Effect of HIV infection on the function of CD8+ polycytotoxic T lymphocytes in human tuberculosis

• Applicant: Professor Dr. Steffen Stenger
• Subject Area: Medical Microbiology and Mycology, Hygiene, Molecular Infection Biology ; Immunology ; Parasitology and Biology of Tropical Infectious Disease Pathogens
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 425963938

Tuberculosis remains a major burden for mankind with close to 10 million new cases per year and 1.5 million fatalities. In Germany more than 5000 new cases were reported in 2019. Besides being a transmissible disease, the increasing frequency of drug-resistant strains, extrapulmonary disease and the management of cases occurring in refugees are emerging issues. For the development of new strategies for the treatment and prophylaxis of tuberculosis it is critical to increase our understanding of the immune response against the intracellular bacterium Mycobacterium tuberculosis, the causative agent of disease. T-lymphocytes are key players by supporting the antimycobacterial effector functions of infected macrophages. Impairment of T-cell function, e.g. by immunosuppressive therapy, severe diabetes or high age enhance the risk for developing. Especially in sub-Saharan Africa infection with the human immunodeficiency virus (HIV) is a risk factor by interfering with T cell functions. In this part of the world the majority of tuberculosis patients are co-infected with HIV. To develop novel concepts on the way of eliminating tuberculosis, it is therefore critical to understand the interaction of these two microbial pathogens. In this project we will compare the T cell functions in patients with tuberculosis, HIV or co-infected individuals. The infrastructure and epidemiology in Blantyre, Malawi is ideal to conduct these experiments. The local research center has a longstanding experience in setting up clinical studies involving the immunological analysis of cells obtained from the bronchoalveolar lavage. In addition the rate of tuberculosis patients co-infected with HIV exceeds 70%. The focus of the immunological studies will be a subpopulation of T-lymphocytes, which recognizes and destroys Mycobacterium tuberculosis-infected macrophages and concomitantly kills the pathogen. These CD8+ T lymphocytes co-express the lytic and antimicrobial molecules perforin, granulysin and granzyme B and have been termed “polycytotoxic T cells”. This population was recently identified by the team from Ulm and initial findings indicate that polycytotoxic T cells have a beneficial effect on the course of tuberculosis. Taken together, the aim of this African-German research collaboration is to investigate the effect of HIV-infection on the frequency and function of polycytotoxic T cells in human tuberculosis. As a future perspective, these studies may build the scientific backbone to introduce the pharmacological manipulation of T-cell function as an adjuvant treatment to complement conventional multi-drug treatment of tuberculosis.

• DFG Programme: Research Grants
• International Connection: Malawi
• International Co-Applicant: Professor Dr. Henry Mwandumba