title: Granuloma correlates of protection against tuberculosis and mechanisms of immune modulation by Mycobacterium tuberculosis.
abstract: BACKGROUND
  The BCG vaccine is ineffective against adult tuberculosis. Hence, new antituberculosis vaccines are needed. Correlates of protection against tuberculosis are not known. We studied the effects of BCG vaccination on gene expression in tuberculosis granulomas using macaques.
  
  
  METHODS
  Macaques were BCG-vaccinated or sham-vaccinated and then challenged with virulent Mycobacterium tuberculosis. Lung lesions were used for comparative transcriptomics.
  
  
  RESULTS
  Vaccinated macaques were protected with lower bacterial burden and immunopathology. Lesions from BCG-vaccinated nonhuman primates (NHPs) showed a better balance of α- and β-chemokine gene expression with higher levels of β-chemokine expression relative to nonvaccinated animals. Consistent with this, sham-vaccinated macaques recruited fewer macrophages relative to neutrophils in their lungs. The expression of indoleamine 2,3-dioxygenase (IDO), a known immunosuppressor, was significantly higher in both week 5 and 10 lesions from sham-vaccinated, relative to BCG-vaccinated, NHPs. IDO expression was primarily limited to the nonlymphocytic region of the lesions, within the inner ring structure surrounding the central necrosis.
  
  
  CONCLUSIONS
  Our study defines lung gene expression correlates of protective response against tuberculosis, relative to disease, which can potentially be employed to assess the efficacy of candidate antituberculosis vaccines. Mycobacterium tuberculosis may modulate protective immune responses using diverse mechanisms, including increased recruitment of inflammatory neutrophils and the concomitant use of IDO to modulate inflammation.
authors.affiliation: Division of Microbiology, Tulane National Primate Research Center, Covington, LA 70433, USA.
authors.forename: Smriti
authors.initials: S
authors.lastname: Mehra
authors.forename: Xavier
authors.initials: X
authors.lastname: Alvarez
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Didier
authors.forename: Lara A
authors.initials: LA
authors.lastname: Doyle
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; D001500:BCG Vaccine / Q000276:immunology / Q000627:therapeutic use*; D058491:Bacterial Load; D019742:Chemokines, CC / Q000276:immunology; D019743:Chemokines, CXC / Q000276:immunology; D018450:Disease Progression; D015971:Gene Expression Regulation, Enzymologic; D006099:Granuloma / Q000201:enzymology / Q000276:immunology* / Q000382:microbiology* / Q000473:pathology; D056747:Immunomodulation; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D008252:Macaca fascicularis; D008264:Macrophages / Q000276:immunology; D009169:Mycobacterium tuberculosis / Q000276:immunology* / Q000472:pathogenicity; D009336:Necrosis / Q000276:immunology / Q000382:microbiology; D009504:Neutrophils / Q000276:immunology; D013997:Time Factors; D059467:Transcriptome; D014397:Tuberculosis, Pulmonary / Q000276:immunology / Q000382:microbiology / Q000473:pathology / Q000628:therapy*; D014611:Vaccination
chemical_list: D001500:BCG Vaccine; D019742:Chemokines, CC; D019743:Chemokines, CXC; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase