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Principal Investigator: Manoj T Duraisingh
Organization: HARVARD UNIVERSITY D/B/A HARVARD SCHOOL OF PUBLIC HEALTH
Fiscal Year: 2024
Award: $239,250
Funding agency: National Institute of Allergy and Infectious Diseases
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.
Terms: <Anopheles><Anopheles Genus><Anophelines><Bacterial Infections><Biology><Blood><Blood Circulation><Blood Reticuloendothelial System><Blood erythrocyte><Bloodstream><CUT&RUN><Causality><Cell Anoxia><Cell Body><Cell Function><Cell Hypoxia><Cell Physiology><Cell Process><Cells><Cellular Anoxia><Cellular Function><Cellular Hypoxia><Cellular Physiology><Cellular Process><Cleavage Targets and Release Using Nuclease><Cleavage Under Targets and Release Using Nuclease><Code><Coding System><Complex><Culicidae><Daughter><Development><Disease><Disorder><Environment><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Erythrocytes><Erythrocytic><Etiology><Family><Gene Expression><Gene Transcription><Generalized Growth><Genes><Genetic Transcription><Glycolysis><Growth><Histone Code><Histones><Human><Human Bites><Immune><Immunes><In Vitro><India><Infection><Intermediary Metabolism><Investigation><L-Lysine><Laboratories><Lactic Acidosis><Life><Link><Lysine><Macrophage><Malaria><Mammalian Cell><Maps><Marrow erythrocyte><Mediating><Mediator><Metabolic><Metabolic Processes><Metabolism><Mice><Mice Mammals><Modern Man><Mosquitoes><Murine><Mus><Mφ><P falciparum><P. falciparum><P.falciparum><Paludism><Parasites><Pathogenesis><Pathway interactions><Patient Isolation><Phenotype><Physiologic><Physiological><Plasmodium><Plasmodium Infections><Plasmodium falciparum><Post-Translational Modification Protein/Amino Acid Biochemistry><Post-Translational Modifications><Post-Translational Protein Modification><Post-Translational Protein Processing><Posttranslational Modifications><Posttranslational Protein Processing><Production><Proliferating><Protein Modification><Proteins><Pyruvate><RNA Expression><RNA Seq><RNA sequencing><RNAseq><Red Blood Cells><Red Cell><Reporting><Role><Severity of illness><Silent Mating Type Information Regulator 2-like Proteins><Sir2-like Proteins><Sirtuins><Subcellular Process><Symptoms><Tail><Tissue Growth><Transcription><Transmission><Virulence><Work><aerobic glycolysis><anaerobic glycolysis><asexual><bacteria infection><bacterial disease><blood corpuscles><causation><developmental><disease causation><disease severity><epigenetically><malaria infection><malaria-infected><malarial infection><novel><ontogeny><pathogenicity gene><pathway><programs><response><social role><transcriptome sequencing><transcriptomic sequencing><transmission process><virulence gene><virulent gene>