title: The Mycobacterium tuberculosis stress response factor SigH is required for bacterial burden as well as immunopathology in primate lungs.
abstract: BACKGROUND
  Sigma H (sigH) is a major Mycobacterium tuberculosis (Mtb) stress response factor. It is induced in response to heat, oxidative stress, cell wall damage, and hypoxia. Infection of macrophages with the Δ-sigH mutant generates more potent innate immune response than does infection with Mtb. The mutant is attenuated for pathology in mice.
  
  
  METHODS
  We used a nonhuman primate (NHP) model of acute tuberculosis, to better understand the phenotype of the Δ-sigH mutant in vivo. NHPs were infected with high doses of Mtb or the mutant, and the progression of tuberculosis was analyzed in both groups using clinical, pathological, microbiological, and immunological parameters.
  
  
  RESULTS
  Animals exposed to Mtb rapidly progressed to acute pulmonary tuberculosis as indicated by worsening clinical correlates, high lung bacterial burden, and granulomatous immunopathology. All the animals rapidly succumbed to tuberculosis. On the other hand, the NHPs exposed to the Mtb:Δ-sigH mutant did not exhibit acute tuberculosis, instead showing significantly blunted disease. These NHPs survived the entire duration of the study.
  
  
  CONCLUSIONS
  The Mtb:Δ-sigH mutant is completely attenuated for bacterial burden as well as immunopathology in NHPs. SigH and its regulon are required for complete virulence in primates. Further studies are needed to identify the molecular mechanism of this attenuation.
authors.affiliation: Division of Bacteriology and Parasitology, Tulane National Primate Research Center, Covington, LA 70433, USA.
authors.forename: Smriti
authors.initials: S
authors.lastname: Mehra
authors.forename: Nadia A
authors.initials: NA
authors.lastname: Golden
authors.forename: Kerstan
authors.initials: K
authors.lastname: Stuckey
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Didier
authors.forename: Lara A
authors.initials: LA
authors.lastname: Doyle
authors.forename: Kasi E
authors.initials: KE
authors.lastname: Russell-Lodrigue
authors.forename: Chie
authors.initials: C
authors.lastname: Sugimoto
authors.forename: Atsuhiko
authors.initials: A
authors.lastname: Hasegawa
authors.forename: Satheesh K
authors.initials: SK
authors.lastname: Sivasubramani
authors.forename: Chad J
authors.initials: CJ
authors.lastname: Roy
authors.forename: Xavier
authors.initials: X
authors.lastname: Alvarez
authors.forename: Marcelo J
authors.initials: MJ
authors.lastname: Kuroda
authors.forename: James L
authors.initials: JL
authors.lastname: Blanchard
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Lackner
authors.forename: Deepak
authors.initials: D
authors.lastname: Kaushal
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D015964:Gene Expression Regulation, Bacterial / Q000502:physiology*; D006099:Granuloma; D007150:Immunohistochemistry; D008168:Lung / Q000276:immunology* / Q000382:microbiology*; D008253:Macaca mulatta; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000378:metabolism*; D012808:Sigma Factor / Q000235:genetics / Q000378:metabolism*; D014397:Tuberculosis, Pulmonary / Q000382:microbiology* / Q000473:pathology
chemical_list: D001426:Bacterial Proteins; C120328:SigH protein, bacteria; D012808:Sigma Factor