- Open Access
Circulating microRNAs in malaria infection: bench to bedside
© The Author(s) 2017
- Received: 21 April 2017
- Accepted: 10 August 2017
- Published: 15 August 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.
- Severe malaria
- Plasmodium infection
- MicroRNA (miRNA)
Malaria is a life-threatening arthropod-borne disease with high fatality rate in tropical countries. Almost one million patients with severe malaria are dying a year in the world . The disease is caused by five distinct species of protozoa, namely Plasmodium falciparum, Plasmodium malariae, Plasmodium ovale, Plasmodium vivax or Plasmodium knowlesi. A majority of malaria infections are caused by P. falciparum (over 90%), followed by others species [2–5]. The 2000 World Health Organization (WHO) malaria case classification categorized the severity of malaria into severe (P. falciparum) and uncomplicated malaria [6, 7]. Diagnosis of severe malaria is evaluated if the condition is caused by P. falciparum infection with one or more of the followings: coma (cerebral malaria), metabolic acidosis, organ failure, and severe anaemia [8, 9]. High-risk factors for severe malaria are non-immune patients, immune-compromised patients, and those with a high burden of malaria parasites. A rapid increase of parasites in blood is the associated finding with severe malaria . Thus, early parasite detection and the immediate start of treatment are key events to reduce severe form in malaria patients . Microscopic examination of blood films, antigen detection, and molecular testing has been standard methods to detect malaria infection [7, 12]. Nowadays, microarray analysis and miRNA approach have helped many researchers to understand the relationship between dysregulation of miRNA and many infectious diseases [13–20].
MicroRNA assay need only a small amount of blood with less invasive sampling . Furthermore, miRNAs have high sensitivity and specificity for the diagnosis of various disorders. Circulating miRNA carry the potential to predict the severe outcome and to improve patient care in malaria patients. This review describes circulating miRNAs as potential biomarkers for severe malaria infection.
The miRNAs testing started as the analysis of miRNAs obtained from cells or tissues. Recent studies have shown that many human body fluids contained miRNAs. Thus, body fluids are analysed as possible biomarkers to demonstrate the relationship between miRNAs and disease severity. There are still controversies about suitable sources to augment the usefulness of miRNAs as biomarkers [22, 23].
Circulating miRNAs were studied in both plasma and serum. Mitchell et al.  found that good stability of miRNAs as the useful biomarker in both sample types. More recent studies have investigated their relationship between the pathophysiology of disease, in particular in malignancy or cardiovascular diseases [22, 33]. Mitchell et al.  also demonstrated that plasma contained miRNAs, and had functions to control gene expression. The correlation between circulating miRNAs and tissue miRNAs was found in this study. They also noted that the levels of circulating miRNAs were high enough to analyse using patient plasma.
Plasma miRNAs are circulating in four different molecular forms . The first is microparticle (MP) miRNAs. Microparticles are vesicles with sizes of 100–1000 nm, produced from the cell surface by budding of the outer cell membrane. Both miRNAs and MP might act together to regulate immune status . The second form is exosome miRNAs. Exosomes are released from multi-vesicular bodies and contain DNA, mRNA, proteins as well as miRNAs . The size of exosome is 50–100 nm. The third form is miRNAs in apoptotic bodies of 1–5 μm produced in the apoptotic process of various cells. The fourth form is a protein or lipid-bound form including argonaute2 (Ago2) and high-density lipoprotein (HDL). All forms of miRNAs are stable in circulation, especially MP or exosome-included miRNAs [34, 36]. The levels of miRNAs in serum, saliva, and urine are lower than in plasma . Therefore, saliva and urine sources of miRNAs need to use a large volume of sample to extracted miRNAs .
Kirschner et al.  described haemolysis of cells related to increasing of miRNAs level, which led to false negative findings to evaluate the levels of red blood cell-derived miRNAs. These effects were detectable in blood samples drawn from healthy individuals or in samples with delayed blood separation. Another factor to modify miRNA levels in plasma was co-extraction of cellular miRNAs from blood cells or cell debris. Membrane filters with low protein binding affinity were recommended, although the timing of filtration was still debated. In the case of unavailable tissue samples, it is a useful solution to detect miRNAs in blood or plasma samples. The analysis of circulating miRNAs is less invasive than tissue biopsy. Thus, these new molecules have been used in many diseases as the new biomarkers such as malignant diseases and cardiovascular diseases [39–41]. However, the knowledge about the usefulness of miRNA in infectious diseases is still not enough.
MicroRNAs in infectious diseases
The evidence for interaction between host and pathogens via the miRNA pathway was documented in mammal infectious diseases . Nukui et al. reported that miRNAs encoded by human herpesvirus 6A (HHV-6A) modulated the function of mammal cells. They demonstrated candidate miRNAs (miR-U86) regulating lytic replication of HHV-6A gene U86 . Umbach et al. showed the latency associated transcript (LAT) was primary miRNA precursor to control four distinct miRNAs in herpes simplex virus. They reported miR-H2-3p related to viral HSV-1 replication by controlling viral gene expression at the latent period of infection . Hook et al. found miR-UL112-1 related to viral target factors (UL114), which regulated cytomegalovirus to attach hematopoietic stem cells in bone marrow for reactivation and replication. Cytomegalovirus used miR-UL148D-1 and miR-UL112-1 to the target gene with the function of immune evasion. This action used RANTES, a chemokine to augment immune cells to infection site and prevented the attack from NK cells to infected cells .
For an infection that can lead to cancer, there were two studies identified the relationship between viral infection and malignancy. Motawi et al. and Bandiera et al. showed a similar result that hepatitis C virus (HCV) had miR-34 and miR-122 related with a chronic condition and more tendency to turn to hepatocellular carcinoma [14, 45]. Two candidate miRNAs can stimulate hepatocytic differentiation and cholesterol/fatty acid synthesis. Liver finally developed into fibrosis stage and malignancy at the high prevalence rate. The human miRNA profile is a useful tool for the diagnosis of organ dysfunction or infection, as well as malignancy. However, all studies were investigated for virus group in both pathophysiology and prognosis of diseases [13, 14, 42–45]. There were only limited studies on other infectious diseases, especially tropical diseases.
Tropical diseases and miRNAs
The majority of miRNAs studies on tropical diseases were done in schistosomiasis, leishmaniasis, cryptosporidium, and toxoplasma infection. Firstly, He et al. and Zhu et al. identified miR-223 and miR-454 as important molecules, respectively, for pathogenesis in schistosomes infection [16, 46, 47]. The miR-223 had a function as the transcription regulator, transcription factor activity, DNA binding, and a role of miR-454 in progression via the TGF-β/Smad4 pathway in this parasite [16, 47]. In Leishmania infection, Geraci et al. demonstrated that the dysregulation of miR-21 and miR-146b-5p that were associated with L. donovani-infected monocyte-derived dendritic cells. Two miRNAs act via the tumor growth factor-beta (TGF-β) signaling pathway . For protozoa infection, they found that decreased miR-221 levels were indicative of Cryptosporidium parvum infected epithelial cells with luciferase activity assay . Saçar et al.  also reported that miR-328 levels relate to toxoplasmosis infection in human. The discovery of many parasite-specific miRNAs profiles can be used to apply in clinical practice. Cryptosporidium spp. and Toxoplasma spp. are Apicomplexa parasites, related to Plasmodium . However, there has been a little body of knowledge of clinical applications of miRNAs in malaria infection.
Identification of potential miRNAs and malaria infection
Malaria-infected RBCs can develop in malaria parasites compose with two asexual stages in human (blood steam and liver) and sexual stage in the mosquito. In human, these parasites invade into human red blood cells (RBCs) until the mature parasite sequestration using cytoadherence ligand of P. falciparum Erythrocyte Membrane Protein-1 (PfEMP-1) [49, 50]. Splenic macrophages are the main of clearance of malaria from blood circulation. The miRNA possibly helps malaria to invade and grow in RBCs via escape from immune responses and defect of opsonization by circulating macrophage [49, 51–53]. Analysis of plasmodium genome demonstrated more than 500 genes . Two groups reported that P. falciparum did not have miRNA-sequences in parasite genome [50, 55]. They made a clone of all RNAs from a mixed stage of malaria-infected RBCs and then tested with bioinformatics method. It showed no matching between those cloned sequences and miRNA structures. There has been no study showing the presence of RNAi-family [siRNA, miRNAs, repeat-associated small interfering RNAs (rasiRNAs), and PIWI-interacting RNAs (piRNAs)] according to the stage of the parasite. In some infectious diseases, interactions between host miRNA and pathogen gene, or vice versa, were reported. For examples, human miRNAs including miR-223 suppress human immunodeficiency virus-1 (HIV-1) mRNA , Epstein-Bar virus miRNA: miR-BHRF1-3 targets human interferon (IFN)-inducible T cell-attracting chemokine (CXCL11) gene expression , and human miR-122 targets to hepatitis C virus (HCV) RNA . However, it is still not known whether human miRNA interacts with malaria mRNAs. Further examination may bring the miRNA-based diagnosis or therapeutic approaches. The posttranscriptional gene silencing in Plasmodium parasites changes alternative pathways other than miRNAs. The possibility is that Plasmodium is utilizing host miRNAs to regulate their gene expression [49, 59, 60].
Summary of discovery miRNAs among patients and animal experimental studies
Rathjen et al. 
P.f. parasite in cell culture
miR-451: significantly accumulated in infected RBCs
Xue et al. 
P.f. infected in human erythroid cells
miR-451, let-7b, miR-16, miR-91, miR-142, miR-144, let-7a, let-7f, miR-92, miR106: identified form infected RBCs
LaMonte et al. 
HbAS and HbCC RBCs with p. f.
miR-451 and miR-223
Chamnanchanunt et al. 
Patients with p.f. and p.v. infection
miR-451 and miR-16 (plasma of p.v. patients than p.f. patients)
Chamnanchanunt et al. 
Patients with malaria infection
miR-451 and miR-16 (RBCs of p.v. patients)
Delic et al. 
P. chabaudi infected in mice model
miR-10b, let-7a, let-7 g, miR-193a-3p, miR-192, miR-14205p, miR-465d, miR-677, miR-98, miR-694, miR-142-5p, miR-465d, miR-677, miR-98, miR-694, miR-374, miR-450b-5p, miR-464, miR-377, miR-20a, miR-466d-3p: (in liver)
miR-26b, miR-M23-1-5p, miR-1274a: (in liver organ)
El-Assaad et al. 
P. berghei infected in mice model
let-7i, miR-27a, miR-150 (in brain organ)
Al-Quraishy et al. 
P. chabaudi infected in mice model
miR-194, miR-192, miR-193A-3P, miR-145, miR-16, miR-99A, miR-99B, miR-15A, miR-152, let-7G, let-7B, miR-455-3P: (in spleen and liver)
For an animal model of demonstration parasite induces organ failure, mice infected with P. chabaudi malaria showed that 12 common miRNAs were downregulated in spleen and liver tissues . A study by Delic et al. found three miRNA species upregulated and 16 miRNA species downregulated . These findings suggested that miRNAs might be reprogrammed to minimize disease severity after infection. Knowledge of the interaction between falciparum parasite and the human genome could be valuable in malaria control. Furthermore, a study by El-Assaad et al. found that mouse with cerebral malaria had overexpression of miR-27a, miR-150, and let7i levels in brain tissue compared to a mouse with no cerebral malaria . Thus, miRNAs would have significant roles as biomarkers to predict early host responses and prognosis of malaria infection.
Clinical or laboratory to diagnosis condition
Artrial pH <7.3 or presence of acidosis
HIF-dependent trasncriptional regulation
ARDS or pulmonary edema
The acute lung injury from noncardiogenic causes
NF-kB mediated vascular inflammation
LPS-induced lung injury
Imparied consciousness or seizures
Regulation of the revascularization
Brain activation by EFNA3, NP1
Stimulate angiogenic factors
Urine output <0.4 ml/kg/hour or serum creatinine >3.0 mg/dl
Renal progenitors and renaly dysfuntion
Haemoglobin ≤8 g/dl
Blood pressure <90/60 mmHg with the sign of cold, clammy extremities
The presence of DIC phenomenon or spontaneous mucosal bleeding
Presence of parasitized erythrocytes >10%
Presence of blood sugar <40 mg/dl
The presence of hemolysis in the patients without G6PD deficiency
Acidosis severe malaria
Patients with severe malaria infection develop acidosis as a serious complication . It comprised with various mechanisms directly target the redox status and tissue hypoxia. Grosso et al. and Ivan et al. showed that miR-210 led to augmented hypoxia-inducible factor (HIF)-dependent transcriptional regulation and hypoxic condition [72, 73]. Further study needs to underline the mechanism of miR-210 in the area of malaria infection.
Acute respiratory distress syndrome (ARDS) is the major complication of severe malaria [6, 74]. ARDS is the defect of gas exchange on the lung and pulmonary/alveolar capillary permeability [6, 75]. Sun et al. found that low levels of miR-181b in patients with ARDS, which regulates NF-kB, mediated vascular inflammation of the lung . Guo et al. observed that miR-125b was downregulated in ARDS patients. MiR-125b was reported to be related LPS-induced lung injury .
Cerebral malaria is the condition of alternation of consciousness due to parasite sequestration and brain hypoxia . The hypoxic condition occurs as the results from apoptosis, microvascular occlusion, cytoadhesion from parasitized RBCs aggregates in brain vessels, and then lead to high lactate levels in cerebrospinal fluid, hypoperfusion or constriction of small vessels . Lou et al. reported the upregulated levels of miR-210 (involved in the regulation of the revascularization) in hypoxic condition. Sabirzhanov et al. showed downregulated miR-23a and miR-27a that injured cortex after traumatic brain injury [79, 80]. He et al.  demonstrated that high levels of miR-150 in the brain during cerebral ischaemia that could directly regulate the angiogenic factors. Moreover, a hypoxic condition induced upregulation of miR-210 in the patients with malignancy and cerebrovascular diseases . The explanation of miR-210 in hypoxia-induced acidosis related to the action of Ephrin-A3 (EFNA3), and neuronal pentraxin 1 (NP1) in the brain. Another study by Krupinski found that miR-120 levels have a positive correlation between an encephalopathy with lactic acidosis patients . These reports showed that miRNAs are relevant biomarkers for brain damage. There are no observations yet on miRNAs involved in brain malaria patients.
Kidney failure is a common complication in severe malaria patients . The mechanism to develop renal damages composes with multiple factors (cytoadherence from infected RBCs leads to obstruction, hypovolaemia from body fluid loss and host immune responsiveness) . Marrone et al. found that down-regulation of miR-17–92 related to renal progenitors and renal dysfunction in adult mice with acute nephropathy . Lorenzne et al.  demonstrated that high levels of miR-24 in the ischemic kidney mice. The effect on apoptosis regulation is an explanation for this miRNAs action. However, the significant miRNAs relate to renal dysfunction after malaria infection is not defined.
The optical microscopic examination is still the gold standard to detect malaria parasites. This method is straightforward and cheap. There are no currently available diagnostic techniques to predict the malaria severity that is very important for saving patient’s life. The new technology has more potential to help the physicians to manage severe malaria is recommended. New investigate applied into tropical diseases such as malaria infection. In vivo study of malaria infection was turn into clinical application. In addition, as a biomarker, it would have prognostic value, especially in early host responses. The objective of this review literature is to systematically review the available data on the relevance of candidate miRNAs among both in vitro and in vivo malaria study.
A useful biomarker has to be an investigation, with high sensitivity, non-invasive and applicable to clinical management. There are more studies about miRNAs as a biomarker in many diseases, most of them related to malignant and cardiovascular diseases. For tropical infectious diseases, the knowledge of miRNAs raises to fill to explain the pathophysiology of diseases. The knowledge of miRNAs in malaria infection is still not enough if compared with antimalaria drug trial. The more studies were required to answer, (1) biomarker to predict malaria severity and further predictor, (2) development of the new treatment directed to malaria life cycle. Further studies will perform to fill the gap between bench and bed by accumulating knowledge in serious complications among malaria patients.
SC, SF, and TU prepared the initial paper. SC wrote the first draft paper. SF and TU reviewed and gave comments on the second draft paper. All authors systematically reviewed the final version of the manuscript. All authors read and approved the final manuscript.
We also thank Associate Professor Varunee Desakorn and Associate Professor Pratap Singhasivanon (Dean of the Faculty of Tropical Medicine, Mahidol University) for their support. This article was funded by Prasert Prasarttong-Osoth Research Foundation which is operated by the Medical Association of Thailand, and JSPS KAKENHI Grant Number JP17K09020.
The authors declare that they have no compeling interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
- Gething PW, Casey DC, Weiss DJ, Bisanzio D, Bhatt S, Cameron E, et al. Mapping Plasmodium falciparum mortality in Africa between 1990 and 2015. N Engl J Med. 2016;375:2435–45.View ArticlePubMedPubMed CentralGoogle Scholar
- Haldar K, Mohandas N. Malaria, erythrocytic infection, and anemia. Hematol Am Soc Hematol Educ Program. 2009;2009:87–93.Google Scholar
- Rasheed A, Saeed S, Khan SA. Clinical and laboratory findings in acute malaria caused by various Plasmodium species. J Pak Med Assoc. 2009;59:220–3.PubMedGoogle Scholar
- WHO. World malaria report. Geneva: World Health Organization; 2015. http://www.who.int/malaria/publications/world-malaria-report-2015/wmr2015-keypoints_eng.pdf?ua=1. Accessed 11 Nov 2016.
- Malaria. https://www.ncbi.nlm.nih.gov/books/NBK2286/. Accessed 11 Nov 2016.
- Trampuz A, Jereb M, Muzlovic I, Prabhu RM. Clinical review: severe malaria. Crit Care. 2003;7:315–23.View ArticlePubMedPubMed CentralGoogle Scholar
- WHO. Severe falciparum malaria. World Health Organization Communicable Diseases Cluster. Trans R Soc Trop Med Hyg. 2000;94(Suppl 1):S1–90.Google Scholar
- Sagaki P, Thanachartwet V, Desakorn V, Sahassananda D, Chamnanchanunt S, Chierakul W, et al. Clinical factors for severity of Plasmodium falciparum malaria in hospitalized adults in Thailand. PLoS ONE. 2013;8:e71503.View ArticlePubMedPubMed CentralGoogle Scholar
- Bruneel F, Tubach F, Corne P, Megarbane B, Mira JP, Peytel E, et al. Severe imported falciparum malaria: a cohort study in 400 critically ill adults. PLoS ONE. 2010;5:e13236.View ArticlePubMedPubMed CentralGoogle Scholar
- Phillips A, Bassett P, Zeki S, Newman S, Pasvol G. Risk factors for severe disease in adults with falciparum malaria. Clin Infect Dis. 2009;48:871–8.View ArticlePubMedGoogle Scholar
- Phommanivong V, Thongkham K, Deyer G, Rene JP, Barennes H. An assessment of early diagnosis and treatment of malaria by village health volunteers in the Lao PDR. Malar J. 2010;9:347.View ArticlePubMedPubMed CentralGoogle Scholar
- Moody A. Rapid diagnostic tests for malaria parasites. Clin Microbiol Rev. 2002;15:66–78.View ArticlePubMedPubMed CentralGoogle Scholar
- Roberts AP, Lewis AP, Jopling CL. The role of microRNAs in viral infection. Prog Mol Biol Transl Sci. 2011;102:101–39.View ArticlePubMedGoogle Scholar
- Motawi TK, Shaker OG, El-Maraghy SA, Senousy MA. Serum MicroRNAs as potential biomarkers for early diagnosis of hepatitis c virus-related hepatocellular carcinoma in Egyptian patients. PLoS ONE. 2015;10:e0137706.View ArticlePubMedPubMed CentralGoogle Scholar
- Broadbent KM, Broadbent JC, Ribacke U, Wirth D, Rinn JL, Sabeti PC. Strand-specific RNA sequencing in Plasmodium falciparum malaria identifies developmentally regulated long non-coding RNA and circular RNA. BMC Genom. 2015;16:454.View ArticleGoogle Scholar
- Zhu D, He X, Duan Y, Chen J, Wang J, Sun X, et al. Expression of microRNA-454 in TGF-beta1-stimulated hepatic stellate cells and in mouse livers infected with Schistosoma japonicum. Parasit Vectors. 2014;7:148.View ArticlePubMedPubMed CentralGoogle Scholar
- He QW, Li Q, Jin HJ, Zhi F, Suraj B, Zhu YY, et al. MiR-150 regulates poststroke cerebral angiogenesis via vascular endothelial growth factor in rats. CNS Neurosci Ther. 2016;22:507–17.View ArticlePubMedGoogle Scholar
- Geraci NS, Tan JC, McDowell MA. Characterization of microRNA expression profiles in Leishmania-infected human phagocytes. Parasite Immunol. 2015;37:43–51.View ArticlePubMedPubMed CentralGoogle Scholar
- Gong A-Y, Hu G, Zhou R, Liu J, Feng Y, Soukup GA, et al. MicroRNA-221 controls expression of intercellular adhesion molecule-1 in epithelial cells in response to Cryptosporidium parvum infection. Int J Parasitol. 2011;41:397–403.View ArticlePubMedPubMed CentralGoogle Scholar
- Sacar MD, Bagci C, Allmer J. Computational prediction of microRNAs from Toxoplasma gondii potentially regulating the hosts’ gene expression. Genom Proteom Bioinform. 2014;12:228–38.View ArticleGoogle Scholar
- Hermsen CC, Telgt DS, Linders EH, van de Locht LA, Eling WM, Mensink EJ, et al. Detection of Plasmodium falciparum malaria parasites in vivo by real-time quantitative PCR. Mol Biochem Parasitol. 2001;118:247–51.View ArticlePubMedGoogle Scholar
- Yan W, Qian L, Chen J, Chen W, Shen B. Comparison of prognostic MicroRNA biomarkers in blood and tissues for gastric cancer. J Cancer. 2016;7:95–106.View ArticlePubMedPubMed CentralGoogle Scholar
- Khoury S, Tran N. Circulating microRNAs. Potential biomarkers for common malignancies. Biomark Med. 2015;9:131–51.View ArticlePubMedGoogle Scholar
- Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell. 1993;75:843–54.View ArticlePubMedGoogle Scholar
- Hu W, Criscione F, Liang S, Tu Z. MicroRNAs of two medically important mosquito species: Aedes aegypti and Anopheles stephensi. Insect Mol Biol. 2015;24:240–52.View ArticlePubMedGoogle Scholar
- Guo Z, Maki M, Ding R, Yang Y, Zhang B, Xiong L. Genome-wide survey of tissue-specific microRNA and transcription factor regulatory networks in 12 tissues. Sci Rep. 2014;4:5150.View ArticlePubMedPubMed CentralGoogle Scholar
- Ibanez-Ventoso C, Vora M, Driscoll M. Sequence relationships among C. elegans, D. melanogaster and human microRNAs highlight the extensive conservation of microRNAs in biology. PLoS ONE. 2008;3:e2818.View ArticlePubMedPubMed CentralGoogle Scholar
- Liu J, Yang B, Ai J. Advance in research of microRNA in Caenorhabditis elegans. J Cell Biochem. 2013;114:994–1000.View ArticlePubMedGoogle Scholar
- Bushati N, Cohen SM. MicroRNA functions. Annu Rev Cell Dev Biol. 2007;23:175–205.View ArticlePubMedGoogle Scholar
- Schwarzenbach H, Nishida N, Calin GA, Pantel K. Clinical relevance of circulating cell-free microRNAs in cancer. Nat Rev Clin Oncol. 2014;11:145–56.View ArticlePubMedGoogle Scholar
- Carthew RW, Sontheimer EJ. Origins and mechanisms of miRNAs and siRNAs. Cell. 2009;136:642–55.View ArticlePubMedPubMed CentralGoogle Scholar
- Mitchell PS, Parkin RK, Kroh EM, Fritz BR, Wyman SK, Pogosova-Agadjanyan EL, et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci USA. 2008;105:10513–8.View ArticlePubMedPubMed CentralGoogle Scholar
- Li YQ, Zhang MF, Wen HY, Hu CL, Liu R, Wei HY, et al. Comparing the diagnostic values of circulating microRNAs and cardiac troponin T in patients with acute myocardial infarction. Clinics. 2013;68:75–80.View ArticlePubMedPubMed CentralGoogle Scholar
- Hu G, Drescher KM, Chen XM. Exosomal miRNAs: biological properties and therapeutic potential. Front Genet. 2012;3:56.PubMedPubMed CentralGoogle Scholar
- Moro L, Bardaji A, Macete E, Barrios D, Morales-Prieto DM, Espana C, et al. Placental microparticles and MicroRNAs in pregnant women with Plasmodium falciparum or HIV infection. PLoS ONE. 2016;11:e0146361.View ArticlePubMedPubMed CentralGoogle Scholar
- Gallo A, Tandon M, Alevizos I, Illei GG. The majority of microRNAs detectable in serum and saliva is concentrated in exosomes. PLoS ONE. 2012;7:e30679.View ArticlePubMedPubMed CentralGoogle Scholar
- Reid G, Kirschner MB, van Zandwijk N. Circulating microRNAs: association with disease and potential use as biomarkers. Crit Rev Oncol Hematol. 2011;80:193–208.View ArticlePubMedGoogle Scholar
- Kirschner MB, Edelman JB, Kao SCH, Vallely MP, van Zandwijk N, Reid G. The impact of hemolysis on cell-free microRNA biomarkers. Front Genet. 2013;4:94.PubMedPubMed CentralGoogle Scholar
- Reis LO, Pereira TC, Lopes-Cendes I, Ferreira U. MicroRNAs: a new paradigm on molecular urological oncology. Urology. 2010;76:521–7.View ArticlePubMedGoogle Scholar
- Masaki S, Ohtsuka R, Abe Y, Muta K, Umemura T. Expression patterns of microRNAs 155 and 451 during normal human erythropoiesis. Biochem Biophys Res Commun. 2007;364:509–14.View ArticlePubMedGoogle Scholar
- Sutar NK, Renapurkar DM, Camoens H. Genetic red cell defects and malaria. Indian J Med Sci. 1992;46:220–7.PubMedGoogle Scholar
- Nukui M, Mori Y, Murphy EA. A human herpesvirus 6A-encoded microRNA: role in viral lytic replication. J Virol. 2015;89:2615–27.View ArticlePubMedGoogle Scholar
- Umbach JL, Kramer MF, Jurak I, Karnowski HW, Coen DM, Cullen BR. MicroRNAs expressed by herpes simplex virus 1 during latent infection regulate viral mRNAs. Nature. 2008;454:780–3.PubMedPubMed CentralGoogle Scholar
- Hook L, Hancock M, Landais I, Grabski R, Britt W, Nelson JA. Cytomegalovirus microRNAs. Curr Opin Virol. 2014;7:40–6.View ArticlePubMedGoogle Scholar
- Bandiera S, Pfeffer S, Baumert TF, Zeisel MB. miR-122–a key factor and therapeutic target in liver disease. J Hepatol. 2015;62:448–57.View ArticlePubMedGoogle Scholar
- Zhu L, Liu J, Cheng G. Role of microRNAs in schistosomes and schistosomiasis. Front Cell Infect Microbiol. 2014;4:165.View ArticlePubMedPubMed CentralGoogle Scholar
- He X, Sai X, Chen C, Zhang Y, Xu X, Zhang D, et al. Host serum miR-223 is a potential new biomarker for Schistosoma japonicum infection and the response to chemotherapy. Parasit Vectors. 2013;6:272.View ArticlePubMedPubMed CentralGoogle Scholar
- Morrissette NS, Sibley LD. Cytoskeleton of apicomplexan parasites. Microbiol Mol Biol Rev. 2002;66:21–38.View ArticlePubMedPubMed CentralGoogle Scholar
- LaMonte G, Philip N, Reardon J, Lacsina JR, Majoros W, Chapman L, et al. Translocation of sickle cell erythrocyte microRNAs into Plasmodium falciparum inhibits parasite translation and contributes to malaria resistance. Cell Host Microbe. 2012;12:187–99.View ArticlePubMedPubMed CentralGoogle Scholar
- Xue X, Zhang Q, Huang Y, Feng L, Pan W. No miRNA were found in Plasmodium and the ones identified in erythrocytes could not be correlated with infection. Malar J. 2008;7:47.View ArticlePubMedPubMed CentralGoogle Scholar
- Carlton JM, Angiuoli SV, Suh BB, Kooij TW, Pertea M, Silva JC, et al. Genome sequence and comparative analysis of the model rodent malaria parasite Plasmodium yoelii. Nature. 2002;419:512–9.View ArticlePubMedGoogle Scholar
- Dups JN, Pepper M, Cockburn IA. Antibody and B cell responses to Plasmodium sporozoites. Front Microbiol. 2014;5:625.View ArticlePubMedPubMed CentralGoogle Scholar
- Schmidt CQ, Kennedy AT, Tham WH. More than just immune evasion: Hijacking complement by Plasmodium falciparum. Mol Immunol. 2015;67:71–84.View ArticlePubMedGoogle Scholar
- Gardner MJ, Hall N, Fung E, White O, Berriman M, Hyman RW, et al. Genome sequence of the human malaria parasite Plasmodium falciparum. Nature. 2002;419:498–511.View ArticlePubMedGoogle Scholar
- Rathjen T, Nicol C, McConkey G, Dalmay T. Analysis of short RNAs in the malaria parasite and its red blood cell host. FEBS Lett. 2006;580:5185–8.View ArticlePubMedGoogle Scholar
- Huang J, Wang F, Argyris E, Chen K, Liang Z, Tian H, et al. Cellular microRNAs contribute to HIV-1 latency in resting primary CD4+ T lymphocytes. Nat Med. 2007;13:1241–7.View ArticlePubMedGoogle Scholar
- Xia T, O’Hara A, Araujo I, Barreto J, Carvalho E, Sapucaia JB, et al. EBV microRNAs in primary lymphomas and targeting of CXCL-11 by ebv-mir-BHRF1-3. Cancer Res. 2008;68:1436–42.View ArticlePubMedPubMed CentralGoogle Scholar
- Wahid F, Shehzad A, Khan T, Kim YY. MicroRNAs: synthesis, mechanism, function, and recent clinical trials. Biochim Biophys Acta. 2010;1803:1231–43.View ArticlePubMedGoogle Scholar
- Coulson RM, Hall N, Ouzounis CA. Comparative genomics of transcriptional control in the human malaria parasite Plasmodium falciparum. Genome Res. 2004;14:1548–54.View ArticlePubMedPubMed CentralGoogle Scholar
- Hall N, Carlton J. Comparative genomics of malaria parasites. Curr Opin Genet Dev. 2005;15:609–13.View ArticlePubMedGoogle Scholar
- Svasti S, Masaki S, Penglong T, Abe Y, Winichagoon P, Fucharoen S, et al. Expression of microRNA-451 in normal and thalassemic erythropoiesis. Ann Hematol. 2010;89:953–8.View ArticlePubMedGoogle Scholar
- Chapman LM, Ture SK, Field DJ, Morrell CN. miR-451 limits CD4+ T cell proliferative responses to infection in mice. Immunol Res. 2017. doi:10.1007/s12026-017-8919-x.Google Scholar
- Chamnanchanunt S, Kuroki C, Desakorn V, Enomoto M, Thanachartwet V, Sahassananda D, et al. Downregulation of plasma miR-451 and miR-16 in Plasmodium vivax infection. Exp Parasitol. 2015;155:19–25.View ArticlePubMedGoogle Scholar
- Chamnanchanunt S, Okada K, Desakorn V, Koga M, Nakamura Y, Shiotsu H, et al. Down-regulated micrornas in plasma and red blood cells of patients with malaria infection. Exp Hematol. 2015;43:S56.View ArticleGoogle Scholar
- Mantel PY, Hjelmqvist D, Walch M, Kharoubi-Hess S, Nilsson S, Ravel D, et al. Infected erythrocyte-derived extracellular vesicles alter vascular function via regulatory Ago2-miRNA complexes in malaria. Nat Commun. 2016;7:12727.View ArticlePubMedPubMed CentralGoogle Scholar
- Baro B, Deroost K, Raiol T, Brito M, Almeida ACG, de Menezes-Neto A, et al. Plasmodium vivax gametocytes in the bone marrow of an acute malaria patient and changes in the erythroid miRNA profile. PLoS Negl Trop Dis. 2017;11:e0005365.View ArticlePubMedPubMed CentralGoogle Scholar
- Al-Quraishy S, Dkhil MA, Delic D, Abdel-Baki AA, Wunderlich F. Organ-specific testosterone-insensitive response of miRNA expression of C57BL/6 mice to Plasmodium chabaudi malaria. Parasitol Res. 2012;111:1093–101.View ArticlePubMedGoogle Scholar
- Delic D, Dkhil M, Al-Quraishy S, Wunderlich F. Hepatic miRNA expression reprogrammed by Plasmodium chabaudi malaria. Parasitol Res. 2011;108:1111–21.View ArticlePubMedGoogle Scholar
- El-Assaad F, Hempel C, Combes V, Mitchell AJ, Ball HJ, Kurtzhals JA, et al. Differential microRNA expression in experimental cerebral and noncerebral malaria. Infect Immun. 2011;79:2379–84.View ArticlePubMedPubMed CentralGoogle Scholar
- Lalloo DG, Shingadia D, Bell DJ, Beeching NJ, Whitty CJ, Chiodini PL. UK malaria treatment guidelines 2016. J Infect. 2016;72:635–49.View ArticlePubMedGoogle Scholar
- Maitland K, Newton CR. Acidosis of severe falciparum malaria: heading for a shock? Trends Parasitol. 2005;21:11–6.View ArticlePubMedGoogle Scholar
- Grosso S, Doyen J, Parks SK, Bertero T, Paye A, Cardinaud B, et al. MiR-210 promotes a hypoxic phenotype and increases radioresistance in human lung cancer cell lines. Cell Death Dis. 2013;4:e544.View ArticlePubMedPubMed CentralGoogle Scholar
- Ivan M, Huang X. miR-210: fine-tuning the hypoxic response. Adv Exp Med Biol. 2014;772:205–27.View ArticlePubMedPubMed CentralGoogle Scholar
- Gachot B, Wolff M, Nissack G, Veber B, Vachon F. Acute lung injury complicating imported Plasmodium falciparum malaria. Chest. 1995;108:746–9.View ArticlePubMedGoogle Scholar
- Marks M, Armstrong M, Walker D, Doherty T. Imported falciparum malaria among adults requiring intensive care: analysis of the literature. Malar J. 2014;13:79.View ArticlePubMedPubMed CentralGoogle Scholar
- Sun X, Icli B, Wara AK, Belkin N, He S, Kobzik L, et al. MicroRNA-181b regulates NF-kappaB-mediated vascular inflammation. J Clin Invest. 2012;122:1973–90.PubMedPubMed CentralGoogle Scholar
- Guo Z, Gu Y, Wang C, Zhang J, Shan S, Gu X, et al. Enforced expression of miR-125b attenuates LPS-induced acute lung injury. Immunol Lett. 2014;162:18–26.View ArticlePubMedGoogle Scholar
- Maitland K, Marsh K. Pathophysiology of severe malaria in children. Acta Trop. 2004;90:131–40.View ArticlePubMedGoogle Scholar
- Lou YL, Guo F, Liu F, Gao FL, Zhang PQ, Niu X, et al. miR-210 activates notch signaling pathway in angiogenesis induced by cerebral ischemia. Mol Cell Biochem. 2012;370:45–51.View ArticlePubMedGoogle Scholar
- Sabirzhanov B, Zhao Z, Stoica BA, Loane DJ, Wu J, Borroto C, et al. Downregulation of miR-23a and miR-27a following experimental traumatic brain injury induces neuronal cell death through activation of proapoptotic Bcl-2 proteins. J Neurosci. 2014;34:10055–71.View ArticlePubMedPubMed CentralGoogle Scholar
- Devlin C, Greco S, Martelli F, Ivan M. miR-210: more than a silent player in hypoxia. IUBMB Life. 2011;63:94–100.PubMedPubMed CentralGoogle Scholar
- Krupinski J, Slevin M. Emerging molecular targets for brain repair after stroke. Stroke Res Treat. 2013;2013:473416.PubMedPubMed CentralGoogle Scholar
- Das BS. Renal failure in malaria. J Vector Borne Dis. 2008;45:83–97.PubMedGoogle Scholar
- Marrone AK, Stolz DB, Bastacky SI, Kostka D, Bodnar AJ, Ho J. MicroRNA-17–92 is required for nephrogenesis and renal function. J Am Soc Nephrol. 2014;25:1440–52.View ArticlePubMedPubMed CentralGoogle Scholar
- Lorenzen JM, Kaucsar T, Schauerte C, Schmitt R, Rong S, Hubner A, et al. MicroRNA-24 antagonism prevents renal ischemia reperfusion injury. J Am Soc Nephrol. 2014;25:2717–29.View ArticlePubMedPubMed CentralGoogle Scholar