Dominant Role of the sst1 Locus in Pathogenesis of Necrotizing Lung Granulomas during Chronic Tuberculosis Infection and Reactivation in Genetically Resistant Hosts

Pichugin, Alexander; Yan, Bin; Sloutsky, Alex; Kobzik, Lester; Kramnik, Igor

doi:10.2353/ajpath.2009.081075

Cited by 110 publications

(111 citation statements)

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“…Finally, M. tuberculosis-infected B6.C3H-sst1 mice, carrying the susceptible C3H-sst1 locus on the B6 background, develop robust granulomas that are fenced from the healthy tissue where lesions contain foamy macrophages and develop late-onset necrosis, resembling pulmonary TB in human adults. In contrast, the B6 strain does not display this phenotype, confirming the specific role for sst1 in the control of cell death (23).…”

mentioning

confidence: 72%

“…For the reactivation model, B6 and B6.C3H-sst1 mice were infected i.v. via the tail vein with 5 3 10 4 CFU M. tuberculosis per mouse as previously described (23). Twelve weeks after challenge the mice were given isoniazid (INH) supplied via the drinking water (10 mg/100 ml) for 90 d. Mice were sacrificed 8 wk after INH treatment withdrawal.…”

Section: Infection Of Micementioning

confidence: 99%

“…All four mouse models were infected with a low-dose aerosol M. tuberculosis inoculum. Additionally, a subset of B6.C3H-sst1 was infected using a previously described TB relapse model to study features of gene expression during M. tuberculosis reactivation (23).…”

Section: Identification Of Ive-tb Genes In the Lungs Of Genetically Rmentioning

confidence: 99%

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An Unbiased Genome-Wide Mycobacterium tuberculosis Gene Expression Approach To Discover Antigens Targeted by Human T Cells Expressed during Pulmonary Infection

Commandeur

Meijgaarden

Prins

et al. 2013

The Journal of Immunology

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Mycobacterium tuberculosis is responsible for almost 2 million deaths annually. Mycobacterium bovis bacillus Calmette-Guérin, the only vaccine available against tuberculosis (TB), induces highly variable protection against TB, and better TB vaccines are urgently needed. A prerequisite for candidate vaccine Ags is that they are immunogenic and expressed by M. tuberculosis during infection of the primary target organ, that is, the lungs of susceptible individuals. In search of new TB vaccine candidate Ags, we have used a genome-wide, unbiased Ag discovery approach to investigate the in vivo expression of 2170 M. tuberculosis genes during M. tuberculosis infection in the lungs of mice. Four genetically related but distinct mouse strains were studied, representing a spectrum of TB susceptibility controlled by the supersusceptibility to TB 1 locus. We used stringent selection approaches to select in vivo–expressed M. tuberculosis (IVE-TB) genes and analyzed their expression patterns in distinct disease phenotypes such as necrosis and granuloma formation. To study the vaccine potential of these proteins, we analyzed their immunogenicity. Several M. tuberculosis proteins were recognized by immune cells from tuberculin skin test-positive, ESAT6/CFP10-responsive individuals, indicating that these Ags are presented during natural M. tuberculosis infection. Furthermore, TB patients also showed responses toward IVE-TB Ags, albeit lower than tuberculin skin test-positive, ESAT6/CFP10-responsive individuals. Finally, IVE-TB Ags induced strong IFN-γ+/TNF-α+ CD8+ and TNF-α+/IL-2+ CD154+/CD4+ T cell responses in PBMC from long-term latently M. tuberculosis–infected individuals. In conclusion, these IVE-TB Ags are expressed during pulmonary infection in vivo, are immunogenic, induce strong T cell responses in long-term latently M. tuberculosis–infected individuals, and may therefore represent attractive Ags for new TB vaccines.

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confidence: 72%

Section: Infection Of Micementioning

confidence: 99%

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An Unbiased Genome-Wide Mycobacterium tuberculosis Gene Expression Approach To Discover Antigens Targeted by Human T Cells Expressed during Pulmonary Infection

Commandeur

Meijgaarden

Prins

et al. 2013

The Journal of Immunology

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“…The lack of a functional ortholog of MMP-1 in mice would explain why infection of immunodeficient mice can result in extremely high bacterial loads and necrosis but cavitation does not occur (4,5). In immunodeficient mice that develop well-organized granulomas containing very high bacterial loads and necrosis, lesions have a fibrotic capsule (33), further suggesting that necrosis and matrix destruction are separate processes. Animals that cavitate after infection with M. tuberculosis, such as humans, primates, and rabbits (5), all have a preserved functional ortholog of MMP-1.…”

Section: Discussionmentioning

confidence: 99%

MMP-1 drives immunopathology in human tuberculosis and transgenic mice

Elkington¹,

Shiomi²,

Breen³

et al. 2011

J. Clin. Invest.

195

230

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IntroductionMycobacterium tuberculosis infects one-third of the world's population (1) and is transmitted by the aerosol route. Although the mechanisms whereby M. tuberculosis evades the host immune response are increasingly well understood (2), those by which M. tuberculosis engages the immune response to drive tissue destruction and hence transmission are relatively poorly characterized (3). The events underlying this immunopathology are not well defined, in part because the mouse, one of the most useful models in which to study M. tuberculosis immunology, does not develop lung pathology similar to that of humans (4, 5). In humans, M. tuberculosis subverts the host immune response to drive proteolytic destruction of the extracellular matrix scaffold. The current paradigm of tuberculosis (TB) pathology proposes that caseation leads directly to cavitation (2, 4, 6). However, this model overlooks that fact that destruction of lung extracellular matrix must be driven by proteases. Fibrillar collagens provide the lung's tensile strength and are highly resistant to enzymatic degradation (7,8). Only collagenolytic MMPs can cleave these helical collagens at neutral pH (9).MMPs are a family of zinc-dependent proteases that can collectively degrade all components of the extracellular matrix (8). MMP activity is tightly regulated at the level of transcription and activation by proteolytic cleavage. MMPs are specifically inhibited by tissue inhibitor of metalloproteinases (TIMPs) (9). Excessive MMP activity is implicated in diverse pulmonary pathologies characterized by extracellular matrix destruction (8). However, despite the potentially key role of MMPs in lung matrix destruction in human TB, the central mechanisms resulting in tissue damage have not been defined.

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“…22 How pulmonary TB develops is not fully understood but is important to investigate. 11 Some contributing mechanisms have been identified such as the sst1 locus, 34 the matrix metalloproteinase-1, 13 interleukin-10, 2 and neutrophils or neutrophil-like cells. 24,30,33 We use CBA/J mice to model pulmonary TB because these mice have no known immunological defects, are relatively susceptible to M.tb infection, and maintain long-term stable M.tb burdens.…”

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confidence: 99%

Tuberculosis in CBA/J Mice

2013

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Tuberculosis (TB) develops in 5% to 10% of people infected with Mycobacterium tuberculosis (M.tb), but we do not understand how TB develops. CBA/J mice may model these events, as sick mice share features with TB patients, including weight loss, M.tb growth, extensive granulomatous infiltrates, neutrophils, necrosis, and fibrosis. Here, M.tb-infected CBA/J mice were categorized clinically: those with no signs or those with 10% weight loss to determine whether clinical state was associated with lung lesions. The type and distribution of infiltrates (granulomatous with lymphoid aggregates and scattered neutrophils) were similar in mice with weight loss and in mice with no signs. The amount of infiltration and neutrophil foci were higher in mice with weight loss than in mice with no clinical signs. Necrosis and fibrosis were only identified in mice that lost weight. Our results suggest that CBA/J mice may be useful to determine if and how neutrophils contribute to TB disease progression in mouse models. Keywords CBA/J, mouse model, mycobacterium tuberculosis, neutrophils, tuberculosisIntact TH1 immunity is essential for resistance to Mycobacterium tuberculosis (M.tb) in animal models and in humans. 9,16,18,26,27,38 However, pulmonary tuberculosis (TB), which is the most common form of TB and is responsible for M.tb transmission, does not appear to be due to severe immune defects.22 How pulmonary TB develops is not fully understood but is important to investigate.11 Some contributing mechanisms have been identified such as the sst1 locus, 34 the matrix metalloproteinase-1, 13 interleukin-10, 2 and neutrophils or neutrophil-like cells. 24,30,33 We use CBA/J mice to model pulmonary TB because these mice have no known immunological defects, are relatively susceptible to M.tb infection, and maintain long-term stable M.tb burdens. 2,3,36 Yet, the manifestation of TB disease in CBA/J mice has not been completely described. Here, we show microscopic features of TB disease in CBA/J mice and in M.tb-infected CBA/J mice that have no clinical signs. This may provide another method to investigate the transition between controlled M.tb infection and TB disease.Specific-pathogen-free, 6-to 8-week-old, female CBA/J mice from Charles River Laboratories (Wilmington, MA) were maintained in ventilated cages within biosafety level 3 (BSL3) facilities at The Ohio State University (Columbus, OH) and provided with sterile food and water ad libitum. All protocols were approved by The Ohio State University's Institutional Laboratory Animal Care and Use Committee (IACUC). Mice were infected with M.tb by aerosol exposure and weighed weekly throughout M.tb infection, as previously described. 3Mice were euthanized when all of the following IACUC removal criteria were met: weight loss of 20%, unthrifty hair coat, social isolation, and tachypnea or dyspnea. In some experiments, mice were euthanized when 10% of their peak body weight was lost and there were no other clinical signs. The M.tb pulmonary burden was calculated by colonyforming u...

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Dominant Role of the sst1 Locus in Pathogenesis of Necrotizing Lung Granulomas during Chronic Tuberculosis Infection and Reactivation in Genetically Resistant Hosts

Cited by 110 publications

References 36 publications

An Unbiased Genome-Wide Mycobacterium tuberculosis Gene Expression Approach To Discover Antigens Targeted by Human T Cells Expressed during Pulmonary Infection

An Unbiased Genome-Wide Mycobacterium tuberculosis Gene Expression Approach To Discover Antigens Targeted by Human T Cells Expressed during Pulmonary Infection

MMP-1 drives immunopathology in human tuberculosis and transgenic mice

Tuberculosis in CBA/J Mice

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