title: DosS Is required for the complete virulence of mycobacterium tuberculosis in mice with classical granulomatous lesions.
abstract: Mycobacterium tuberculosis (Mtb) must counter hypoxia within granulomas to persist. DosR, in concert with sensor kinases DosS and DosT, regulates the response to hypoxia. Yet Mtb lacking functional DosR colonize the lungs of C57Bl/6 mice, presumably owing to the lack of organized lesions with sufficient hypoxia in that model. We compared the phenotype of the Δ-dosR, Δ-dosS, and Δ-dosT mutants to Mtb using C3HeB/FeJ mice, an alternate mouse model where lesions develop hypoxia. C3HeB/FeJ mice were infected via aerosol. The progression of infection was analyzed by tissue bacterial burden and histopathology. A measure of the comparative global immune responses was also analyzed. Although Δ-dosR and Δ-dosT grew comparably to wild-type Mtb, Δ-dosS exhibited a significant defect in bacterial burden and pathology in vivo, accompanied by ablated proinflammatory response. Δ-dosS retained the ability to induce DosR. The Δ-dosS mutant was also attenuated in murine macrophages ex vivo, with evidence of reduced expression of the proinflammatory signature. Our results show that DosS, but not DosR and DosT, is required by Mtb to survive in C3HeB/FeJ mice. The attenuation of Δ-dosS is not due to its inability to induce the DosR regulon, nor is it a result of the accumulation of hypoxia. That the in vivo growth restriction of Δ-dosS could be mimicked ex vivo suggested sensitivity to macrophage oxidative burst. Anoxic caseous centers within tuberculosis lesions eventually progress to cavities. Our results provide greater insight into the molecular mechanisms of Mtb persistence within host lungs.
authors.affiliation: Divisions of 1 Bacteriology and Parasitology.
authors.forename: Uma S
authors.initials: US
authors.lastname: Gautam
authors.forename: Amanda
authors.initials: A
authors.lastname: McGillivray
authors.forename: Smriti
authors.initials: S
authors.lastname: Mehra
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Didier
authors.forename: Cecily C
authors.initials: CC
authors.lastname: Midkiff
authors.forename: Ryan S
authors.initials: RS
authors.lastname: Kissee
authors.forename: Nadia A
authors.initials: NA
authors.lastname: Golden
authors.forename: Xavier
authors.initials: X
authors.lastname: Alvarez
authors.forename: Tianhua
authors.initials: T
authors.lastname: Niu
authors.forename: Jyothi
authors.initials: J
authors.lastname: Rengarajan
authors.forename: David R
authors.initials: DR
authors.lastname: Sherman
authors.forename: Deepak
authors.initials: D
authors.lastname: Kaushal
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics* / Q000378:metabolism; D015687:Cell Hypoxia; D002478:Cells, Cultured; D015964:Gene Expression Regulation, Bacterial; D015769:Granuloma, Respiratory Tract / Q000382:microbiology*; D008264:Macrophages / Q000382:microbiology; D008297:Male; D008809:Mice, Inbred C3H; D050296:Microbial Viability; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000472:pathogenicity*; D006656:Protamine Kinase / Q000235:genetics* / Q000378:metabolism; D018085:Regulon; D014397:Tuberculosis, Pulmonary / Q000382:microbiology*; D014774:Virulence
chemical_list: D001426:Bacterial Proteins; C506260:DevS protein, Mycobacterium tuberculosis; D006656:Protamine Kinase
keywords: Mycobacterium tuberculosis; hypoxia; latency; response regulator; sensor kinase