Abstract
Cerebral malaria (CM) is a life-threatening neurological syndrome caused by Plasmodium falciparum infection afflicting mainly children in Africa. Current pathogenesis models implicate parasite and host-derived factors in impairing brain vascular endothelium (BVE) integrity. Sequestration of Plasmodium-infected red blood cells (iRBCs) in brain microvessels is a hallmark of CM pathology. However, the precise mechanisms driving loss of blood-brain barrier (BBB) function with consequent brain injury are still unsettled and it is plausible that distinct pathophysiology trajectories are involved. Studies in humans and in the mouse model of CM indicate that inflammatory reactions intertwined with microcirculatory and coagulation disturbances induce alterations in vascular permeability and impair BBB integrity. Yet, the role of BVE as initiator of immune responses against parasite molecules and iRBCs is largely unexplored. Brain endothelial cells express pattern recognition receptors (PRR) and are privileged sensors of blood-borne infections. Here, we focus on the hypothesis that innate responses initiated by BVE and subsequent interactions with immune cells are critical to trigger local effector immune functions and induce BBB damage. Uncovering mechanisms of BVE involvement in sensing Plasmodium infection, recruiting of immune cells and directing immune effector functions could reveal pharmacological targets to promote BBB protection with potential applications in CM clinical management.
Highlights
Malaria is caused by Plasmodium parasites and transmitted to humans by the bite of an infective Anopheles mosquito
IRBCs-derived extracellular vesicles contain parasite genomic DNA that binds to cyclic GMP-AMP synthase inducing type I IFN in human monocytes through the cGAS-stimulator of interferon genes (STING) pathway [62]. These lines of evidence illustrate that parasite-derived factors such as hemozoin and MVs are inducers of innate immunity pathways namely by carrying into the cell plasmodial nucleic acids and allowing recognition by intracellular receptors. We propose that these receptors are potential candidates for parasite sensing and activation of the brain vascular endothelium (BVE) subsequently leading to blood-brain barrier (BBB) disruption during cerebral malaria (CM)
We have shown that IFN (α/β) receptor 1 (IFNAR1) expression on CD8+ T cells is required for cells to induce BBB disruption in CM [35] and it is plausible that IFNα/β produced in the brain endothelium triggers IFNAR1 signaling on CD8+ T cells licensing cytotoxic activity
Summary
Malaria is caused by Plasmodium parasites and transmitted to humans by the bite of an infective Anopheles mosquito. Release of parasite and inflammatory factors in the perivascular space allows activation of other brain cells such as pericytes, astrocytes and microglia. These cells may produce locally inflammatory and neurotoxic factors that change neuronal activity and may cause neurological impairment even in patients who recover from CM [14, 32]. The level of microvessel congestion and iRBCs accumulation is lower than in human cerebral microvasculature of fatal CM cases This may reflect differences in human and mouse microvessel anatomy as well as in erythrocyte cytoadherence conferred by P. falciparum vs P. berghei infection.
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