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Immunological mechanisms of human resistance to persistent Mycobacterium tuberculosis infection.

ABSTRACT: Mycobacterium tuberculosis is a leading cause of mortality worldwide and establishes a long-lived latent infection in a substantial proportion of the human population. Multiple lines of evidence suggest that some individuals are resistant to latent M. tuberculosis infection despite long-term and intense exposure, and we term these individuals 'resisters'. In this Review, we discuss the epidemiological and genetic data that support the existence of resisters and propose criteria to optimally define and characterize the resister phenotype. We review recent insights into the immune mechanisms of M. tuberculosis clearance, including responses mediated by macrophages, T cells and B cells. Understanding the cellular mechanisms that underlie resistance to M. tuberculosis infection may reveal immune correlates of protection that could be utilized for improved diagnostics, vaccine development and novel host-directed therapeutic strategies.

SUBMITTER: Simmons JD

PROVIDER: S-EPMC6278832 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Immunological mechanisms of human resistance to persistent Mycobacterium tuberculosis infection.

Simmons Jason D JD Stein Catherine M CM Seshadri Chetan C Campo Monica M Alter Galit G Fortune Sarah S Schurr Erwin E Wallis Robert S RS Churchyard Gavin G Mayanja-Kizza Harriet H Boom W Henry WH Hawn Thomas R TR

Nature reviews. Immunology 20180901 9

Mycobacterium tuberculosis is a leading cause of mortality worldwide and establishes a long-lived latent infection in a substantial proportion of the human population. Multiple lines of evidence suggest that some individuals are resistant to latent M. tuberculosis infection despite long-term and intense exposure, and we term these individuals 'resisters'. In this Review, we discuss the epidemiological and genetic data that support the existence of resisters and propose criteria to optimally defi ...[more]

PMID: 29895826

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Project description:UnlabelledMost ?-lactam antibiotics are ineffective against Mycobacterium tuberculosis due to the microbe's innate resistance. The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains has prompted interest to repurpose this class of drugs. To identify the genetic determinants of innate ?-lactam resistance, we carried out a synthetic lethality screen on a transposon mutant library for susceptibility to imipenem, a carbapenem ?-lactam antibiotic. Mutations in 74 unique genes demonstrated synthetic lethality. The majority of mutations were in genes associated with cell wall biosynthesis. A second quantitative real-time PCR (qPCR)-based synthetic lethality screen of randomly selected mutants confirmed the role of cell wall biosynthesis in ?-lactam resistance. The global transcriptional response of the bacterium to ?-lactams was investigated, and changes in levels of expression of cell wall biosynthetic genes were identified. Finally, we validated these screens in vivo using the MT1616 transposon mutant, which lacks a functional acyl-transferase gene. Mice infected with the mutant responded to ?-lactam treatment with a 100-fold decrease in bacillary lung burden over 4 weeks, while the numbers of organisms in the lungs of mice infected with wild-type bacilli proliferated. These findings reveal a road map of genes required for ?-lactam resistance and validate synthetic lethality screening as a promising tool for repurposing existing classes of licensed, safe, well-characterized antimicrobials against tuberculosis.ImportanceThe global emergence of multidrug-resistant and extensively drug-resistant M. tuberculosis strains has threatened public health worldwide, yet the pipeline of new tuberculosis drugs under development remains limited. One strategy to cope with the urgent need for new antituberculosis agents is to repurpose existing, approved antibiotics. The carbapenem class of ?-lactam antibiotics has been proposed as one such class of drugs. Our study identifies molecular determinants of innate resistance to ?-lactam drugs in M. tuberculosis, and we demonstrate that functional loss of one of these genes enables successful treatment of M. tuberculosis with ?-lactams in the mouse model.

Dataset Information

Immunological mechanisms of human resistance to persistent Mycobacterium tuberculosis infection.

Publications

Immunological mechanisms of human resistance to persistent Mycobacterium tuberculosis infection.

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