Impact of Plasmodium falciparum small-sized extracellular vesicles on host peripheral blood mononuclear cells

• Published in: Wellcome open research Vol. 5; p. 197
• Main Authors: Mwangi, Shaban J., Gwela, Agnes, Mwikali, Kioko, Bargul, Joel L., Nduati, Eunice W., Ndungu, Francis M., Bejon, Philip, Rayner, Julian C., Abdi, Abdirahman I.
• Format: Journal Article
• Language: English
• Published: London Wellcome Trust Limited 21.08.2020
• Subjects: Blood; Erythrocytes; Extracellular vesicles; Laboratories; Parasites; Peer review; Plasma; Proteins
• ISSN: 2398-502X; 2398-502X
• DOI: 10.12688/wellcomeopenres.16131.1

Background: Exagerated immune activation has a key role in the pathogenesis of malaria . During blood-stage infection, Plasmodium falciparum can interact directly with host immune cells through infected red blood cells ( Pf iRBCs), or indirectly by the release of extracellular vesicles (EVs). Here, we compared the impact of Pf iRBCs and P. falciparum small-sized EVs ( Pf sEVs, also known as exosomes) from a Kenyan clinical isolate ( Pf KE12) adapted to short-term laboratory culture conditions on host peripheral blood mononuclear cells (PBMC). Methods: Pf sEVs were isolated from cell-free culture-conditioned media by ultracentrifugation while mature trophozoite Pf iRBCs were purified by magnetic column separation. The Pf sEVs and the Pf iRBCs were co-cultured for 18 hours with PBMC. Cellular responses were quantified by cell surface expression of activation markers (CD25, CD69) and cytokine/chemokine levels in the supernatant. Results: Relative to negative control conditions, Pf sEVs induced CD25 expression on CD4 + , CD19 + and CD14 + cells, while Pf iRBCs induced on CD19 + and CD14 + cells. Both Pf sEVs and Pf iRBCs induced CD69 on CD4 + , CD8 + and CD19 + cells. In addition, Pf iRBCs induced higher expression of CD69 on CD14 + cells. CD69 induced by Pf iRBCs on CD4 + and CD19 + cells was significantly higher than that induced by Pf sEVs. Secretion of MIP1α, MIP1β, GM-CSF, IL-6, IL-8, and TNFα were significantly induced by both Pf sEVs and Pf iRBCs whereas MCP-1, IL-10, IL-17α  were preferentially induced by Pf sEVs and IP-10 and IFN-γ by Pf iRBCs. Prior exposure to malaria (judged by antibodies to schizont extract) was associated with lower monocyte responses to Pf sEVs. Conclusions: Pf sEVs and Pf iRBCs showed differential abilities to induce secretion of IL-17α  and IFN-γ, suggesting that the former are better at inducing Th17, whilst  the latter induce Th1 immune responses respectively. Prior exposure to malaria significantly reduces the ability of Pf sEVs to activate monocytes, suggesting immune tolerance to Pf sEVs may play a role in naturally acquired  anti-disease immunity.