Plasmodium knowlesi Infection Is Associated With Elevated Circulating Biomarkers of Brain Injury and Endothelial Activation

Background Malaria remains a major public health concern with substantial morbidity and mortality worldwide. In Malaysia, the emergence of Plasmodium knowlesi has led to a surge in zoonotic malaria cases and deaths in recent years. Signs of cerebral involvement have been observed in a noncomatose, fatal case of knowlesi infection, but the potential impact of this malaria species on the brain remains unexplored. To address this gap, we investigated circulating levels of brain injury, inflammation, and vascular biomarkers in a cohort of knowlesi-infected patients and controls. Methods Archived plasma samples from 19 Malaysian patients with symptomatic knowlesi infection and 19 healthy, age-matched controls were analyzed. Fifty-two biomarkers of brain injury, inflammation, and vascular activation were measured. Wilcoxon tests were used to examine group differences, and biomarker profiles were explored through hierarchical clustering heatmap analysis. Results Bonferroni-corrected analyses revealed significantly elevated brain injury biomarker levels in knowlesi-infected patients, including S100B (P < .0001), Tau (P = .0007), UCH-L1 (P < .0001), αSyn (P < .0001), Park7 (P = .0006), NRGN (P = .0022), and TDP-43 (P = .005). Compared to controls, levels were lower in the infected group for BDNF (P < .0001), CaBD (P < .0001), CNTN1 (P < .0001), NCAM-1 (P < .0001), GFAP (P = .0013), and KLK6 (P = .0126). Hierarchical clustering revealed distinct group profiles for brain injury and vascular activation biomarkers. Conclusions Our findings highlight for the first time a potential impact of P knowlesi infection on the brain, with specific changes in cerebral injury and endothelial activation biomarker profiles. Further studies are warranted to investigate the pathophysiology and clinical significance of these altered markers, through neuroimaging and long-term neurocognitive assessments.