Impact of recurrent malaria on γδ T cell-mediated trained immunity
BACKGROUND: Clinical immunity to the most deadly human malaria parasite, Plasmodium falciparum (Pf), develops slowly over an individual’s lifetime; while immunity limits symptomatic infections in older children and adults, protection against parasite replication is partial. Our group has previously shown that repeated malaria exposure among Ugandan children is associated with reduced percentages of innate-like γδ T cells, decreased cytokine production and proliferation in response to malaria antigens, and increased expression of immunoregulatory genes.
GAP: Building on observations that loss and dysfunction of the Vd2+ subset of γδ T cells during recurrent malaria associates with a reduced likelihood of symptoms upon subsequent infection, we will investigate the role of attenuation of the γδ T cell pro-inflammatory response in the development of anti-malarial immunity. We will leverage new approaches coordinating genetic, epigenetic, transcriptional, metabolic, and functional analyses to elucidate molecular mechanisms driving altered γδ T cell function, including interaction with the adaptive memory compartment.
HYPOTHESIS: We hypothesize that repeated malaria antigen exposure leads to epigenetic and transcriptional reprogramming of malaria-responsive γδ T cell populations (Aim 1) and that these changes impede effective B and T cell memory (Aim 2).
METHODS: Both aims first analyze immune responses at different timepoints from children with or without recurrent malaria (20 children per group) and then expand these findings to in vitro priming assays. Obtained from individuals enrolled in 2 longitudinal observational cohorts in Eastern Uganda with varying transmission intensities, samples will be analyzed by ATAC-seq, RNA-seq, and in vitro functional assays established in our lab.
IMPACT: By providing needed insight into the mechanisms driving short-lived antimalarial immunity in children, as well as interaction between innate and adaptive memory, results from the proposed studies could lead to novel therapeutics that reverse this henomenon and induce highly functional, long-lasting immune responses. Such therapeutics are needed to reduce the devastating global mortality and morbidity due to malaria.
Website Link: https://profiles.stanford.edu/kathleen-dantzler