MiRNA: Biological Regulator in Host-Parasite Interaction during Malaria Infection (original) (raw)
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Circulating microRNAs in malaria infection: bench to bedside
Malaria Journal, 2017
Severe malaria has a poor prognosis with a morbidity rate of 80% in tropical areas. The early parasite detection is one of the effective means to prevent severe malaria of which specific treatment strategies are limited. Many clinical characteristics and laboratory testings have been used for the early diagnosis and prediction of severe disease. However, a few of these factors could be applied to clinical practice. MicroRNAs (miRNAs) were demonstrated as useful biomarkers in many diseases such as malignant diseases and cardiovascular diseases. Recently it was found that plasma miR-451 and miR-16 were downregulated in malaria infection at parasitic stages or with multi-organ failure involvement. MiR-125b,-27a,-23a,-150, 17-92 and-24 are deregulated in malaria patients with multiple organ failures. Here, the current findings of miRNAs were reviewed in relation to clinical severity of malaria infection and emphasized that miRNAs are potential biomarkers for severe malaria infection.
Tying malaria and microRNAs: from the biology to future diagnostic perspectives
Malaria Journal, 2016
Symptoms caused by bacterial, viral and malarial infections usually overlap and aetiologic diagnosis is difficult. Patient management in low-resource countries with limited laboratory services has been based predominantly on clinical evaluation and syndromic approaches. However, such clinical assessment has limited accuracy both for identifying the likely aetiological cause and for the early recognition of patients who will progress to serious or fatal disease. Plasma-detectable biomarkers that rapidly and accurately diagnose severe infectious diseases could reduce morbidity and decrease the unnecessary use of usually scarce therapeutic drugs. The discovery of microRNAs (miRNAs) has opened exciting new avenues to identify blood biomarkers of organ-specific injury. This review assesses current knowledge on the relationship between malaria disease and miRNAs, and evaluates how future research might lead to the use of these small molecules for identifying patients with severe malaria disease and facilitate treatment decisions.
Dichotomous miR expression and immune responses following primary blood-stage malaria
JCI insight, 2017
Clinical responses to infection or vaccination and the development of effective immunity are characterized in humans by a marked interindividual variability. To gain an insight into the factors affecting this variability, we used a controlled human infection system to study early immune events following primary infection of healthy human volunteers with blood-stage Plasmodium falciparum malaria. By day 4 of infection, a dichotomous pattern of high or low expression of a defined set of microRNAs (miRs) emerged in volunteers that correlated with variation in parasite growth rate. Moreover, high-miR responders had higher numbers of activated CD4+ T cells, and developed significantly enhanced antimalarial antibody responses. Notably, a set of 17 miRs was identified in the whole blood of low-miR responders prior to infection that differentiated them from high-miR responders. These data implicate preexisting host factors as major determinants in the ability to effectively respond to prima...
International Journal of Gastroenterology Hepatology and Endoscopy
Plasmodium falciparum infection causes paroxysmal fever that is triggered by strong pro-inflammatory responses involving pyrogenic cytokines such as interleukin (IL)-1β and tumor necrosis factor alpha (TNF-α). Although inflammatory responses, including interferon gamma (IFN-γ), IL-12, IL-1β, IL-2, and TNF-α, play important roles that facilitate parasite clearance, circulating high levels of these cytokines have been associated with malaria immunopathology (Ademolue et al., 2017). The miRNAs and malaria is a dynamic interaction still incomplete understood. Therefore, authors come up with selected genes such as CD36, IFN-γ, toll-like receptor 4 (TLR4) and proline rich 15 (PRR15) consider as candidate genes that expressed become miRNAs and can be served as potential biomarkers in malaria infection. Micro ribonucleic acids (miRNAs) are a class of small non-coding endogenous RNA molecules (Rangel G et al., 2019) that regulate a wide range of biological processes by post-transcriptionally regulating
Plasma microRNA profiling for malaria disease: association with severity and P. falciparum biomass
medRxiv, 2020
Severe malaria (SM) is a major public health problem in malaria-endemic countries. Sequestration of Plasmodium falciparum (Pf) infected erythrocytes in vital organs and the associated inflammation leads to organ dysfunction. MicroRNAs (miRNAs), which are rapidly released from damaged tissues into the host fluids, constitute a promising biomarker for the prognosis of SM. This study applied next-generation sequencing to evaluate the differential expression of miRNAs in SM compared to uncomplicated malaria (UM). Six miRNAs were associated with in vitro Pf cytoadhesion, severity in Mozambican children and Pf biomass. Relative expression of hsa-miR-4497 quantified by TaqMan-RT-qPCR, was higher in SM children plasmas compared to that of UM (p<0.048), and again correlated with Pf biomass (p=0.033). These findings suggest that different physiopathological processes in SM and UM lead to differential expression of miRNAs and pave the way to future studies aiming to assess the prognostic va...
Erythrocyte miRNA-92a-3p interactions with PfEMP1 as determinants of clinical malaria
Functional & Integrative Genomics
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 infect...
Scientific Reports, 2017
Drastic changes in gene expression occur after adult female mosquitoes take a blood meal and use the nutrients for egg maturation. A growing body of evidence indicates that microRNAs (miRNAs) contribute to this tightly controlled tissue-and stage-specific gene expression. To investigate the role of miRNAs, we monitored miRNA expression in the mosquito Anopheles gambiae during the 72-h period immediately after blood feeding. We also measured the association of miRNAs with Argonaute 1 (Ago1) and Argonaute 2 (Ago2) to assess the functional status of individual miRNA species. Overall, 173 mature miRNAs were precipitated with Ago1 and Ago2, including 12 new miRNAs, the orthologs of which are found thus far only in other Anopheles species. Ago1 is the predominant carrier of miRNAs in Anopheles gambiae. The abundance and Ago loading of most of the mature miRNAs were relatively stable after blood ingestion. However, miRNAs of the miR-309/286/2944 cluster were considerably upregulated after blood feeding. Injection of the specific antagomir for miR-309 resulted in smaller developing oocytes and ultimately fewer eggs. In addition, the Ago association of some miRNAs was not proportional to their cellular abundance, suggesting that integration of miRNAs into the Ago complexes is regulated by additional mechanisms. The Anopheles gambiae mosquito is the major vector of human malaria in Africa. Malaria is caused by protozoan parasites belonging to the genus Plasmodium and is spread between hosts by the bites of parasite-infected female mosquitoes. Female adults of An. gambiae must obtain blood from vertebrates to acquire nutrients for egg production. The female mosquitoes digest a protein-rich blood meal, greater than their original body weight, within 48 h after ingestion and use the nutrients to synthesize egg yolk proteins. Substantial physiological changes occur after blood ingestion in mosquitoes, and over 50% of all genes show significant variation in transcript accumulation 1. Recent studies suggest that blood digestion and egg production in An. gambiae and other mosquito species are also regulated by mosquito microRNAs (miRNAs) 2. Expression of some miRNAs is considerably altered after blood ingestion in An. gambiae 3 , An. stephensi 4 , Aedes aegypti 5 , and Aedes albopictus 6. Functional studies in Ae. aegypti have shown that perturbation of individual miRNAs in female mosquitoes leads to defects in blood digestion and egg production 7-10. miRNAs are small endogenous non-coding RNAs that play important roles in post-transcriptional gene regulation in plants and animals 11. Most miRNAs are transcribed by RNA polymerase II as primary-miRNA (pri-miRNA) transcripts. The canonical miRNA pathway converts the pri-miRNA hairpins into ∼22-nucleotide (nt) mature duplex miRNAs via consecutive cleavages by two RNase III enzymes, Drosha and Dicer, with the help of some double-stranded RNA-binding proteins 12. The two strands of the mature miRNA duplex are denoted by the suffix-5p or-3p, depending on whether they originate from the 5′ or 3′ end of the pri-miRNA. Only one strand of the miRNA duplex is usually loaded onto an Argonaute (Ago) protein as part of the miRNA-induced silencing complex (miRISC). The strand in miRISC is known as the guide strand; the other strand (the passenger strand) is excluded and subsequently degraded 12. The guide strand directs the miRISC to messenger RNA
Parasites & Vectors, 2015
Background: MicroRNAs are small non-coding RNAs that are involved in various biological processes including insect development. Anopheles stephensi serves as primary vector of malaria parasite in Asia and exhibits holometabolous life cycle that involves four different stages of development. Regulation and role of mosquito miRNAs during various stages of mosquito development remain largely unknown. Methods: High throughput small RNA sequencing was employed for identification and profiling of miRNAs across immature and adult stages of malaria vector, which were further validated using Northern hybridization and real time PCR. Target prediction and pathway analysis was carried out to understand the role of regulated miRNAs in insect development. Degradome sequencing was employed to identify cleaved targets of some regulated miRNAs. Loss of function strategy was employed for miR-989 to understand its probable role in female reproductive process. Results: Small RNA sequencing and data analysis revealed 111 and 14 known and novel miRNAs respectively across all stages of Anopheles stephensi. Nine miRNAs showed gender specific regulation across different stages of mosquito development. Analysis of miRNAs revealed regulation of 24 and 26 miRNAs across different stages of male and female mosquito development respectively. mRNA targets and significant pathways targeted by regulated miRNAs were identified for each stage of mosquito development. Degradome sequencing revealed twenty nine cleaved targets of insect miRNAs. MicroRNA-989 showed significant up-regulation in the adult female as compared to adult male mosquito. Knockdown of miR-989 expression in adult female using miRNA specific antagomir affected targets playing roles in protein binding, proteolysis and nucleic acid binding in ovary tissue of female mosquito post blood feeding. Conclusions: This is the first comprehensive effort to understand regulation of Anopheles stephensi miRNAs across developmental stages of male and female mosquito. Preliminary role of regulated miRNAs in mosquito development was revealed by target prediction and pathway analysis. MicroRNA-989 emerged to have important roles in adult female mosquitoes showing significant up-regulation which was further studied using miR-989 specific antagomir. This study provides insights into mosquito development and reproductive process and has implications for effective control of mosquito population required for reducing spread of mosquito-borne infectious diseases.
Blood feeding and Plasmodium infection alters the miRNome of Anopheles stephensi
PloS one, 2014
Blood feeding is an integral process required for physiological functions and propagation of the malaria vector Anopheles. During blood feeding, presence of the malaria parasite, Plasmodium in the blood induces several host effector molecules including microRNAs which play important roles in the development and maturation of the parasite within the mosquito. The present study was undertaken to elucidate the dynamic expression of miRNAs during gonotrophic cycle and parasite development in Anopheles stephensi. Using next generation sequencing technology, we identified 126 miRNAs of which 17 were novel miRNAs. The miRNAs were further validated by northern hybridization and cloning. Blood feeding and parasitized blood feeding in the mosquitoes revealed regulation of 13 and 16 miRNAs respectively. Expression profiling of these miRNAs revealed that significant miRNAs were down-regulated upon parasitized blood feeding with a repertoire of miRNAs showing stage specific up-regulation. Expression profiles of significantly modulated miRNAs were further validated by real time PCR. Target prediction of regulated miRNAs revealed overlapping targeting by different miRNAs. These targets included several metabolic pathways including metabolic, redox homeostasis and protein processing machinery components. Our analysis revealed tight regulation of specific miRNAs post blood feeding and parasite infection in An. stephensi. Such regulated expression suggests possible role of these miRNAs during gonotrophic cycle in mosquito. Another set of miRNAs were also significantly regulated at 42 h and 5 days post infection indicating parasite stage-specific role of host miRNAs. This study will result in better understanding of the role of miRNAs during gonotrophic cycle and parasite development in mosquito and can probably facilitate in devising novel malaria control strategies at vector level. Citation: Jain S, Rana V, Shrinet J, Sharma A, Tridibes A, et al. (2014) Blood Feeding and Plasmodium Infection Alters the miRNome of Anopheles stephensi. PLoS ONE 9(5): e98402.
Downregulation of plasma miR-451 and miR-16 in Plasmodium vivax infection
Experimental Parasitology, 2015
The objective is to develop the new biomarker for malaria infections. • This is the first observation of plasma microRNAs in malaria. • Plasma miR-451 and miR-16 were downregulated in Plasmodium vivax infection. • We discuss the usefulness of plasma microRNAs as the biomarkers for malaria infections.