Insights into physiological roles of unique metabolites released from Plasmodium-infected RBCs and their potential as clinical biomarkers for malaria

Beri, Divya; Ramdani, Ghania; Balan, Balu; Gadara, Darshak; Poojary, M. Damodara; Momeux, Laurence; Tatu, Utpal; Langsley, Gordon

doi:10.1038/s41598-018-37816-9

Cited by 28 publications

(48 citation statements)

References 43 publications

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“…The largest overall increase in metabolite abundance occurred for pipecolate, a product of lysine catabolism. The increase in pipecolate was associated with the schizont stage (32-40 h) of the iRBC (Additional file 5), in broad agreement with a recent study [18]. Furthermore, pipecolate, which accumulates in the plasma [17] and urine [31,32] of patients with severe malaria, has been suggested as a candidate clinical biomarker of malaria.…”

Section: Metabolite Changes Characterizing Uninfected and Infected Ersupporting

confidence: 88%

“…The abundance of nicotinate ribonucleoside (NR) increased ~ fivefold in the iRBC cultures. During the IDC, NR increases up to ~ 15-fold in the extra-cellular medium of iRBC cultures, but is undetectable in uRBC cultures [18], confirming the observation that NR was specific to the iRBC cultures. P. falciparum encodes an enzyme that spontaneously synthesizes NR from nicotinate mononucleotide [27,38].…”

Section: Metabolites Uniquely Associated With Parasite Infectionsupporting

confidence: 76%

“…Interestingly, nicotinate mononucleotide increased ~ 34-fold in iRBC cultures ( Table 2). These results suggest that excessive glucose utilization in the iRBC cultures can cause accumulation of NR, which is then excreted to the extra-cellular medium [18]. As discussed above, nicotinate mononucleotide (Table 2) was associated with excessive glucose utilization.…”

Section: Metabolites Uniquely Associated With Parasite Infectionmentioning

confidence: 53%

“…Specifically, methods have been developed to quench the metabolism of parasite-infected erythrocytes and study their metabolite extracts [6]. Metabolic profiling approaches are used to characterize blood-stage parasite development [4,16], discover biomarkers [17,18], and identify novel therapeutic targets [19]. Table 1 lists studies that have examined the blood stage of malaria parasites using metabolomics.…”

Section: Metabolomics Of Blood-stage Malaria Parasitesmentioning

confidence: 99%

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Metabolic alterations in the erythrocyte during blood-stage development of the malaria parasite

Tewari

Swift

Reifman

et al. 2020

Malar J

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Background: Human blood cells (erythrocytes) serve as hosts for the malaria parasite Plasmodium falciparum during its 48-h intraerythrocytic developmental cycle (IDC). Established in vitro protocols allow for the study of host-parasite interactions during this phase and, in particular, high-resolution metabolomics can provide a window into host-parasite interactions that support parasite development. Methods: Uninfected and parasite-infected erythrocyte cultures were maintained at 2% haematocrit for the duration of the IDC, while parasitaemia was maintained at 7% in the infected cultures. The parasite-infected cultures were synchronized to obtain stage-dependent information of parasite development during the IDC. Samples were collected in quadruplicate at six time points from the uninfected and parasite-infected cultures and global metabolomics was used to analyse cell fractions of these cultures. Results: In uninfected and parasite-infected cultures during the IDC, 501 intracellular metabolites, including 223 lipid metabolites, were successfully quantified. Of these, 19 distinct metabolites were present only in the parasite-infected culture, 10 of which increased to twofold in abundance during the IDC. This work quantified approximately five times the metabolites measured in previous studies of similar research scope, which allowed for more detailed analyses. Enrichment in lipid metabolism pathways exhibited a time-dependent association with different classes of lipids during the IDC. Specifically, enrichment occurred in sphingolipids at the earlier stages, and subsequently in lysophospholipid and phospholipid metabolites at the intermediate and end stages of the IDC, respectively. In addition, there was an accumulation of 18-, 20-, and 22-carbon polyunsaturated fatty acids, which produce eicosanoids and promote gametocytogenesis in infected erythrocyte cultures. Conclusions: The current study revealed a number of heretofore unidentified metabolic components of the hostparasite system, which the parasite may exploit in a time-dependent manner to grow over the course of its development in the blood stage. Notably, the analyses identified components, such as precursors of immunomodulatory molecules, stage-dependent lipid dynamics, and metabolites, unique to parasite-infected cultures. These conclusions are reinforced by the metabolic alterations that were characterized during the IDC, which were in close agreement with those known from previous studies of blood-stage infection.

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Section: Metabolite Changes Characterizing Uninfected and Infected Ersupporting

confidence: 88%

Section: Metabolites Uniquely Associated With Parasite Infectionsupporting

confidence: 76%

Section: Metabolites Uniquely Associated With Parasite Infectionmentioning

confidence: 53%

Section: Metabolomics Of Blood-stage Malaria Parasitesmentioning

confidence: 99%

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Metabolic alterations in the erythrocyte during blood-stage development of the malaria parasite

Tewari

Swift

Reifman

et al. 2020

Malar J

View full text Add to dashboard Cite

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“…P. falciparum is capable enough to mediate the import of lipids like ceramide, sphingolipids, and LysoPC and utilize these lipid molecules to fulfill its own metabolic needs (Haldar et al, 1991;Gerold and Schwarz, 2001;Asahi et al, 2005). A recent report by Beri et al (2019) highlighted that parasite-infected RBCs release sphingolipid metabolites, and alteration in the sphingolipid metabolism post infection might contribute toward change in RBC membrane dynamics. An additional study by Sana et al (2013) also demonstrated a global metabolomic profiling of P. falciparum-infected erythrocytes that revealed modulation of various host lipids including S1P during parasite infection.…”

Section: Discussionmentioning

confidence: 99%

Reduction of Sphingosine Kinase 1 Phosphorylation and Activity in Plasmodium-Infected Erythrocytes

Sah

Pati

Saini

et al. 2020

Front. Cell Dev. Biol.

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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.

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Unraveling the mystery of the spleen

Tubman

2024

American J Hematol

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Despite the earliest descriptions of the spleen dating back to 1500 BC, the mechanisms that underlay the functions of the spleen remain shrouded in mystery. 1 At its simplest, the spleen is seen as an extraneous, dispensable organ. A more nuanced viewing of the organ recognizes its complex role human physiology. Approximately 5% of blood volume passes through the spleen with each heartbeat. The red pulp of the spleen serves as an excellent mechanical filter for the blood by removing damaged, senescent, and infected red blood cells from circulation. The immune cells in the white pulp of the spleen are regularly exposed to the entirety of circulating blood, enabling them to serve as the largest immune organ in the body. The spleen mediates immune response to circulating bacteria, organisms without a specific host antibody, and intracellular pathogens. The spleen is far more complicated than is often perceived.In this issue of American Journal of Hematology, a study by Kho et al. explores mechanisms of malarial splenomegaly and highlights the importance of the spleen in worsening anemia during infections with Plasmodium spp. 2 The spleen serves as a reservoir for malaria parasites during

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Insights into physiological roles of unique metabolites released from Plasmodium-infected RBCs and their potential as clinical biomarkers for malaria

Cited by 28 publications

References 43 publications

Metabolic alterations in the erythrocyte during blood-stage development of the malaria parasite

Metabolic alterations in the erythrocyte during blood-stage development of the malaria parasite

Reduction of Sphingosine Kinase 1 Phosphorylation and Activity in Plasmodium-Infected Erythrocytes

Unraveling the mystery of the spleen

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