Tumour necrosis factor, interleukin-6 and interleukin-10 are possibly involved in Plasmodium vivax-associated thrombocytopaenia in southern Pakistani population

Background: Severe thrombocytopenia can be a determinant factor in the morbidity of Plasmodium vivax (Pv), the most widespread human malaria. Although immune mechanisms may drive Pv-induced severe thrombocytopenia (PvST), the current data on the cytokine landscape in PvST is scarce, and often conflicting. The analysis of the bidirectional circuit of inflammatory mediators and miRNAs would lead to a better understanding of the mechanisms underlying PvST. Methods: We combined Luminex proteomics, NanoString miRNA quantification, and machine learning, to evaluate an extensive array of plasma mediators in uncomplicated Pv patients, whose blood platelet counts varied from reference values to PvST. Results: Unsupervised clustering analysis identified PvST-linked signatures comprised of both inflammatory (CXCL10, CCL4, and IL-18) and regulatory (IL-10, IL-1Ra, HGF) mediators. As part of PvST signatures, IL-6 and IL-8 were critical to discriminate Pv subgroups, while CCL2 and IFN-γ from healthy controls. Supervised machine learning spotlighted IL-10 in Pv-mediated thrombocytopenia, and provided evidence for a potential signaling route involving IL-8 and HGF. Finally, we identified a set of miRNAs capable of modulating these signaling pathways. Conclusions: The results place IL-10 and IL-8/HGF in the center of PvST and propose investigating these signaling pathways across the spectrum of malaria infections.

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“…Previous studies supported a similar association between IL-10 and decreased blood platelet counts [14,16,28,29].…”

Section: Discussionsupporting

confidence: 64%

“…Scarce, fragmented, and occasionally conflicting data are available on the cytokine/chemokine network in PvST [14,16,28,29]. Here, we hypothesize that the combined analysis of circulating proteins and miRNAs could provide a more realistic portrait of PvST.…”

Section: Discussionmentioning

confidence: 87%

A distinct fingerprint of inflammatory mediators and miRNAs inPlasmodium vivaxsevere thrombocytopenia

Santos

Coimbra

Sousa

et al. 2020

Preprint

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“…A subset of 4 studies [ 24 , 35 , 41 , 58 ] reported the mean platelet counts. Decreased platelet counts were recorded in patients with P. vivax malaria compared to the healthy controls ( P < 0.001 in all four studies) (Additional file 6 ).…”

Section: Resultsmentioning

confidence: 99%

Severe thrombocytopaenia in patients with vivax malaria compared to falciparum malaria: a systematic review and meta-analysis

Naing

Whittaker

2018

Infect Dis Poverty

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BackgroundPlasmodium vivax is the most geographically widespread species among human malaria parasites. Immunopathological studies have shown that platelets are an important component of the host innate immune response against malaria infections. The objectives of this study were to quantify thrombocytopaenia in P. vivax malaria patients and to determine the associated risks of severe thrombocytopaenia in patients with vivax malaria compared to patients with P. falciparum malaria.Main bodyA systematic review and meta-analysis of the available literature on thrombocytopaenia in P. vivax malaria patients was undertaken. Relevant studies in health-related electronic databases were identified and reviewed. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. Fifty-eight observational studies (n = 29 664) were included in the current review. Severe thrombocytopaenia (< 50 000/mm3) to very severe thrombocytopaenia (< 20 000/mm3) was observed in 10.1% of patients with P. vivax infection. A meta-analysis of 11 observational studies showed an equal risk of developing severe/very severe thrombocytopaenia between the patients with P. vivax malaria and those with P. falciparum malaria (OR: 1.98, 95% CI: 0.92–4.25). This indicates that thrombocytopaenia is as equally a common manifestation in P. vivax and P. falciparum malaria patients. One study showed a higher risk of developing very severe thrombocytopaenia in children with severe P. vivax malaria than with severe P. falciparum malaria (OR: 2.80, 95% CI: 1.48–5.29). However, a pooled analysis of two studies showed an equal risk among adult severe cases (OR: 1.19, 95% CI: 0.51–2.77). This indicates that the risk of developing thrombocytopaenia in P. vivax malaria can vary with immune status in both children and adults. One study reported higher levels of urea and serum bilirubin in patients with P. vivax malaria and severe thrombocytopaenia compared with patients mild thrombocytopaenia or no thrombocytopaenia, (P < 0.001 in all comparisons). A pooled analysis of two other studies showed a similar proportion of bleeding episodes with thrombocytopaenia in severe P. vivax patients and severe P. falciparum patients (P = 0.09). This implied that both P. vivax and P. falciparum infections could present with bleeding episodes, if there had been a change in platelet counts in the infected patients. A pooled analysis of another two studies showed an equal risk of mortality with severe thrombocytopaenia in both P. vivax and P. falciparum malaria patients (OR: 1.16, 95% CI: 0.30–4.60). However, due to the low number of studies with small sample sizes within the subset of studies that provided clinically relevant information, our confidence in the estimates is limited.ConclusionThe current review has provided some evidence of the clinical relevance of severe thrombocytopaenia in P. vivax malaria. To substantiate these findings, there is a need for well designed, large-scale, prospective studies among patients infected with P. vivax. These sho...

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“…IL-6, IL-10 and TNF production has been associated with thrombocytopenia in P . vivax malaria patients [ 73 ]. IFN-γ production is associated with protection against pre-erythrocyte malarial stages through both in vitro and in vivo nitric oxide (NO) production following infection with P .…”

Section: Discussionmentioning

confidence: 99%

Plasmodium vivax Pv12 B-cell epitopes and HLA-DRβ1*-dependent T-cell epitopes in vitro antigenicity

et al. 2018

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Malaria is an infectious disease caused by parasites from the genus Plasmodium (P. falciparum and P. vivax are responsible for 90% of all clinical cases); it is widely distributed throughout the world’s tropical and subtropical regions. The P. vivax Pv12 protein is involved in invasion, is expressed on merozoite surface and has been recognised by antibodies from individuals exposed to the disease. In this study, B- and T-cell epitopes from Pv12 were predicted and characterised to advance in the design of a peptide-based vaccine against malaria.For evaluating the humoral response of individuals exposed to natural P. vivax infection from two endemic areas in Colombia, BepiPred-1.0 software was used for selecting B-cell epitopes. B-cell epitope 39038 displayed the greatest recognition by naturally-acquired antibodies and induced an IgG2/IgG4 response. NetMHCIIpan-3.1 prediction software was used for selecting peptides having high affinity binding for HLA-DRβ1* allele lineages and this was confirmed by in-vitro binding assays. T-epitopes 39113 and 39117 triggered a memory T-cell response (Stimulation Index≥2) and significant cytokine production.Combining in-silico, in-vitro and functional assays, two Pv12 protein regions (containing peptides 39038, 39040, 39113 and 39117) have thus been characterised as promising vaccine candidates against P. vivax malaria.

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Tumour necrosis factor, interleukin-6 and interleukin-10 are possibly involved in Plasmodium vivax-associated thrombocytopaenia in southern Pakistani population

Cited by 18 publications

References 42 publications

A distinct fingerprint of inflammatory mediators and miRNAs inPlasmodium vivaxsevere thrombocytopenia

A distinct fingerprint of inflammatory mediators and miRNAs inPlasmodium vivaxsevere thrombocytopenia

Severe thrombocytopaenia in patients with vivax malaria compared to falciparum malaria: a systematic review and meta-analysis

Plasmodium vivax Pv12 B-cell epitopes and HLA-DRβ1*-dependent T-cell epitopes in vitro antigenicity

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