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Project Topic
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Tuberculosis (TB) is one of the world's leading cause of death, accounting for about 9.6 million new cases and 1.5 million deaths annually. While TB has been for a long time classified into two categories: latent TB infection (LTBI) or active clinical disease (aTB), the current understanding is that Mycobacterium tuberculosis (Mtb) infection represents a dynamic continuum of pathology. Depending on changes in the host immunity and/or concomitant co-infections, individuals’ TB status will evolve on this continuum. However, immunological determinants of TB risk and/or protection are still elusive and, to date, there are no reliable tests permitting to identify those at highest risk of TB. We have recently shown that specific attributes of Mtb-specific CD4+ T cells (such as their activation, memory maturation or inflammatory profile) allow discriminating between latent and active tuberculosis, regardless of HIV status. Moreover, we also recently identified that a unique subpopulation of Mtb-specific CD4+ T cells expressing CD153 (known to confer protection in mice) is ignificantly enriched in LTBI compared to aTB patients. Given this finding, we propose to comprehensibly characterize the phenotypic, functional and transcriptional attributes of Mtb-specific T cell responses across the TB spectrum (focusing on the biomarkers described above) to identify correlates of TB risk and/or protection. We hypothesize that increased TB risk (HIV co-infection, subclinical TB or incipient TB) is associated with specific alterations to Mtb responses, with Mtb-specific CD4+ T cells exhibiting an exacerbated inflammatory/activated profile even before TB clinical symptoms are apparent. Moreover, we anticipate that upon prophylactic TB treatment or ART, known to lower TB risk, the Mtb-specific response profile will be, at least, partially normalized. To test this hypothesis, we will use stored samples from carefully designed cross-sectional and longitudinal clinical cohorts to pursue three aims: 1) To identify the immune signature across the TB spectrum of infection and disease 2) To define the impact of HIV infection on Mtb immune responses across TB spectrum of infection 3) To evaluate the extent to which TB and/or HIV treatment restore the profile of Mtb-specific immune responses. Overall, this project will improve the understanding of host determinants of TB protection or risk, and guide the development of novel tools for TB diagnostic, monitoring treatment response and identifying those at highest risk of TB. Moreover, these studies will contribute to the career development of two PhD, one post-doctoral fellow and the applicant.
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