Mendelian susceptibility to mycobacterial disease in tuberculosis-hyperendemic South Africa.

BACKGROUND: Severe infections in the absence of secondary immunodeficiency can alert clinicians to single-gene inborn errors of immunity/primary immunodeficiency disorders (PIDDs). Mendelian susceptibility to mycobacterial disease (MSMD) is characterised by selective susceptibility to mycobacterial infections due to inborn errors in the interleukin 12-interferon gamma pathway. The South African (SA) burden of hyperendemic tuberculosis (TB) infection provides an interesting context for the study of MSMD. OBJECTIVES:  To evaluate whether severe, persistent, unusual or recurrent (SPUR) definitions of TB can be applied in the context of MSMD in SA. METHODS: This study is a retrospective review of an SA PIDD cohort. Patients aged 0 - 15 years with SPUR TB infections, assessed between 2013 and 2018, were identified using a proposed algorithm. HIV infection or other secondary causes for immunodeficiency were excluded. Basic investigations, then focused immunophenotyping and next-generation sequencing, were performed. RESULTS:  A total of 20 patients with a clinical diagnosis of MSMD were identified. A further two, forming part of a family cohort, had pathogenic variants but remain asymptomatic. Infection with Mycobacterium tuberculosis complex predominated (64%), while 27% had BCG infection or non-tuberculous mycobacteria (NTM) infection. Molecular analysis revealed pathogenic variants in 41% of patients with SPUR mycobacterial infection, mainly in those with BCG/NTM infection. CONCLUSIONS:  In the SA paediatric population, SPUR TB infections, particularly BCG/NTM, in the absence of secondary immunodeficiency, can alert to possible MSMD. The molecular diagnosis is pivotal, guiding disease classification and influencing clinical approach and management. The diagnosis is complex and requires a multidisciplinary approach with close collaboration between clinical immunologists, bioinformaticians, immunologists, clinical geneticists and genetic counsellors.

Granule-dependent cytolysis of Mycobacterium tuberculosis-infected macrophages by human gammadelta+ T cells has no effect on intracellular mycobacterial viability.

One of the most important effector functions of activated gammadelta+ T cells in tuberculosis is their strong cytolytic activity against a variety of target cells, including M. tuberculosis-infected macrophages. In the present study, we investigated the relationship between the mechanism of cytolysis utilized by gammadelta+ CTL and intracellular M. tuberculosis survival using a panel of cytolytic human M. tuberculosis-specific gammadelta+ CTL clones. Cytolysis mediated by the gammadelta+ T-cell clones was found to be Ca2+-dependent, sensitive to Cyclosporin A, and was completely abrogated following Sr2+-induced de-granulation of the gammadelta+ T cell effectors. These data demonstrate that gammadelta+ T-cell-mediated cytoxicity was mediated via the granule exocytosis/perforin pathway. Despite significant cytolytic activity against mycobacteria infected U937 cells, the gammadelta+ CTL clones had no impact on the survival of intracellular M. tuberculosis.