H Mwandumba, CoM, Characterisation of the breakdown in immune competence of the lung that favours development of tuberculosis in HIV-infected adults

Tuberculosis (TB) remains a major health problem in sub-Saharan Africa where the morbidity and mortality due to this infection are high, predominantly as a consequence of human immunodeficiency virus (HIV) infection. While it is unequivocal that infection with HIV results in loss of immune control of Mycobacterium tuberculosis (Mtb) by the host, it is unclear if the increased risk of TB disease is due solely to depletion of CD4+ T-cells (a type of immune cells), or due to the loss of other immune functions. For instance, the risk of developing active TB starts to increase soon after HIV infection, even before significant depletion of CD4+ T-cells in peripheral blood. Furthermore, antiretroviral therapy (ART)-mediated immune recovery does not eliminate the increased risk of TB in HIV-infected individuals, indicating that reconstitution of the CD4+ T-cell subset alone is not sufficient to recover full protection against active TB. Accumulating evidence also indicates that in regions of high Mtb transmission, many TB cases in HIV-infected individuals result from recent Mtb infections and not reactivation of pre-existing infection. Since the majority of Mtb infections are acquired through the respiratory route, this suggests strongly that the lung environment in HIV-infected individuals is altered to permit the establishment and progression of new Mtb infections. In view of existing limitations in current understanding of the pulmonary protective immune response against Mtb infections in humans, this project will utilize human lung immune cells and ex vivo experimental infections with characterized, reporter Mtb strains to probe the mechanistic basis underlying the successful control of Mtb in the lung. It will also explore the impact of HIV co-infection and ART on immune competence of the lung in general, and the Mtb-limiting immune response in particular. The project will capitalize on the long-standing links between the Liverpool School of Tropical Medicine, Cornell University and the Malawi-Liverpool-Wellcome Trust Clinical Research Programme (MLW)'s strongly integrated clinical research base, high quality laboratories and excellent training infrastructure. It will strengthen existing collaborations and forge new ones to promote the development and transfer of cutting-edge technology to Malawi. By exploiting the HIV-mediated breakdown in immune control of Mtb, the project is bold and highly innovative in its approach to gain a comprehensive understanding of the optimal pulmonary immune environment for successful control of this pathogen. It will charter new areas of investigation and has tremendous potential to contribute to the field important new insights that will impact the design and implementation of public health interventions for control of TB in both HIV-uninfected and HIV-infected individuals.