Immunopathogenesis of Severe Malaria: Characterizing T Regulatory Cell Dysfunction and PD-1/PD-L1 Immune Checkpoint Activation in Nigerian Children

Severe malaria pathogenesis involves profound dysregulation of the host immune response, yet the precise mechanisms by which Plasmodium falciparum exploits immune regulatory networks including T regulatory cells and PD-1/PD-L1 checkpoint pathways to suppress protective immunity remain incompletely defined. This immunopathogenesis study recruited 80 children with WHO-defined severe malaria, 80 with uncomplicated malaria, and 80 healthy controls from the University of Maiduguri Teaching Hospital, Borno State, in the North East geopolitical zone, and Jos University Teaching Hospital, Plateau State, in the North Central zone. Flow cytometric immunophenotyping characterized CD4+CD25+FOXP3+ T regulatory cells, exhausted CD8+ T cells, PD-1 and PD-L1 expression, and effector T cell cytokine profiles by intracellular cytokine staining. T regulatory cell frequency was significantly expanded in severe malaria (9.8 percent of CD4 cells) versus uncomplicated malaria (4.6 percent) and controls (2.1 percent). PD-1 upregulation on CD8+ T cells correlated inversely with parasite clearance rate. IL-10 production by T regulatory cells was markedly elevated in cerebral malaria cases. IL-17A and IFN-gamma were suppressed in the severe disease group despite high parasitemia. FOXP3+ cell expansion was reversible upon parasite clearance. This work establishes a mechanistic basis for T regulatory cell and PD-1 pathway-driven immune privilege for P. falciparum and identifies potential immunomodulatory therapeutic targets for severe malaria management. Keywords: severe malaria, T regulatory cells, PD-1 pathway, immunopathogenesis, Plasmodium falciparum.