Overexpression of Sphingosine Kinase-1 and Sphingosine-1-Phosphate Receptor-3 in Severe Plasmodium falciparum Malaria with Pulmonary Edema

Abstract

Pulmonary edema (PE) is a major cause of pulmonary manifestations of severe Plasmodium falciparum malaria and is usually associated with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). The sphingosine kinase-1 (SphK-1)/sphingosine-1-phosphate receptor-3 (S1PR-3) pathway has recently been reported to affect the pathogenesis of lung injury, but the expression of these proteins in the lungs of severe P. falciparum malaria patients has not been investigated. The cellular expression of SphK-1 and S1PR-3 in lung tissues from autopsied patients with P. falciparum malaria was investigated using immunohistochemistry (IHC). Lung tissues from patients who died of severe P. falciparum malaria were classified into two groups based on histopathological findings: those with PE (18 patients) and those without PE (non-PE, 19 patients). Ten samples of normal lung tissues were used as the control group. The protein expression levels of SphK-1 and S1PR-3 were significantly upregulated in endothelial cells (ECs), alveolar epithelial cells, and alveolar macrophages (AMs) in the lungs of severe P. falciparum malaria patients with PE compared to those in the non-PE and control groups (all p < 0:001). In addition, the SphK-1 and S1PR-3 expression levels were significantly positively correlated in pulmonary ECs (r s = 0:922, p < 0:001), alveolar epithelial cells (r s = 0:995, p < 0:001), and AMs (r s = 0:969, p < 0:001). In conclusion, both the SphK-1 and S1PR-3 proteins were overexpressed in the lung tissues of severe P. falciparum malaria patients with PE, suggesting that SphK-1 and S1PR-3 mediate the pathogenesis of PE in severe malaria. Targeting the regulation of SphK-1 and/or S1PR-3 may be an approach to treat pulmonary complications in severe P. falciparum patients.

Role of sphingosine kinase and sphingosine-1-phosphate receptor in the liver pathology of mice infected with Plasmodium berghei ANKA

“…In addition, the current study demonstrated an increase in SphK1 in malaria-infected mice, which was consistent with previous reports on inflammatory conditions and cancer [ 9 , 14 , 15 , 46 – 48 ]. This finding may stem from inflammation-induced apoptosis.…”

Lysophospholipids in Lung Inflammatory Diseases

“…Synthesis of S1P is catalyzed by SphK1/2. Severe Plasmodium falciparum malaria causes lung edema and an increase in SphK1 in lung tissues [99], suggesting a role of the SphK1/S1P axis in lung edema. The effects of SphK1/2 on acute lung injury were examined using SphK1/2 deficient mice.…”

Sphingosine 1-Phosphate in Malaria Pathogenesis and Its Implication in Therapeutic Opportunities

“…Over expression of both SPHK-1 and S1PR-3 proteins were observed in lung tissues of PE indicating their role in the pathogenesis of pulmonary complications in severe malaria. (Viriyavejakul and Punsawad, 2020) 10 Human Endothelial glycocalyx breakdown products, markers of endothelial dysfunction, parasite biomass, S1P and NO levels were compared between Indonesian adults with falciparum malaria (severe and moderately severe) and healthy control…”

“…Further, the involvement of S1P receptors, specifically increased S1PR 3 concentration with mortality has been documented in acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) patients (Sun et al, 2012 ), yet another severe complication of falciparum malaria which ranges from 5 to 25% of adults and 29% of pregnant women (Taylor et al, 2012 ). Anticipating implication of circulating S1PR 3 as a potential biomarker of severity in malaria induced ARDS, when the expression of the Sphk1 and S1PR 3 proteins were investigated in malaria-associated ALI/ARDS, up-regulated expression of these were demonstrated in the lung tissues of experimental mice and human malaria patients (Punsawad and Viriyavejakul, 2019 ; Viriyavejakul and Punsawad, 2020 ). However, agreeing to evidence from previous studies (Finney et al, 2011 ; Punsawad and Viriyavejakul, 2017 ), plasma and lung tissues level of S1P was significantly less in malaria infected mice with ALI/ARDS) compared to non-ALI/ARDS and control (Punsawad and Viriyavejakul, 2019 ).…”