Platelets kill circulating parasites of all major Plasmodium species in human malaria

Abstract

Platelets are understood to assist host innate immune responses against infection, although direct evidence of this function in any human disease, including malaria, is unknown. Here we characterized platelet-erythrocyte interactions by microscopy and flow cytometry in patients with malaria naturally infected with ,, , or Blood samples from 376 participants were collected from malaria-endemic areas of Papua, Indonesia, and Sabah, Malaysia. Platelets were observed binding directly with and killing intraerythrocytic parasites of each of the species studied, particularly mature stages, and was greatest in patients. Platelets preferentially bound to the infected more than to the uninfected erythrocytes in the bloodstream. Analysis of intraerythrocytic parasites indicated the frequent occurrence of platelet-associated parasite killing, characterized by the intraerythrocytic accumulation of platelet factor-4 and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling of parasite nuclei (PF4TUNEL parasites). These PF4TUNEL parasites were not associated with measures of systemic platelet activation. Importantly, patient platelet counts, infected erythrocyte-platelet complexes, and platelet-associated parasite killing correlated inversely with patient parasite loads. These relationships, taken together with the frequency of platelet-associated parasite killing observed among the different patients and species, suggest that platelets may control the growth of between 5% and 60% of circulating parasites. Platelet-erythrocyte complexes made up a major proportion of the total platelet pool in patients with malaria and may therefore contribute considerably to malarial thrombocytopenia. Parasite killing was demonstrated to be platelet factor-4-mediated in culture. Collectively, our results indicate that platelets directly contribute to innate control of infection in human malaria.

Immune role of platelets in malaria

“…We have also confirmed Peyron and colleagues' observations of the in vitro parasite killing activity of purified human platelets against P. falciparum [18, 92] and observed a similar action against cultured P. knowlesi [93]. Further, we have demonstrated that platelets bind and kill intraerythrocytic parasites in malaria patients infected with P. falciparum, P. vivax, P. malariae or P. knowlesi [93]. In parasite cultures, infected mice and in human patients, platelets were observed preferentially bound to infected cells, although noninfected red cells also bound.…”

The Utility of a Three Part Differential Hematology Analyzer with CRP for Assessing Malaria

“…Moreover, in hematological analyzers, PLTs complexed with RBCs are not identified, therefore complexed particles would lead to an apparent platelet loss [20]. In the present study, thrombocytopenia (< 3 /µL) was predominantly observed in malaria P. falciparum cases (83.87%) than P. vivax (76.44%), which is similar to the observations reported in [21,22].…”

Platelet disturbances correlate with endothelial cell activation in uncomplicated Plasmodium vivax malaria

“…Whether a systemic activation of circulating platelets occur in malaria is still unclear. While a study has reported altered platelet responses after exposure to P. falciparum infected erythrocytes (P-IE) in vitro (22), direct assessment of platelet activation through flow cytometry has rendered negative results (10, 23). However, evidence of some grade of platelet activation in vivo , through measurement of circulating factors, have been shown by other groups (5, 24).…”

“…In addition, platelets lead to a deleterious inflammatory response in the disease through platelet-factor 4 (PF4), with PF4-KO mice surviving the infection (8). However, PF4 also plays a protective role in the disease, as it mediates P. falciparum killing by platelets in vitro (9) and in vivo , as shown in patients from Southeast Asia, and this was correlated with reduced parasitemias (10).…”