Project Title

NK and B cell determinants of immunity to Mycobacterium tuberculosis in humans

EDCTP Project Call

Career Development Fellowship (CDF)

Project Objectives

We will study these cell subsets in much greater detail in human TB progressors by characterizing these cell subsets in samples collected while they were completely healthy, before disease manifestation. This will allow us to determine the role of these cells in successful control of the infection and, subsequently, during disease progression.

Study Design

Clinical Trial

Project Summary

Tuberculosis (TB) is the major human killer from a single infectious agent. A better understanding of the immunopathogenesis of Mycobacterium tuberculosis (Mtb) infection and disease is critical for rational development of improved interventions needed to control and eradicate TB. The mechanisms that govern how humans control infection with Mtb are not understood. Recent studies have shown that CD4 T cell responses are necessary but not sufficient for immunological protection against TB. We propose that NK and B cells participate alongside antigen-specific Th1 responses in the successful immune response to Mtb and are dysregulated in persons who progress to active disease. We aim to identify new NK and B cell subsets involved in tuberculosis progression. Firstly, in Aims 1.1 and 2.1 we will re-analyse a longitudinal mass cytometry CyTOF dataset of 37 progressors who transitioned from Mtb infection to incident TB disease and 37 matched Mtb-infected controls, who remained asymptomatic during 2 years of follow-up. This complex dataset was generated to primarily study T cell response correlates of TB disease risk. Re-analysis will now allow us to characterise changes in NK and B cell phenotypes and functions in the context of the Mtb-specific T cell response using 16 NK-specific and 17 B-cell specific markers. In Aim 1.2, we will investigate the mechanisms of activation of NK cells whether they are directly activated by the pathogen or through nonspecific cytokine stimulations. In Aims 1.3 and 2.2, we will define the relevance of the findings made in the peripheral blood in Aims 1.1 and 2.1 by analysing post-mortem tissue samples from the site of Mtb-infection from TB patients and healthy Mtb-infected individuals who died from trauma/accidents. We will define a new 40 marker mass cytometry antibody panel to deeply decipher phenotype and functions of NK and B cells at the site of infection in humans after stimulation with Mtb. We will define the role of NK cells in IL-22 production and the memory profile and cytokine production capabilities of B cells and their contribution to the milieu at the site of infection. The proposed study will uncover new potential targets for host directed therapies, early diagnosis and vaccine design and will provide the fellow with the opportunity to expand her knowledge and technical capacities as well as her international network of collaborations, essential skills to become a research leader in the field of infectious diseases and particularly tuberculosis in South Africa.

Host Organisation

Current Organisation

UCT

Current Job Title

Postdoctoral Fellow

Biography