The simian parasite Plasmodium knowlesi can cause severe and fatal human
malaria. However, little is known about the pathogenesis of this disease. In
falciparum malaria, reduced red blood cell deformability (RBC-D) contributes to microvascular obstruction and impaired organ perfusion. In P knowlesi
infection, impaired microcirculatory flow has been observed in Macaca mulatta (rhesus macaques), unnatural hosts who develop severe and fatal disease. However, RBC-D has not been measured in human
infection or in the natural host M fascicularis (long-tailed macaques). Using ektacytometry, we measured RBC-D in adults with severe and non-severe knowlesi and
falciparum malaria and in healthy controls. In addition, we used micropipette aspiration to determine the relative stiffness of infected RBCs (iRBCs) and uninfected RBCs (uRBCs) in P knowlesi-infected humans and M fascicularis Ektacytometry demonstrated that RBC-D overall was reduced in human knowlesi
malaria in proportion to disease severity, and in severe knowlesi
malaria, it was comparable to that of severe
falciparum malaria. RBC-D correlated inversely with
parasitemia and
lactate in knowlesi
malaria and HRP2 in
falciparum malaria, and it correlated with
hemoglobin nadir in knowlesi
malaria. Micropipette aspiration confirmed that in humans, P knowlesi
infection increased stiffness of both iRBCs and uRBCs, with the latter mostly the result of echinocytosis. In contrast, in the natural host M fascicularis, echinocyte formation was not observed, and the RBC-D of uRBCs was unaffected. In unnatural primate hosts of P knowlesi, including humans, reduced deformability of iRBCs and uRBCs may represent a key pathogenic mechanism leading to microvascular accumulation, impaired organ perfusion, and
anemia.