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      Tuberculosis Susceptibility and Vaccine Protection Are Independently Controlled by Host Genotype

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          ABSTRACT

          The outcome of Mycobacterium tuberculosis infection and the immunological response to the bacillus Calmette-Guerin (BCG) vaccine are highly variable in humans. Deciphering the relative importance of host genetics, environment, and vaccine preparation for the efficacy of BCG has proven difficult in natural populations. We developed a model system that captures the breadth of immunological responses observed in outbred individual mice, which can be used to understand the contribution of host genetics to vaccine efficacy. This system employs a panel of highly diverse inbred mouse strains, consisting of the founders and recombinant progeny of the “Collaborative Cross” project. Unlike natural populations, the structure of this panel allows the serial evaluation of genetically identical individuals and the quantification of genotype-specific effects of interventions such as vaccination. When analyzed in the aggregate, our panel resembled natural populations in several important respects: the animals displayed a broad range of susceptibility to M. tuberculosis, differed in their immunological responses to infection, and were not durably protected by BCG vaccination. However, when analyzed at the genotype level, we found that these phenotypic differences were heritable. M. tuberculosis susceptibility varied between lines, from extreme sensitivity to progressive M. tuberculosis clearance. Similarly, only a minority of the genotypes was protected by vaccination. The efficacy of BCG was genetically separable from susceptibility to M. tuberculosis, and the lack of efficacy in the aggregate analysis was driven by nonresponsive lines that mounted a qualitatively distinct response to infection. These observations support an important role for host genetic diversity in determining BCG efficacy and provide a new resource to rationally develop more broadly efficacious vaccines.

          IMPORTANCE

          Tuberculosis (TB) remains an urgent global health crisis, and the efficacy of the currently used TB vaccine, M. bovis BCG, is highly variable. The design of more broadly efficacious vaccines depends on understanding the factors that limit the protection imparted by BCG. While these complex factors are difficult to disentangle in natural populations, we used a model population of mice to understand the role of host genetic composition in BCG efficacy. We found that the ability of BCG to protect mice with different genotypes was remarkably variable. The efficacy of BCG did not depend on the intrinsic susceptibility of the animal but, instead, correlated with qualitative differences in the immune responses to the pathogen. These studies suggest that host genetic polymorphism is a critical determinant of vaccine efficacy and provide a model system to develop interventions that will be useful in genetically diverse populations.

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          Most cited references60

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          Disseminated tuberculosis in interferon gamma gene-disrupted mice

          The expression of protective immunity to Mycobacterium tuberculosis in mice is mediated by T lymphocytes that secrete cytokines. These molecules then mediate a variety of roles, including the activation of parasitized host macrophages, and the recruitment of other mononuclear phagocytes to the site of the infection in order to initiate granuloma formation. Among these cytokines, interferon gamma (IFN-gamma) is believed to play a key role is these events. In confirmation of this hypothesis, we show in this study that mice in which the IFN-gamma gene has been disrupted were unable to contain or control a normally sublethal dose of M. tuberculosis, delivered either intravenously or aerogenically. In such mice, a progressive and widespread tissue destruction and necrosis, associated with very high numbers of acid- fast bacilli, was observed. In contrast, despite the lack of protective immunity, some DTH-like reactivity could still be elicited. These data, therefore, indicate that although IFN-gamma may not be needed for DTH expression, it plays a pivotal and essential role in protective cellular immunity to tuberculosis infection.
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            Efficacy of BCG vaccine in the prevention of tuberculosis. Meta-analysis of the published literature.

            To quantify the efficacy of BCG vaccine against tuberculosis (TB). MEDLINE with index terms BCG vaccine, tuberculosis, and human. Experts from the Centers for Disease Control and Prevention and the World Health Organization, among others, provided lists of all known studies. A total of 1264 articles or abstracts were reviewed for details on BCG vaccination, concurrent vaccinated and unvaccinated groups, and TB outcome; 70 articles were reviewed in depth for method of vaccine allocation used to create comparable groups, equal surveillance and follow-up for recipient and concurrent control groups, and outcome measures of TB cases and/or deaths. Fourteen prospective trials and 12 case-control studies were included in the analysis. We recorded study design, age range of study population, number of patients enrolled, efficacy of vaccine, and items to assess the potential for bias in study design and diagnosis. At least two readers independently extracted data and evaluated validity. The relative risk (RR) or odds ratio (OR) of TB provided the measure of vaccine efficacy that we analyzed. The protective effect was then computed by 1-RR or 1-OR. A random-effects model estimated a weighted average RR or OR from those provided by the trials or case-control studies. In the trials, the RR of TB was 0.49 (95% confidence interval [CI], 0.34 to 0.70) for vaccine recipients compared with nonrecipients (protective effect of 51%). In the case-control studies, the OR for TB was 0.50 (95% CI, 0.39 to 0.64), or a 50% protective effect. Seven trials reporting tuberculous deaths showed a protective effect from BCG vaccine of 71% (RR, 0.29; 95% CI, 0.16 to 0.53), and five studies reporting on meningitis showed a protective effect from BCG vaccine of 64% (OR, 0.36; 95% CI, 0.18 to 0.70). Geographic latitude of the study site and study validity score explained 66% of the heterogeneity among trials in a random-effects regression model. On average, BCG vaccine significantly reduces the risk of TB by 50%. Protection is observed across many populations, study designs, and forms of TB. Age at vaccination did not enhance predictiveness of BCG efficacy. Protection against tuberculous death, meningitis, and disseminated disease is higher than for total TB cases, although this result may reflect reduced error in disease classification rather than greater BCG efficacy.
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              Tumor necrosis factor-alpha is required in the protective immune response against Mycobacterium tuberculosis in mice.

              Understanding the immunological mechanisms of protection and pathogenesis in tuberculosis remains problematic. We have examined the extent to which tumor necrosis factor-alpha (TNF alpha) contributes to this disease using murine models in which the action of TNF alpha is inhibited. TNF alpha was neutralized in vivo by monoclonal antibody; in addition, a mouse strain with a disruption in the gene for the 55 kDa TNF receptor was used. The data from both models established that TNF alpha and the 55 kDa TNF receptor are essential for protection against tuberculosis in mice, and for reactive nitrogen production by macrophages early in infection. Granulomas were formed in equal numbers in control and experimental mice, but necrosis was observed only in mice deficient in TNF alpha or TNF receptor. TNF alpha and the 55 kDa TNF receptor are necessary conditions for protection against murine M. tuberculosis infection, but are not solely responsible for the tissue damage observed.
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                Author and article information

                Journal
                mBio
                MBio
                mbio
                mbio
                mBio
                mBio
                American Society for Microbiology (1752 N St., N.W., Washington, DC )
                2150-7511
                20 September 2016
                Sep-Oct 2016
                : 7
                : 5
                : e01516-16
                Affiliations
                [a ]Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, USA
                [b ]AERAS, Rockville, Maryland, USA
                [c ]Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA
                [d ]Department of Infectious Diseases and Global Health, Cummings School of Veterinary Medicine, Tufts University, North Grafton, Massachusetts, USA
                [e ]Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, Braga, Portugal
                [f ]ICVS/3B's, Portuguese Government Associate Laboratory, Braga/Guimaraes, Portugal
                Author notes
                Address correspondence to Christopher M. Sassetti, Christopher.Sassetti@ 123456umassmed.edu .

                Editor Barry R. Bloom, Harvard School of Public Health

                This article is a direct contribution from a Fellow of the American Academy of Microbiology. External solicited reviewers: Deepak Kaushal, Tulane National Primate Research Center; Marcel Behr, McGill University.

                Author information
                http://orcid.org/0000-0003-2601-0955
                http://orcid.org/0000-0002-9524-8302
                http://orcid.org/0000-0003-3441-3113
                http://orcid.org/0000-0003-0232-9953
                http://orcid.org/0000-0002-8970-7306
                Article
                mBio01516-16
                10.1128/mBio.01516-16
                5030360
                27651361
                b1f7d016-1b57-4f14-aed3-20edf9466780
                Copyright © 2016 Smith et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

                History
                : 17 August 2016
                : 22 August 2016
                Page count
                supplementary-material: 2, Figures: 5, Tables: 0, Equations: 0, References: 75, Pages: 13, Words: 10226
                Funding
                Funded by: HHS | National Institutes of Health (NIH) http://dx.doi.org/10.13039/100000002
                Award ID: HL081149
                Award Recipient : Hardy Kornfeld
                Funded by: HHS | National Institutes of Health (NIH) http://dx.doi.org/10.13039/100000002
                Award ID: AI123286-01
                Award Recipient : Sam Behar
                Funded by: Howard Hughes Medical Institute (HHMI) http://dx.doi.org/10.13039/100000011
                Award Recipient : Clare Margaret Smith Award Recipient : Christopher Sassetti
                Categories
                Research Article
                Custom metadata
                September/October 2016

                Life sciences
                Life sciences

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