title: In mice, tuberculosis progression is associated with intensive inflammatory response and the accumulation of Gr-1 cells in the lungs.
abstract: BACKGROUND
  Infection with Mycobacterium tuberculosis (Mtb) results in different clinical outcomes ranging from asymptomatic containment to rapidly progressing tuberculosis (TB). The mechanisms controlling TB progression in immunologically-competent hosts remain unclear.
  
  
  RESULTS
  To address these mechanisms, we analyzed TB progression in a panel of genetically heterogeneous (A/SnxI/St) F2 mice, originating from TB-highly-susceptible I/St and more resistant A/Sn mice. In F2 mice the rates of TB progression differed. In mice that did not reach terminal stage of infection, TB progression did not correlate with lung Mtb loads. Nor was TB progression correlated with lung expression of factors involved in antibacterial immunity, such as iNOS, IFN-gamma, or IL-12p40. The major characteristics of progressing TB was high lung expression of the inflammation-related factors IL-1beta, IL-6, IL-11 (p<0.0003); CCL3, CCL4, CXCL2 (p<0.002); MMP-8 (p<0.0001). The major predictors of TB progression were high expressions of IL-1beta and IL-11. TNF-alpha had both protective and harmful effects. Factors associated with TB progression were expressed mainly by macrophages (F4-80(+) cells) and granulocytes (Gr-1(hi)/Ly-6G(hi) cells). Macrophages and granulocytes from I/St and A/Sn parental strains exhibited intrinsic differences in the expression of inflammatory factors, suggesting that genetically determined peculiarities of phagocytes transcriptional response could account for the peculiarities of gene expression in the infected lungs. Another characteristic feature of progressing TB was the accumulation in the infected lungs of Gr-1(dim) cells that could contribute to TB progression.
  
  
  CONCLUSIONS
  In a population of immunocompetent hosts, the outcome of TB depends on quantitatively- and genetically-controlled differences in the intensity of inflammatory responses, rather than being a direct consequence of mycobacterial colonization. Local accumulation of Gr-1(dim) cells is a newly identified feature of progressing TB. High expression of IL-1beta and IL-11 are potential risk factors for TB progression and possible targets for TB immunomodulation.
authors.affiliation: Department of Immunology, Central Tuberculosis Research Institute, Russian Academy of Medical Sciences, Moscow, Russian Federation. ivlyadova@mail.ru
authors.forename: Irina V
authors.initials: IV
authors.lastname: Lyadova
authors.forename: Evgeny N
authors.initials: EN
authors.lastname: Tsiganov
authors.forename: Marina A
authors.initials: MA
authors.lastname: Kapina
authors.forename: Galena S
authors.initials: GS
authors.lastname: Shepelkova
authors.forename: Vasily V
authors.initials: VV
authors.lastname: Sosunov
authors.forename: Tatiana V
authors.initials: TV
authors.lastname: Radaeva
authors.forename: Konstantin B
authors.initials: KB
authors.lastname: Majorov
authors.forename: Natalya S
authors.initials: NS
authors.lastname: Shmitova
authors.forename: Henk-Jan
authors.initials: HJ
authors.lastname: van den Ham
authors.forename: Vitaly V
authors.initials: VV
authors.lastname: Ganusov
authors.forename: Rob J
authors.initials: RJ
authors.lastname: De Boer
authors.forename: Rachael
authors.initials: R
authors.lastname: Racine
authors.forename: Gary M
authors.initials: GM
authors.lastname: Winslow
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D015169:Colony Count, Microbial; D003433:Crosses, Genetic; D018450:Disease Progression; D004198:Disease Susceptibility; D005260:Female; D006098:Granulocytes / Q000378:metabolism / Q000473:pathology*; D018836:Inflammation Mediators / Q000378:metabolism; D008168:Lung / Q000382:microbiology / Q000473:pathology*; D008297:Male; D051379:Mice; D009169:Mycobacterium tuberculosis / Q000254:growth & development; D010586:Phagocytes / Q000378:metabolism / Q000473:pathology; D011014:Pneumonia / Q000150:complications / Q000382:microbiology / Q000473:pathology*; D040641:Quantitative Trait Loci / Q000235:genetics; D014376:Tuberculosis / Q000150:complications / Q000235:genetics / Q000382:microbiology / Q000473:pathology*; D015431:Weight Loss
chemical_list: D000950:Antigens, Ly; D018836:Inflammation Mediators; C480309:Ly6G antigen, mouse
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