Mouse Model of Necrotic Tuberculosis Granulomas Develops Hypoxic Lesions

Harper, Jamie; Skerry, Ciaran; Davis, S. Lindsey; Tasneen, Rokeya; Weir, Mariah; Kramnik, Igor; Bishai, William R.; Pomper, Martin G.; Nuermberger, Eric L.; Jain, Sanjay

doi:10.1093/infdis/jir786

Cited by 222 publications

(225 citation statements)

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“…The pneumonic distribution is common among M.tb-infected mice. 1,8,21,34 Necrosis, neutrophils, and bronchiolar exudate characterized the second pattern. Necrotic foci contained basophilic nuclear debris (not shown) or lightly eosinophilic macrophage ''ghosts'' consistent with caseation necrosis 25,29 (Fig.…”

Section: Features Of Pulmonary Tb Disease In Cba/j Micementioning

confidence: 96%

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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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Section: Features Of Pulmonary Tb Disease In Cba/j Micementioning

confidence: 96%

“…Fibrotic, cell-poor granulomas associated with healed primary M.tb infection in humans 25 were absent in CBA/J mice, and that absence is consistent across mouse strains. 1,8,21,34 Collagen, Mineral, and M.tb Bacilli in CBA/J Lungs With TB Disease…”

Section: Features Of Pulmonary Tb Disease In Cba/j Micementioning

confidence: 99%

Tuberculosis in CBA/J Mice

2013

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“…C57Bl/6 mice do not faithfully reproduce certain aspects of human TB. In contrast, Mtb-infected C3HeB/FeJ mice display lesions with prominent necrotic degeneration, thus more closely resembling human granulomas (11)(12)(13)(14)(15). Harper and colleagues first demonstrated that tubercle lesions in this model develop hypoxia (15).…”

Section: Clinical Relevancementioning

confidence: 99%

DosS Is Required for the Complete Virulence of Mycobacterium tuberculosis in Mice with Classical Granulomatous Lesions

Gautam¹,

McGillivray²,

Mehra

et al. 2015

Am J Respir Cell Mol Biol

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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 D-dosR, D-dosS, and D-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 D-dosR and D-dosT grew comparably to wild-type Mtb, D-dosS exhibited a significant defect in bacterial burden and pathology in vivo, accompanied by ablated proinflammatory response. D-dosS retained the ability to induce DosR. The D-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 D-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 D-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.Keywords: Mycobacterium tuberculosis; hypoxia; response regulator; sensor kinase; latency Clinical RelevanceOur research indicates that the C3HeB/FeJ mouse model is appropriate for the study of Mycobacterium tuberculosis pathogenesis because it reveals attenuation in the D-dosS mutation. It appears that this attenuation is not the result of hypoxia in lung granulomas.

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“…In the setting of pulmonary tuberculosis (TB), the sessile organisms are insulated in sac-like granuloma lesions, somewhat similar to encasement in biofilm observed in in vitro cultures [6][7][8]. During TB chemotherapy with rifampicin and isoniazid, planktonic bacteria are killed rapidly (within 2 weeks), whilst eradication of sessile organisms necessitates extended exposure to higher concentrations of these agents [1,4,9].…”

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confidence: 93%