Granuloma Correlates of Protection Against Tuberculosis and Mechanisms of Immune Modulation by Mycobacterium tuberculosis

Mehra, Smriti; Álvarez, Xavier; Didier, Peter J.; Doyle, Lara A.; Blanchard, James; Lackner, Andrew A.; Kaushal, Deepak

doi:10.1093/infdis/jis778

Cited by 97 publications

(131 citation statements)

References 46 publications

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“…CD4 + T cells respond to infected pulmonary macrophages and limit bacterial growth through synergistic IFN-γ/TNF-α signaling (5); these responses to foci of infected macrophages initiate the formation of the tuberculoid granuloma, which is composed of lymphocytes, macrophages, dendritic cells, and neutrophils (6). The granuloma acts to contain bacteria; however, the events that ensue upon interaction of Mtb with the host can result in microenvironmental changes, leading to an enduring subclinical infection defined as latent TB infection (LTBI) (7,8). Despite the critical role of CD4 + T cells, their influx into granulomas does not necessarily correlate with protection (9).…”

Section: Nonhuman Primate | B Cells | Tuberculosis | Cd4 T Cells | CDmentioning

confidence: 99%

CD4 ⁺ T-cell–independent mechanisms suppress reactivation of latent tuberculosis in a macaque model of HIV coinfection

Foreman

Mehra

LoBato

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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120

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The synergy between Mycobacterium tuberculosis (Mtb) and HIV in coinfected patients has profoundly impacted global mortality because of tuberculosis (TB) and AIDS. HIV significantly increases rates of reactivation of latent TB infection (LTBI) to active disease, with the decline in CD4 + T cells believed to be the major causality. In this study, nonhuman primates were coinfected with Mtb and simian immunodeficiency virus (SIV), recapitulating human coinfection. A majority of animals exhibited rapid reactivation of Mtb replication, progressing to disseminated TB and increased SIV-associated pathology. Although a severe loss of pulmonary CD4 + T cells was observed in all coinfected macaques, a subpopulation of the animals was still able to prevent reactivation and maintain LTBI. Investigation of pulmonary immune responses and pathology in this cohort demonstrated that increased CD8 + memory T-cell proliferation, higher granzyme B production, and expanded B-cell follicles correlated with protection from reactivation. Our findings reveal mechanisms that control SIV-and TB-associated pathology. These CD4-independent protective immune responses warrant further studies in HIV coinfected humans able to control their TB infection. Moreover, these findings will provide insight into natural immunity to Mtb and will guide development of novel vaccine strategies and immunotherapies.Nonhuman primate | B cells | tuberculosis | CD4 T cells | CD8 T cells

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Section: Nonhuman Primate | B Cells | Tuberculosis | Cd4 T Cells | CDmentioning

confidence: 99%

CD4 ⁺ T-cell–independent mechanisms suppress reactivation of latent tuberculosis in a macaque model of HIV coinfection

Foreman

Mehra

LoBato

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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120

202

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“…Lung tissue was fixed for hematoxylin-eosin histology and confocal microscopy (18)(19)(20)(21)(22). Ten images of each slide were used for analysis (Inform; PerkinElmer, Waltham, MA).…”

Section: Staining Procedures Histopathology and Microscopymentioning

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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“…However, vaccination has thus far not been investigated using these routes together with very low M. tuberculosis challenge doses. The BCG studies in nonhuman primates (NHPs) conducted thus far have utilized high challenge doses (250 to 3,000 CFU per animal), and in these studies, reduction in bacterial loads and hematogenous spread, but no evidence of sterilizing immunity, have been observed (136)(137)(138). Although the pathological, radiographic, and sample culturing techniques do not definitively demonstrate M. tuberculosis clearance, the high inocula utilized are a limitation for interpreting the potential efficacy of BCG in preventing primary infection.…”

Section: Lessons From Bcgmentioning

confidence: 99%

Tuberculosis Vaccines and Prevention of Infection

Hawn

Day

Scriba

et al. 2014

Microbiol Mol Biol Rev

138

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SUMMARY Tuberculosis (TB) is a leading cause of death worldwide despite the availability of effective chemotherapy for over 60 years. Although Mycobacterium bovis bacillus Calmette-Guérin (BCG) vaccination protects against active TB disease in some populations, its efficacy is suboptimal. Development of an effective TB vaccine is a top global priority that has been hampered by an incomplete understanding of protective immunity to TB. Thus far, preventing TB disease, rather than infection, has been the primary target for vaccine development. Several areas of research highlight the importance of including preinfection vaccines in the development pipeline. First, epidemiology and mathematical modeling studies indicate that a preinfection vaccine would have a high population-level impact for control of TB disease. Second, immunology studies support the rationale for targeting prevention of infection, with evidence that host responses may be more effective during acute infection than during chronic infection. Third, natural history studies indicate that resistance to TB infection occurs in a small percentage of the population. Fourth, case-control studies of BCG indicate that it may provide protection from infection. Fifth, prevention-of-infection trials would have smaller sample sizes and a shorter duration than disease prevention trials and would enable opportunities to search for correlates of immunity as well as serve as a criterion for selecting a vaccine product for testing in a larger TB disease prevention trial. Together, these points support expanding the focus of TB vaccine development efforts to include prevention of infection as a primary goal along with vaccines or other interventions that reduce the rate of transmission and reactivation.

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Granuloma Correlates of Protection Against Tuberculosis and Mechanisms of Immune Modulation by Mycobacterium tuberculosis

Cited by 97 publications

References 46 publications

CD4 ⁺ T-cell–independent mechanisms suppress reactivation of latent tuberculosis in a macaque model of HIV coinfection

CD4 ⁺ T-cell–independent mechanisms suppress reactivation of latent tuberculosis in a macaque model of HIV coinfection

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

Tuberculosis Vaccines and Prevention of Infection

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Granuloma Correlates of Protection Against Tuberculosis and Mechanisms of Immune Modulation by Mycobacterium tuberculosis

Cited by 97 publications

References 46 publications

CD4 + T-cell–independent mechanisms suppress reactivation of latent tuberculosis in a macaque model of HIV coinfection

CD4 + T-cell–independent mechanisms suppress reactivation of latent tuberculosis in a macaque model of HIV coinfection

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

Tuberculosis Vaccines and Prevention of Infection

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Product

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CD4 ⁺ T-cell–independent mechanisms suppress reactivation of latent tuberculosis in a macaque model of HIV coinfection

CD4 ⁺ T-cell–independent mechanisms suppress reactivation of latent tuberculosis in a macaque model of HIV coinfection