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

Steven Kho, Bridget E. Barber, Edison Johar, Benediktus Andries, Jeanne R. Poespoprodjo, Enny Kenangalem, Kim A. Piera, Anna Ehmann, Ric N. Price, Timothy William, Tonia Woodberry, Simon Foote, Gabriela Minigo, Tsin W. Yeo, Matthew J. Grigg, Nicholas M. Anstey, Brendan J. McMorran

Research output: Contribution to journalArticleResearchpeer-review

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 Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, or Plasmodium knowlesi. 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 Plasmodium species studied, particularly mature stages, and was greatest in P vivax 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 (PF4+TUNEL+ parasites). These PF4+TUNEL+ 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 Plasmodium 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 P knowlesi culture. Collectively, our results indicate that platelets directly contribute to innate control of Plasmodium infection in human malaria.

Original languageEnglish
Pages (from-to)1332-1344
Number of pages13
JournalBlood
Volume132
Issue number12
DOIs
Publication statusPublished - 20 Sep 2018

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Plasmodium
Platelets
Malaria
Parasites
Blood Platelets
Platelet Factor 4
Malaysia
In Situ Nick-End Labeling
Plasmodium knowlesi
Erythrocytes
Plasmodium malariae
Parasite Load
Vivax Malaria
Indonesia
DNA Nucleotidylexotransferase
Platelet Activation
Plasmodium falciparum
Platelet Count
Innate Immunity
Flow cytometry

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Kho, S., Barber, B. E., Johar, E., Andries, B., Poespoprodjo, J. R., Kenangalem, E., ... McMorran, B. J. (2018). Platelets kill circulating parasites of all major Plasmodium species in human malaria. Blood, 132(12), 1332-1344. https://doi.org/10.1182/blood-2018-05-849307
Kho, Steven ; Barber, Bridget E. ; Johar, Edison ; Andries, Benediktus ; Poespoprodjo, Jeanne R. ; Kenangalem, Enny ; Piera, Kim A. ; Ehmann, Anna ; Price, Ric N. ; William, Timothy ; Woodberry, Tonia ; Foote, Simon ; Minigo, Gabriela ; Yeo, Tsin W. ; Grigg, Matthew J. ; Anstey, Nicholas M. ; McMorran, Brendan J. / Platelets kill circulating parasites of all major Plasmodium species in human malaria. In: Blood. 2018 ; Vol. 132, No. 12. pp. 1332-1344.
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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 Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, or Plasmodium knowlesi. 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 Plasmodium species studied, particularly mature stages, and was greatest in P vivax 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 (PF4+TUNEL+ parasites). These PF4+TUNEL+ 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 Plasmodium 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 P knowlesi culture. Collectively, our results indicate that platelets directly contribute to innate control of Plasmodium infection in human malaria.",
author = "Steven Kho and Barber, {Bridget E.} and Edison Johar and Benediktus Andries and Poespoprodjo, {Jeanne R.} and Enny Kenangalem and Piera, {Kim A.} and Anna Ehmann and Price, {Ric N.} and Timothy William and Tonia Woodberry and Simon Foote and Gabriela Minigo and Yeo, {Tsin W.} and Grigg, {Matthew J.} and Anstey, {Nicholas M.} and McMorran, {Brendan J.}",
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Kho, S, Barber, BE, Johar, E, Andries, B, Poespoprodjo, JR, Kenangalem, E, Piera, KA, Ehmann, A, Price, RN, William, T, Woodberry, T, Foote, S, Minigo, G, Yeo, TW, Grigg, MJ, Anstey, NM & McMorran, BJ 2018, 'Platelets kill circulating parasites of all major Plasmodium species in human malaria', Blood, vol. 132, no. 12, pp. 1332-1344. https://doi.org/10.1182/blood-2018-05-849307

Platelets kill circulating parasites of all major Plasmodium species in human malaria. / Kho, Steven; Barber, Bridget E.; Johar, Edison; Andries, Benediktus; Poespoprodjo, Jeanne R.; Kenangalem, Enny; Piera, Kim A.; Ehmann, Anna; Price, Ric N.; William, Timothy; Woodberry, Tonia; Foote, Simon; Minigo, Gabriela; Yeo, Tsin W.; Grigg, Matthew J.; Anstey, Nicholas M.; McMorran, Brendan J.

In: Blood, Vol. 132, No. 12, 20.09.2018, p. 1332-1344.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Barber, Bridget E.

AU - Johar, Edison

AU - Andries, Benediktus

AU - Poespoprodjo, Jeanne R.

AU - Kenangalem, Enny

AU - Piera, Kim A.

AU - Ehmann, Anna

AU - Price, Ric N.

AU - William, Timothy

AU - Woodberry, Tonia

AU - Foote, Simon

AU - Minigo, Gabriela

AU - Yeo, Tsin W.

AU - Grigg, Matthew J.

AU - Anstey, Nicholas M.

AU - McMorran, Brendan J.

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N2 - 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 Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, or Plasmodium knowlesi. 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 Plasmodium species studied, particularly mature stages, and was greatest in P vivax 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 (PF4+TUNEL+ parasites). These PF4+TUNEL+ 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 Plasmodium 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 P knowlesi culture. Collectively, our results indicate that platelets directly contribute to innate control of Plasmodium infection in human malaria.

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Kho S, Barber BE, Johar E, Andries B, Poespoprodjo JR, Kenangalem E et al. Platelets kill circulating parasites of all major Plasmodium species in human malaria. Blood. 2018 Sep 20;132(12):1332-1344. https://doi.org/10.1182/blood-2018-05-849307