{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T05:36:14Z","timestamp":1792647374869,"version":"4.5.0"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,2,18]],"date-time":"2025-02-18T00:00:00Z","timestamp":1739836800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI170504"],"award-info":[{"award-number":["AI170504"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:p>Like other tuberculous and nontuberculous mycobacterial pathogens of human lung such as <jats:italic>Mycobacterium tuberculosis<\/jats:italic> and <jats:italic>M. abscessus<\/jats:italic>, <jats:italic>M. avium<\/jats:italic> is likely exposed to a variety of stressors during infection, including hypoxic conditions inside activated macrophages and in the avascular necrotic regions of granulomas. How <jats:italic>M. avium<\/jats:italic> survives hypoxic stress to establish a chronic infection is currently not well understood. Using RNA-sequencing, we here show that <jats:italic>M. avium<\/jats:italic> grown under progressive microaerophilic conditions activates more than 4-fold a subset of 16 genes, the expression of 13 of which is dependent on the two-component system regulator DosRS. A subset of <jats:italic>M. avium<\/jats:italic> DosR regulon genes was confirmed to also be activated upon exposure to nitric oxide. Although a second sensor kinase besides DosS has been proposed to function with the transcriptional regulator DosR in <jats:italic>M. avium<\/jats:italic>, we show that this other kinase cannot compensate for a deficiency in DosS. Loss of <jats:italic>dosRS<\/jats:italic> expression in <jats:italic>M. avium<\/jats:italic> led to a significant reduction in viability under hypoxia that was more marked at acidic than at neutral pH. Unlike the situation in <jats:italic>M. abscessus<\/jats:italic>, however, loss of DosRS did not significantly impact the ability of <jats:italic>M. avium<\/jats:italic> to establish a drug tolerant state <jats:italic>in vitro<\/jats:italic> or form biofilms under host relevant conditions. Collectively, these results are suggestive of a lesser impact of DosRS on the ability of <jats:italic>M. avium<\/jats:italic> to develop antibiotic tolerance compared to other nontuberculous mycobacteria. The <jats:italic>M. avium dosRS<\/jats:italic> mutant further showed no signs of virulence attenuation in murine macrophages and in chronically infected immunocompetent BALB\/c mice.<\/jats:p>","DOI":"10.3389\/fcimb.2025.1545856","type":"journal-article","created":{"date-parts":[[2025,2,18]],"date-time":"2025-02-18T06:52:11Z","timestamp":1739861531000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["The DosR regulon of Mycobacterium avium and adaptation to hypoxia"],"prefix":"10.3389","volume":"15","author":[{"given":"Juan M.","family":"Belardinelli","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte","family":"Avanzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelsey E.","family":"Martin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ha","family":"Lam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marte S.","family":"Dragset","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William H.","family":"Wheat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brendan K.","family":"Podell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mercedes","family":"Gonzalez-Juarrero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary","family":"Jackson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,2,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.1001065","article-title":"Metabolic regulation of mycobacterial growth and antibiotic sensitivity","volume":"9","author":"Baek","year":"2011","journal-title":"PloS Biol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"310","DOI":"10.1016\/j.tube.2009.06.001","article-title":"The DosR regulon of M. tuberculosis and antibacterial tolerance","volume":"89","author":"Bartek","year":"2009","journal-title":"Tuberculosis (Edinb)"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2021.743126","article-title":"Unique features of Mycobacterium abscessus biofilms formed in synthetic cystic fibrosis medium","volume":"12","author":"Belardinelli","year":"2021","journal-title":"Front. 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