Abstract
Sphingosine-1-phosphate (S1P), a bioactive lipid mediator is involved in an array of biological processes and linked to pathological manifestations. Erythrocyte is known as the major reservoir for S1P as they lack S1P-degrading enzymes (S1P lyase and S1P phosphohydrolase) and harbor sphingosine kinase-1 (SphK-1) essential for sphingosine conversion to S1P. Reduced S1P concentration in serum was correlated with disease severity in patients with Plasmodium falciparum and Plasmodium vivax infections. Herein, we aimed to identify the underlying mechanism and contribution of host erythrocytes toward depleted S1P levels in Plasmodium-infected patients vs. healthy individuals. The level and activity of SphK-1 were measured in vitro in both uninfected and cultured P. falciparum-infected erythrocytes. Infected erythrocytes demonstrated a significant decrease in SphK-1 level in a time-dependent manner. We found that 10–42 h post invasion (hpi), SphK1 level was predominantly reduced to ∼50% in rings, trophozoites, and schizonts compared to uninfected erythrocytes. We next analyzed the phosphorylation status of SphK-1, a modification responsible for its activity and S1P production, in both uninfected control and Plasmodium-infected erythrocytes. Almost ∼50% decrease in phosphorylation of SphK-1 was observed that could be corroborated with significant reduction in the production and release of S1P in infected erythrocytes. Serum S1P levels were studied in parallel in P. falciparum (N = 15), P. vivax (N = 36)-infected patients, and healthy controls (N = 6). The findings revealed that S1P concentration was significantly depleted in uncomplicated malaria cases and was found to be lowest in complicated malaria and thrombocytopenia in both P. falciparum and P. vivax-infected groups (∗∗p < 0.01). The lower serum S1P level could be correlated with the reduced platelet count defining the role of S1P level in platelet formation. In conclusion, erythrocyte SphK-1 and S1P levels were studied in Plasmodium-infected individuals and erythrocytes that helped in characterizing the complications associated with malaria and thrombocytopenia, providing insights into the contribution of host erythrocyte biology in malaria pathogenesis. Finally, this study proposes the use of S1P and its analog as a novel adjunct therapy for malaria complications.
Highlights
According to World Health Organization (WHO) report, an estimate of 219 million malaria cases have been detected with 435,000 number of deaths (World Health Organization [WHO], 2018)
It is noteworthy that the cytoadhesion of infected erythrocytes to vascular endothelial cells as well as the dysregulated production of inflammatory cytokines are considered to be the major reasons underlying the systemic inflammatory illness linked to disease severity in malaria that leads to death of the patient (Pongponratn et al, 1991; Lyke et al, 2004)
Sphingosine kinase-1 catalyzes the phosphorylation of S1P from sphingosine in erythrocytes (Nakahara et al, 2012), and its level can be directly correlated with levels of IC or circulating S1P
Summary
According to World Health Organization (WHO) report, an estimate of 219 million malaria cases have been detected with 435,000 number of deaths (World Health Organization [WHO], 2018). Ceramide can be generated by de novo or hydrolysis of membrane sphingomyelin by sphingomyelinase (SMase), and subsequently metabolized by ceramidase to generate sphingosine (Sph), which in turn is phosphorylated by sphingosine kinases 1 and 2 (SphK1, 2) to generate S1P, a pleotropic bioactive lipid mediator Both ceramide and S1P regulate cellular responses to stress, with generally opposing effects (Maceyka et al, 2012; Nakahara et al, 2012). Serum S1P levels were estimated in parallel in P. falciparum (N = 15)-, P. vivax (N = 36)-infected patients, and healthy controls (N = 6) to understand the clinical relevance of SphK-1 activity linked to S1P production. This study suggests the use of S1P and its analog as a novel adjunct therapy for malaria complications
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