Differential Effect of Extracellular Vesicles Derived from Plasmodium falciparum-Infected Red Blood Cells on Monocyte Polarization

Abstract

Malaria is a life-threatening tropical arthropod-borne disease caused by Plasmodium spp. Monocytes are the primary immune cells to eliminate malaria-infected red blood cells. Thus, the monocyte’s functions are one of the crucial factors in controlling parasite growth. It is reasoned that the activation or modulation of monocyte function by parasite products might dictate the rate of disease progression. Extracellular vesicles (EVs), microvesicles, and exosomes, released from infected red blood cells, mediate intercellular communication and control the recipient cell function. This study aimed to investigate the physical characteristics of EVs derived from culture-adapted P. falciparum isolates (Pf-EVs) from different clinical malaria outcomes and their impact on monocyte polarization. The results showed that all P. falciparum strains released similar amounts of EVs with some variation in size characteristics. The effect of Pf-EV stimulation on M1/M2 monocyte polarization revealed a more pronounced effect on CD14+CD16+ intermediate monocytes than the CD14+CD16− classical monocytes with a marked induction of Pf-EVs from a severe malaria strain. However, no difference in the levels of microRNAs (miR), miR-451a, miR-486, and miR-92a among Pf-EVs derived from virulent and nonvirulent strains was found, suggesting that miR in Pf-EVs might not be a significant factor in driving M2-like monocyte polarization. Future studies on other biomolecules in Pf-EVs derived from the P. falciparum strain with high virulence that induce M2-like polarization are therefore recommended.

Exosome‐derived long noncoding RNAs: Mediators of host–Plasmodium parasite communication

“…EVs derived from P. falciparum or P. berghei-infected RBCs have the capacity to activate the innate immune response by releasing both pro-inflammatory and antiinflammatory cytokines (Couper et al, 2010;Mantel et al, 2013). Additionally, monocytes have the ability to uptake EVs secreted by P. falciparum-infected RBCs (Pf-EVs), leading to monocyte activation and an increased proportion of M2-like intermediate monocytes (Couper et al, 2010;Khowawisetsut et al, 2023). Consequently, these EVs might contribute to the initiation of the observed "cytokine storm" during the initial stages of malaria infection.…”

“…Additionally, monocytes have the ability to uptake EVs secreted by P . falciparum ‐infected RBCs ( Pf ‐EVs), leading to monocyte activation and an increased proportion of M2‐like intermediate monocytes (Couper et al, 2010; Khowawisetsut et al, 2023). Consequently, these EVs might contribute to the initiation of the observed “cytokine storm” during the initial stages of malaria infection.…”

“…falciparum strain, which induces M2‐like polarization. The effect of Pf ‐EV stimulation on M1/M2 monocyte polarization has been found to be more pronounced on CD14 + CD16 + intermediate monocytes, leading to a significant induction of M2‐like polarization compared to CD14 + CD16 − classical monocytes (Khowawisetsut et al, 2023). Moreover, parasite‐derived EVs harbor conserved parasite components, including proteins, various RNA molecules (mRNAs, lncRNAs, miRNAs, circRNAs, and other noncoding RNAs), and nucleic acids, which actively participate in parasite immune evasion and modulation of the host immune system.…”

“…Multiple parasitic pathogens, such as P . falciparum (Khowawisetsut et al, 2023), Leishmania (Weber et al, 2023), T . cruzi (Cornet‐Gomez et al, 2023), Echinococcus multilocularis (Liu et al, 2023), and Giardia intestinalis (Salas et al, 2023), secrete EVs containing an assortment of bioactive molecules, including lipids, proteins, glycans, DNA, and RNA during infections (Chen et al, 2023; Gutierrez et al, 2022; Szempruch et al, 2016).…”

“…EVs play a critical role as mediators of intercellular communication in the interaction between parasites and their hosts or among parasites themselves (Mantel & Marti, 2014;Marcilla et al, 2014;Mardahl et al, 2019;Ofir-Birin et al, 2017). Multiple parasitic pathogens, such as P. falciparum (Khowawisetsut et al, 2023), Leishmania (Weber et al, 2023), T.cruzi (Cornet-Gomez et al, 2023), Echinococcus multilocularis (Liu et al, 2023), and Giardia intestinalis (Salas et al, 2023), secrete EVs containing an assortment of bioactive molecules, including lipids, proteins, glycans, DNA, and RNA during infections (Chen et al, 2023;Gutierrez et al, 2022;Szempruch et al, 2016). These EVs serve as an efficient delivery system, transferring bioactive signals to target cells (Ofir-Birin & Regev-Rudzki, 2019;Szempruch et al, 2016).…”