ArticleAmerican journal of respiratory and critical care medicine2015
The DosR Regulon Modulates Adaptive Immunity and Is Essential for Mycobacterium tuberculosis Persistence.
Article in American journal of respiratory and critical care medicine, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 113 papers.
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113 citing papers in PubMed, 176 citations in OpenAlex.
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- Increased vaccine efficacy against tuberculosis with a recombinant BCG overexpressing the STING agonist cyclic di-AMP.bioRxiv : the preprint server for biology · 2025Article
- Prevention of tuberculosis in cynomolgus macaques by an attenuated Mycobacterium tuberculosis vaccine candidate.Nature communications · 2025Article
- Harnessing hypoxia: bacterial adaptation and chronic infection in cystic fibrosis.FEMS microbiology reviews · 2025Review
- Physiological stage-dependent effects ofFrontiers in microbiology · 2025Article
- The DosR regulon ofFrontiers in cellular and infection microbiology · 2025Article
- Microenvironments of tuberculous granuloma: advances and opportunities for therapy.Frontiers in immunology · 2025Review
53 more citing papers are in PubMed but not listed here.
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Authors and funding
19 authors at 6 institutions in 3 countries.
Funding
Abstract
rationaleHypoxia promotes dormancy by causing physiologic changes to actively replicating Mycobacterium tuberculosis. DosR controls the response of M. tuberculosis to hypoxia.
objectivesTo understand DosR's contribution in the persistence of M. tuberculosis, we compared the phenotype of various DosR regulon mutants and a complemented strain to M. tuberculosis in macaques, which faithfully model M. tuberculosis infection.
methodsWe measured clinical and microbiologic correlates of infection with M. tuberculosis relative to mutant/complemented strains in the DosR regulon, studied lung pathology and hypoxia, and compared immune responses in lung using transcriptomics and flow cytometry. MEASUREMENTS AND MAIN
resultsDespite being able to replicate initially, mutants in DosR regulon failed to persist or cause disease. On the contrary, M. tuberculosis and a complemented strain were able to establish infection and tuberculosis. The attenuation of pathogenesis in animals infected with the mutants coincided with the appearance of a Th1 response and organization of hypoxic lesions wherein M. tuberculosis expressed dosR. The lungs of animals infected with the mutants (but not the complemented strain) exhibited early transcriptional signatures of T-cell recruitment, activation, and proliferation associated with an increase of T cells expressing homing and proliferation markers.
conclusionsDelayed adaptive responses, a hallmark of M. tuberculosis infection, not only lead to persistence but also interfere with the development of effective antituberculosis vaccines. The DosR regulon therefore modulates both the magnitude and the timing of adaptive immune responses in response to hypoxia in vivo, resulting in persistent infection. Hence, DosR regulates key aspects of the M. tuberculosis life cycle and limits lung pathology.
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