摘要：SummaryHuman cerebral malaria (HCM) is a severe complication ofPlasmodium falciparum (P.f.)infection that is characterized by capillary occlusions, rupture of the blood-brain barrier (BBB), perivascular cellular injury, and brain swelling.P.f.histidine-rich protein 2 (HRP2), a byproduct of parasitized red blood cell (pRBC) lysis, crosses the BBB when compromised to cause brain injury. We hypothesized that HRP2-induced neuronal damage can be attenuated by Neuregulin-1 (NRG1), an anti-inflammatory neuroprotective factor. Using brain cortical organoids, we determined that HRP2 upregulated cell death and inflammatory markers and disorganized brain organoid tissue. We identified toll-like receptors (TLR1 and 2) as potential mediators of HRP2-induced cellular damage and inflammation. Exogenous acute treatment of organoids with NRG1 attenuated HRP2 effects. The results indicate that HRP2 mediates malaria-associated HRP2-induced brain injury and inflammation and that NRG1 may be an effective therapy against HRP2 effects in the brain.Graphical abstractDisplay OmittedHighlights•HRP2 induces neuronal injury and microglia activation in cortical organoids•Upregulation of TLR1/TLR2 expression mediates HRP2 effects in brain organoids•NRG1 (100 ng/mL) attenuates HRP2-induced damage via ErbB4 signalingCell biology; Molecular microbiology; Neuroscience; Parasitology
