Epigenetic Regulation of Macrophage Innate Immune Memory in Response to Repeated Plasmodium falciparum Exposure: Implications for Naturally Acquired Malaria Immunity in Borno State

Trained innate immunity, mediated by epigenetic reprogramming of macrophage chromatin through histone methylation and acetylation, has emerged as a critical mechanism of non-specific immune memory with profound implications for understanding naturally acquired malaria immunity in high-transmission settings. This mechanistic immunological study recruited 60 adults with lifetime high malaria exposure (more than 20 documented episodes) and 60 malaria-naive urban controls from Maiduguri, Borno State, in the North East geopolitical zone of Nigeria. Ex-vivo monocyte-derived macrophages were trained with P. falciparum glycosylphosphatidylinositol (PfGPI) anchors and challenged with heterologous bacterial and viral stimuli. Epigenetic analyses included ChIP-seq for H3K4me3 and H3K27ac marks at trained immunity loci. Transcriptomic profiling of trained versus naive macrophages was conducted by RNA-seq. Chromatin immunoprecipitation sequencing revealed extensive H3K4me3 enrichment at innate immune gene promoters in macrophages from high-exposure participants compared to controls. Trained macrophages demonstrated significantly elevated TNF-alpha, IL-6, and reactive oxygen species production upon heterologous challenge. H3K27ac enrichment at NLRP3 and TLR4 gene loci was correlated with protection against febrile illness episodes in the high-exposure cohort. These findings establish epigenetic trained immunity as an active mechanism contributing to naturally acquired malaria protection in Borno State adults and identify chromatin-modifying interventions as a novel strategy to enhance malaria vaccine efficacy. Keywords: trained innate immunity, malaria, epigenetics, macrophage, Borno State.