Elucidating unique host-virus-parasite interaction with unseen depth an breadth (IMMUNO)

Visceral Leishmaniasis (VL) patients coinfected with Human Immunodeficiency Virus (HIV) constitute a rapidly growing challenge for VL control. HIV patients have a 100-fold increased risk of developing VL, followed by very poor patient outcomes and compounded by a unique chronic immunological ‘tolerance’ to the parasite, even with good virological suppression. Yet, basic understanding of this host-virus-parasite interaction is limited. The impact of HIV on VL protective CD4 T-cell immunity remains unexplored territory, but is believed to be multiple. We argue that a severe depletion of T helper (Th)1 and Th17 cells, as target cells of HIV, promotes VL development. In addition, a persistent suppression in T-cell functionality is observed after apparent cure from VL. We hypothesize that a HIV and VL amplified T-cell silencing is the reason why VL-HIV patients lack immune recovery and develop chronic disease. Tapping the ultimate frontier of genomics research while averting pre-set dogmas from simplified animal models (e.g. Th1/Th2 dichotomy), we plan to conduct a genome-wide single T-cell analysis. This approach enables us to timely comprehend the complete spectrum of general and pathogen-specific CD4 functional and differentiation T-cell subsets (high cell-to-cell variation in human) and a concurrent in-depth characterization of highly dynamic inhibitory processes at single T-cell resolution, which is otherwise tedious to study with marker-based approaches. Besides proof-of-concept, this pilot data will generate first critical insights in protective T-cell immunity against VL in HIV patients that will increase competitiveness and credibility in envisioned applications.

Project type:PhD project