresponding":false},{"id":217934,"name":"Herbert W. Virgin","orcid":"0000-0001-8580-7628","position":15,"is_corresponding":false},{"id":638709,"name":"Yating Wang","orcid":"0000-0002-5057-4083","position":16,"is_corresponding":false},{"id":593272,"name":"Christina L. Stallings","orcid":"0000-0002-2747-5618","position":17,"is_corresponding":false},{"id":991544,"name":"Siwei Feng","orcid":null,"position":0,"is_corresponding":true}],"reference_count":52,"raw_metadata":null,"created_at":"2026-07-19T00:31:53.559757Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}