Inhibition of Platelet Adherence to Brain Microvasculature Protects against SeverePlasmodium bergheiMalaria

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Abstract
Some patients withPlasmodium falciparuminfections develop cerebral malaria, acute respiratory distress, and shock and ultimately die even though drug therapy has eliminated the parasite from the blood, suggesting that a systemic inflammatory response contributes to malarial pathogenesis.Plasmodium berghei-infected mice are a well-recognized model of severe malaria (experimental severe malaria [ESM]), and infected mice exhibit a systemic inflammatory response. Because platelets are proposed to contribute to ESM and other systemic inflammatory responses, we determined whether platelet adherence contributes to experimental malarial pathogenesis. Indeed, a significant (P< 0.005) increase in the number of rolling and adherent platelets was observed by intravital microscopy in brain venules ofP. berghei-infected mice compared with the number in uninfected controls. P-selectin- or ICAM-1-deficient mice exhibit increased survival afterP. bergheiinfection. We observed a significant (P< 0.0001) reduction in the morbidity of mice injected with anti-CD41 (αIIbor gpIIb) monoclonal antibody on day 1 ofP. bergheiinfection compared with the morbidity of infected controls injected with rat immunoglobulin G. Additionally, platelet rolling and adhesion in brain venules were reduced inP. bergheimice lacking either P-selectin or ICAM-1 or when the platelets were coated with anti-CD41 monoclonal antibody. Unlike other inflammatory conditions, we did not detect platelet-leukocyte interactions duringP. bergheimalaria. Because (i) leukocyte adhesion is not markedly altered in the absence of P-selectin or ICAM-1 and (ii) CD41 is not an adhesion molecule for parasitized erythrocytes, these findings support the hypothesis that inhibition of platelet adhesion to the brain microvasculature protects against development of malarial pathogenesis.