The malaria toxin hemozoin induces apoptosis in human neurons and astrocytes: Potential role in the pathogenesis of cerebral malaria

Malaria, caused by an intracellular protozoan parasite of the genus Plasmodium, is one of the most important infectious diseases worldwide. In 2017, a total of 219 millions cases were reported with 435,000 deaths related to malaria. A major complication of malaria infection is cerebral malaria (CM), characterized by enhanced blood-brain barrier permeability, leukocyte infiltration and/or activation, and neuronal dropout resulting in coma and death in significant numbers of individuals, especially children. Despite the high incidence and mortality, the pathogenesis of cerebral malaria is not well characterized. Hemozoin (HMZ) or “malaria pigment,” a by-product of intraerythrocytic parasite-mediated hemoglobin catabolism, is released into the bloodstream after lysis of the host infected erythrocyte. The effects of HMZ on brain cells has not been studied due to the contamination/adhesion/aggregation of the HMZ with host and toxic parasitic factors. We now demonstrate that extracellular purified HMZ is taken up by human neurons and astrocytes, resulting in cellular dysfunction and toxicity. These findings contribute to a better understanding of the neuropathogenesis of CM and provide evidence that HMZ accumulation in the bloodstream could result in CNS compromise. Thus, alternative approaches to reducing circulating HMZ could serve as a potential treatment.