Abstract:The mechanisms behind the ability of Plasmodium falciparum to evade host immune system are poorly understood and are a major roadblock in achieving malaria elimination. Here, we use integrative genomic profiling and a longitudinal pediatric cohort in Burkina Faso to demonstrate the role of post-transcriptional regulation in host immune response in malaria. We report a strong signature of miRNA expression differentiation associated with P. falciparum infection (127 out of 320 miRNAs, B-H FDR 5%) and parasitemia… Show more
“…Red cells contribute significantly to the levels of whole blood miRNAs during malaria infection (Dieng et al 2020 ). On analyzing the expression for the seven potential miRNAs in peripheral blood cells from blood miRNA datasets (Juzenas et al 2017 ), we observed an enhanced expression for miR-451a, miR-92a-3p, and miR-16-5p while, moderate expression for miR-142-3p, miR-15b-5p, miR19b-3p, and miR-223-3p in the erythrocytes, thus confirming their presence in enucleated red cells (Fig.…”
Section: Resultsmentioning
confidence: 99%
“…1 ) for which transcripts of all reference sequences were retrieved from PlasmoDB (release 54) presented in Supplementary Table S 1 (Aurrecoechea et al 2009 ). The published data of LaMonte et al 2012 , Mantel et al 2016 , and Dieng et al 2020 were used as the source data for all our analysis of host erythrocytic miRNAs and their expression profiles (LaMonte et al 2012 ; Mantel et al 2016 ; Dieng et al 2020 ). Fig.…”
Based on the recently added high throughput analysis data on small noncoding RNAs in modulating disease pathophysiology of malaria, we performed an integrative computational analysis for exploring the role of human-host erythrocytic microRNAs (miRNAs) and their influence on parasite survival and host homeostasis. An in silico analysis was performed on transcriptomic datasets accessed from PlasmoDB and Gene Expression Omnibus (GEO) repositories analyzed using miRanda, miRTarBase, mirDIP, and miRDB to identify the candidate miRNAs that were further subjected to network analysis using MCODE and DAVID. This was followed by immune infiltration analysis and screening for RNA degradation mechanisms. Seven erythrocytic miRNAs, miR-451a, miR-92a-3p, miR-16-5p, miR-142-3p, miR-15b-5p, miR-19b-3p, and miR-223-3p showed favourable interactions with parasite genes expressed during blood stage infection. The miR-92a-3p that targeted the virulence gene PfEMP1 showed drastic reduction during infection. Performing pathway analysis for the human-host gene targets for the miRNA identified TOB1, TOB2, CNOT4, and XRN1 genes that are associated to RNA degradation processes, with the exoribonuclease XRN1, highly enriched in the malarial samples. On evaluating the role of exoribonucleases in miRNA degradation further, the pattern of Plasmodium falciparum_XRN1 showed increased levels during infection thus suggesting a defensive role for parasite survival. This study identifies miR-92a-3p, a member of C13orf25/ miR-17-92 cluster, as a novel miRNA inhibitor of the crucial parasite genes responsible for symptomatic malaria. Evidence for a plausible link to chromosome 13q31.3 loci controlling the epigenetic disease regulation is also suggested.
“…Red cells contribute significantly to the levels of whole blood miRNAs during malaria infection (Dieng et al 2020 ). On analyzing the expression for the seven potential miRNAs in peripheral blood cells from blood miRNA datasets (Juzenas et al 2017 ), we observed an enhanced expression for miR-451a, miR-92a-3p, and miR-16-5p while, moderate expression for miR-142-3p, miR-15b-5p, miR19b-3p, and miR-223-3p in the erythrocytes, thus confirming their presence in enucleated red cells (Fig.…”
Section: Resultsmentioning
confidence: 99%
“…1 ) for which transcripts of all reference sequences were retrieved from PlasmoDB (release 54) presented in Supplementary Table S 1 (Aurrecoechea et al 2009 ). The published data of LaMonte et al 2012 , Mantel et al 2016 , and Dieng et al 2020 were used as the source data for all our analysis of host erythrocytic miRNAs and their expression profiles (LaMonte et al 2012 ; Mantel et al 2016 ; Dieng et al 2020 ). Fig.…”
Based on the recently added high throughput analysis data on small noncoding RNAs in modulating disease pathophysiology of malaria, we performed an integrative computational analysis for exploring the role of human-host erythrocytic microRNAs (miRNAs) and their influence on parasite survival and host homeostasis. An in silico analysis was performed on transcriptomic datasets accessed from PlasmoDB and Gene Expression Omnibus (GEO) repositories analyzed using miRanda, miRTarBase, mirDIP, and miRDB to identify the candidate miRNAs that were further subjected to network analysis using MCODE and DAVID. This was followed by immune infiltration analysis and screening for RNA degradation mechanisms. Seven erythrocytic miRNAs, miR-451a, miR-92a-3p, miR-16-5p, miR-142-3p, miR-15b-5p, miR-19b-3p, and miR-223-3p showed favourable interactions with parasite genes expressed during blood stage infection. The miR-92a-3p that targeted the virulence gene PfEMP1 showed drastic reduction during infection. Performing pathway analysis for the human-host gene targets for the miRNA identified TOB1, TOB2, CNOT4, and XRN1 genes that are associated to RNA degradation processes, with the exoribonuclease XRN1, highly enriched in the malarial samples. On evaluating the role of exoribonucleases in miRNA degradation further, the pattern of Plasmodium falciparum_XRN1 showed increased levels during infection thus suggesting a defensive role for parasite survival. This study identifies miR-92a-3p, a member of C13orf25/ miR-17-92 cluster, as a novel miRNA inhibitor of the crucial parasite genes responsible for symptomatic malaria. Evidence for a plausible link to chromosome 13q31.3 loci controlling the epigenetic disease regulation is also suggested.
“…Similarly, host genetics can regulate Pf infection ( Gupta et al., 2013 ; Gupta et al., 2015b ; Gupta et al., 2017a ), and the protective effect of rs114136945 minor allele on parasitemia mediated through miR-598-3p expression was recently reported ( Dieng et al., 2020 ). In a study carried out in Thailand, the downregulation of both miR-451 and miR-16 was reported in 19 malaria patients compared to healthy individuals ( Chamnanchanunt et al., 2015 ).…”
Section: And Seek: the Symptomatic Erythrocytic Phasementioning
Despite encouraging progress over the past decade, malaria remains a major global health challenge. Its severe form accounts for the majority of malaria-related deaths, and early diagnosis is key for a positive outcome. However, this is hindered by the non-specific symptoms caused by malaria, which often overlap with those of other viral, bacterial and parasitic infections. In addition, current tools are unable to detect the nature and degree of vital organ dysfunction associated with severe malaria, as complications develop silently until the effective treatment window is closed. It is therefore crucial to identify cheap and reliable early biomarkers of this wide-spectrum disease. microRNAs (miRNAs), a class of small non-coding RNAs, are rapidly released into the blood circulation upon physiological changes, including infection and organ damage. The present review details our current knowledge of miRNAs as biomarkers of specific organ dysfunction in patients with malaria, and both promising candidates identified by pre-clinical models and important knowledge gaps are highlighted for future evaluation in humans. miRNAs associated with infected vectors are also described, with a view to expandind this rapidly growing field of research to malaria transmission and surveillance.
“…Furthermore, human miRNA cis‐eQTL analysis using whole‐genome sequencing data, identified 1376 genetic variants associated with the expression of 34 miRNAs. Specifically, they reported a protective effect of rs114136945 minor allele on parasitemia mediated by miR‐598‐3p expression (Dieng et al, 2020 ). Accordingly, a common miRNA‐146a polymorphism (rs2910164) increased the chances of P. falciparum malaria in pregnant African women (Van Loon et al, 2019 ).…”
Malaria is one of the most severe infectious diseases affecting humans and it is caused by protozoan pathogens of the species Plasmodium (spp.). The malaria parasite Plasmodium is characterized by a complex, multistage life cycle that requires tight gene regulation which allows for host invasion and defense against host immune responses. Unfortunately, the mechanisms regulating gene expression during Plasmodium infection remain largely elusive, though several lines of evidence implicate a major involvement of non‐coding RNAs (ncRNAs). The ncRNAs have been found to play a key role in regulating transcriptional and post‐transcriptional events in a broad range of organisms including Plasmodium. In Plasmodium ncRNAs have been shown to regulate key events in the multistage life cycle and virulence ability. Here we review recent progress involving ncRNAs (microRNAs, long non‐coding RNAs, and circular RNAs) and their role as regulators of gene expression during Plasmodium infection in human hosts with focus on the possibility of using these molecules as biomarkers for monitoring disease status. We also discuss the surprising function of ncRNAs in mediating the complex interplay between parasite and human host and future perspectives of the field.
This article is categorized under:
RNA in Disease and Development > RNA in Disease
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