Abstract

Plasmodium falciparum infection triggered complex host immune responses that determined disease severity, with 
cerebral malaria representing the most lethal complication characterized by profound neuroinflammation, 
endothelial dysfunction, and blood-brain barrier disruption. Emerging evidence indicates that parasite-derived 
epigenetic factors, including histones, nucleosomes, extracellular vesicles, and microRNAs, actively modulate host 
immune signaling pathways and contribute to immunopathology. This review examined the mechanisms by which 
Plasmodium-derived epigenetic factors influenced host immune responses and evaluated their contribution to the 
pathogenesis of severe and cerebral malaria. A comprehensive analysis of recent literature focused on parasite 
epigenetic regulators, host immune modulation, inflammatory pathways, and cerebral malaria pathophysiology was 
conducted. Plasmodium releases histones, DNA complexes, and extracellular vesicles during schizont rupture that 
activate toll-like receptors, induce proinflammatory cytokine cascades, promote endothelial activation, and trigger 
neutrophil extracellular trap formation. Parasite-derived microRNAs transferred via extracellular vesicles 
reprogrammed host gene expression, suppressing antimalarial responses while enhancing inflammatory pathways. 
Epigenetic modifications in host immune cells, including altered histone acetylation and DNA methylation patterns, 
establish persistent immune dysfunction and contribute to cytokine storm generation. These mechanisms 
collectively drove severe malaria complications, including cerebral pathology, respiratory distress, and metabolic 
acidosis. Plasmodium-derived epigenetic factors represented critical mediators of immunopathology in severe 
malaria through multifaceted modulation of innate and adaptive immunity. Understanding these molecular 
interactions provided opportunities for developing host-directed therapies that mitigated excessive inflammation 
while preserving antimalarial immune responses and improving clinical outcomes in life-threatening malaria.