Platelet disturbances correlate with endothelial cell activation in uncomplicatedPlasmodium vivaxmalaria

Author(s):Show less -

Dos-Santos, Joao Conrado Khouri ^{[1, 2]} ; Silva-Filho, Joao Luiz ^[1] ; Judice, Carla C. ^[1] ; Kayano, Ana Carolina Andrade Vitor ^[1] ; Aliberti, Julio ^[3] ; Khouri, Ricardo ^[4] ; de Lima, Diogenes S. ^[5] ; Nakaya, Helder ^[5] ; Lacerda, Marcus Vinicius Guimaraes ^{[6, 7]} ; De Paula, Erich Vinicius ^[8] ; Lopes, Stefanie Costa Pinto ^[7] ; Costa, Fabio Trindade Maranhao ^[1]

Affiliation

^[1] Univ Estadual Campinas, Inst Biol, Lab Doencas Trop Prof Luiz Jacintho da Silva, Campinas - Brazil

^[2] Univ Estadual Campinas, Fac Ciencias Med, Posgrad Fisiopatol Med, Campinas - Brazil

^[3] NIAID, 9000 Rockville Pike, Bethesda, MD 20892 - USA

^[4] Fiocruz MS, Inst Goncalo Moniz, Salvador, BA - Brazil

^[5] Univ Sao Paulo, Sch Pharmaceut Sci, Dept Clin & Toxicol Anal, Sao Paulo - Brazil

^[6] Fundacao Med Trop Dr Heitor Vieira Dourado, Manaus, Amazonas - Brazil

^[7] Fiocruz Amazonia, Inst Leonidas & Maria Deane, Manaus, Amazonas - Brazil

^[8] Univ Estadual Campinas, Ctr Hematol & Hemoterapia Hemoctr, Campinas - Brazil

• Document type: Journal article
• Source: PLoS Neglected Tropical Diseases; v. 14, n. 7 JUL 2020.
• Web of Science Citations: 0

Abstract

Author summary Endothelial cell activation is a key process in the pathogenesis ofPlasmodium vivaxmalaria. Platelets are classically involved in endothelial cell activation in several diseases, but their role in the context of vivax malaria remains unclear. Thrombocytopenia is the most common hematological disturbance inP.vivax-infected patients, and platelets have been implicated in parasitemia control. In this work, we studied the activation of platelets in association with endothelial cell activation in vivax malaria. Platelets retrieved from infected peripheral blood were non-activated when analyzed by flow cytometry; however, they displayed higher mean volume and significantly reduced counts. We also found higher levels of circulating factors associated with platelet activation (especially soluble CD40L), thrombopoiesis and endothelial cell activation in infected patients. Further, through pair-wise correlation and clustering analysis, we found a subgroup of patients showing significant associations between markers of platelet and endothelial activation in a pattern different from that of endemic controls. Collectively, our findings indicate a role of platelets in endothelial cell activation in vivax malaria and indicate a heterogeneous host response in the setting of uncomplicated disease, a finding to be further explored in future studies. Platelets drive endothelial cell activation in many diseases. However, if this occurs inPlasmodium vivaxmalaria is unclear. As platelets have been reported to be activated and to play a role in inflammatory response during malaria, we hypothesized that this would correlate with endothelial alterations during acute illness. We performed platelet flow cytometry of PAC-1 and P-selectin. We measured platelet markers (CXCL4, CD40L, P-selectin, Thrombopoietin, IL-11) and endothelial activation markers (ICAM-1, von Willebrand Factor and E-selectin) in plasma with a multiplex-based assay. The values of each mediator were used to generate heatmaps, K-means clustering and Principal Component analysis. In addition, we determined pair-wise Pearson's correlation coefficients to generate correlation networks. Platelet counts were reduced, and mean platelet volume increased in malaria patients. The activation of circulating platelets in flow cytometry did not differ between patients and controls. CD40L levels (Median {[}IQ]: 517 {[}406-651] vs. 1029 {[}732-1267] pg/mL,P= 0.0001) were significantly higher in patients, while P-selectin and CXCL4 showed a nonsignificant trend towards higher levels in patients. The network correlation approach demonstrated the correlation between markers of platelet and endothelial activation, and the heatmaps revealed a distinct pattern of activation in two subsets ofP.vivaxpatients when compared to controls. Although absolute platelet activation was not strong in uncomplicated vivax malaria, markers of platelet activity and production were correlated with higher endothelial cell activation, especially in a specific subset of patients. (AU)

• FAPESP's process: 16/12855-9 - Mechanism of action of lipoxin in the protection against experimental cerebral malaria
• Grantee: João Luiz da Silva Filho
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 17/18611-7 - Development of new tools for search and validation of molecular targets for therapy against Plasmodium vivax
• Grantee: Fabio Trindade Maranhão Costa
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 12/16525-2 - Plasmodium vivax: pathogenesis and infectivity
• Grantee: Fabio Trindade Maranhão Costa
• Support Opportunities: Research Projects - Thematic Grants