Thursday, November 21, 2024
11/21/2024
Malaria is a life-threatening disease that is transmitted to humans by the bite of Anopheline mosquitoes infected with Plasmodium parasites. Proliferation of parasites within erythrocytes in the bloodstream is central to the parasite’s survival and results in the pathogenesis of malaria. Little is known about how the metabolic environment of the parasite is sensed and linked to changes in gene expression. One of the major factors underlying severe malaria, caused by infection with Plasmodium falciparum, is lactic acidosis, which has a complex etiology, with lactate being produced by both the parasite and the host. During the asexual stages, P. falciparum parasites carry out fermentative glycolysis leading to the conversion of pyruvate into lactate. In addition, the host, due to aerobic glycolysis in proliferating immune cells and anaerobic glycolysis in hypoxic cells, contributes to increased lactate levels in the bloodstream. In vitro studies have shown that the parasite responds to changes in host lactate levels. Lactate accumulation can retard parasite growth, alter the rate of switching to transmissible forms, and has been associated with virulence gene expression. However, the mechanism underlying these profound changes in parasite phenotypes is unknown. In a recent study, a new post-translational modification (PTM), lactylation, was reported in human and mouse cells, that responds to lactate levels. In mammalian cells, several hundred proteins including histones are lactylated, and increased lactate levels in the course of a bacterial infection resulted in gene expression changes in macrophages, providing a link between cellular metabolism and gene expression. We have discovered this new PTM on the tails of multiple histones in P. falciparum. We hypothesize that lactate-derived lactylation of parasite histones is a novel histone code signature that mediates gene expression changes linked to lactate metabolism. We will comprehensively assess histone lactylation dynamics through the parasite asexual cycle as well as the ability of histone lactylation to be altered by perturbations in lactate metabolism. These investigations will be performed both in a diverse panel of laboratory strains, as well as patient isolates with different disease severity. We will also identify the target genes of histone lactylation and their association with transcriptional programs linked to parasite cellular processes. The findings from this proposed work have the potential to establish a critical role for histone lactylation at the fulcrum between lactate metabolism and gene expression in asexual stages of P. falciparum, with significant implications for malaria pathogenesis and transmission.
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