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Journal of Translational Medicine

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Open Access 01-12-2018 | Research

Screening and identification of potential novel biomarker for diagnosis of complicated Plasmodium vivax malaria

Authors: Hargobinder Kaur, Rakesh Sehgal, Archit Kumar, Alka Sehgal, Devendra Bansal, Ali A. Sultan

Published in: Journal of Translational Medicine | Issue 1/2018

Abstract

Background

In the recent years Plasmodium vivax has been reported to cause severe infections associated with mortality. Clinical evaluation has limited accuracy for the early identification of the patients progressing towards the fatal condition. Researchers have tried to identify the serum and the plasma-based indicators of the severe malaria. Discovery of MicroRNA (miRNA) has opened up an era of identification of early biomarkers for various infectious and non-infectious diseases. MicroRNAs (miRNA) are the small non-coding RNA molecules of length 19–24 nts and are responsible for the regulation of the majority of human gene expressions at post transcriptional level.

Methods

We identified the differentially expressed miRNAs by microarray and validated the selected miRNAs by qRT-PCR. We assessed the diagnostic potential of these up-regulated miRNAs for complicated P. vivax malaria. Futher, the bioinformtic analysis was performed to construct protein–protein and mRNA–miRNA networks to identify highly regulated miRNA.

Results

In the present study, utility of miRNA as potential biomarker of complicated P. vivax malaria was explored. A total of 276 miRNAs were found to be differentially expressed by miRNA microarray and out of which 5 miRNAs (hsa-miR-7977, hsa-miR-28-3p, hsa-miR-378-5p, hsa-miR-194-5p and hsa-miR-3667-5p) were found to be significantly up-regulated in complicated P. vivax malaria patients using qRT-PCR. The diagnostic potential of these 5 miRNAs were found to be significant with sensitivity and specificity of 60–71% and 69–81% respectively and area under curve (AUC) of 0.7 (p < 0.05). Moreover, in silico analysis of the common targets of up-regulated miRNAs revealed UBA52 and hsa-miR-7977 as majorly regulated hubs in the PPI and mRNA–miRNA networks, suggesting their putative role in complicated P. vivax malaria.

Conclusion

miR-7977 might act as a potential biomarker for differentiating complicated P. vivax malaria from uncomplicated type. The elevated levels of miR-7977 may have a role to play in the disease pathology through UBA52 or TGF-beta signalling pathway.

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Wassmer SC, Taylor TE, Rathod PK, Mishra SK, Mohanty S, Arevalo-Herrera M, et al. Investigating the pathogenesis of severe malaria: a multidisciplinary and cross-geographical approach. Am J Trop Med Hyg. 2015;93(3 Suppl):42–56. https://doi.org/10.4269/ajtmh.14-0841.CrossRefPubMedPubMedCentral

World Health Organization. World Malaria Report 2017. Geneva: WHO; 2017. http://www.who.int/malaria/publications/world-malaria-report-2017/en/. Accessed 2 Jul 2018.

Im JH, Kwon HY, Baek J, Park SW, Durey A, Lee KH, et al. Severe Plasmodium vivax infection in Korea. Malaria J. 2017;16(1):51. https://doi.org/10.1186/s12936-017-1684-4.CrossRef

Rahimi BA, Thakkinstian A, White NJ, Sirivichayakul C, Dondorp AM, Chokejindachai W. Severe vivax malaria: a systematic review and meta-analysis of clinical studies since 1900. Malaria J. 2014;13(1):481. https://doi.org/10.1186/1475-2875-13-481.CrossRef

Kochar A, Kalra P, Sb V, Ukirade V, Chahar A, Kochar DK, et al. Retinopathy of vivax malaria in adults and its relation with severity parameters. Pathog Glob Health. 2016;110(4–5):185–93. https://doi.org/10.1080/20477724.2016.1213948.CrossRefPubMedPubMedCentral

White NJ, Pukrittayakamee S, Hien TT, Faiz MA, Mokuolu OA, Dondorp AM. Malaria. Lancet (London, England). 2014;383(9918):723–35. http://linkinghub.elsevier.com/retrieve/pii/S0140673613600240. Accessed 9 Jul 2018.

Kaur H, Sehgal R, Bansal D, Sultan AA, Bhalla A, Singhi SC. Development of visually improved loop mediated isothermal amplification for the diagnosis of Plasmodium vivax malaria in a tertiary hospital in Chandigarh, North India. Am J Trop Med Hyg. 2018;98(5):1374–81. https://doi.org/10.4269/ajtmh.17-0857.CrossRefPubMed

Prakash J, Singh AK, Kumar NS, Saxena RK. Acute renal failure in Plasmodium vivax malaria. J Assoc Physicians India. 2003;51:265–7.PubMed

Beg MA, Khan R, Baig SM, Gulzar Z, Hussain R, Smego RA. Cerebral involvement in benign tertian malaria. Am J Trop Med Hyg. 2002;67(3):230–2.CrossRef

10.

Lomar AV, Vidal JE, Lomar FP, Barbas CV, de Matos GJ, Boulos M. Acute respiratory distress syndrome due to vivax malaria: case report and literature review. Braz J Infect Dis. 2005;9(5):425–30.CrossRef

11.

Kochar DK, Das A, Kochar SK, Saxena V, Sirohi P, Garg S, et al. Severe Plasmodium vivax malaria: a report on serial cases from Bikaner in northwestern India. Am J Trop Med Hyg. 2009;80(2):194–8.CrossRef

12.

Kumari M, Ghildiyal R. Clinical profile of Plasmodium vivax malaria in children and study of severity parameters in relation to mortality: a tertiary care centre perspective in Mumbai, India. Malaria Res Treat. 2014;2014:765657. http://www.hindawi.com/journals/mrt/2014/765657/. Accessed 9 Jul 2018.

13.

Chamnanchanunt S, Fucharoen S, Umemura T. Circulating microRNAs in malaria infection: bench to bedside. Malaria J. 2017;16(1):334. https://doi.org/10.1186/s12936-017-1990-x.CrossRef

14.

Miotto P, Mwangoka G, Valente IC, Norbis L, Sotgiu G, Bosu R, et al. miRNA signatures in sera of patients with active pulmonary tuberculosis. PloS ONE. 2013;8(11):e80149. https://doi.org/10.1371/journal.pone.0080149.CrossRefPubMedPubMedCentral

15.

Verma P, Pandey RK, Prajapati P, Prajapati VK. Circulating microRNAs: potential and emerging biomarkers for diagnosis of human infectious diseases. Front Microbiol. 2016;7:1274. https://doi.org/10.3389/fmicb.2016.01274/abstract.CrossRefPubMedPubMedCentral

16.

Serafin A, Foco L, Blankenburg H, Picard A, Zanigni S, Zanon A, et al. Identification of a set of endogenous reference genes for miRNA expression studies in Parkinson’s disease blood samples. BMC Res Notes. 2014;7(1):715. https://doi.org/10.1186/1756-0500-7-715.CrossRefPubMedPubMedCentral

17.

Pordzik J, Pisarz K, De Rosa S, Jones AD, Eyileten C, Indolfi C, et al. The potential role of platelet-related microRNAs in the development of cardiovascular events in high-risk populations, including diabetic patients: a review. Front Endocrinol. 2018;9:74. https://doi.org/10.3389/fendo.2018.00074/full.CrossRef

18.

Qi Y, Cui L, Ge Y, Shi Z, Zhao K, Guo X, et al. Altered serum microRNAs as biomarkers for the early diagnosis of pulmonary tuberculosis infection. BMC Infect Dis. 2012;12(1):384. https://doi.org/10.1186/1471-2334-12-384.CrossRefPubMedPubMedCentral

19.

Zhao Q, Sun X, Liu C, Li T, Cui J, Qin C. Expression of the microRNA-143/145 cluster is decreased in hepatitis B virus-associated hepatocellular carcinoma and may serve as a biomarker for tumorigenesis in patients with chronic hepatitis B. Oncol Lett. 2018;15(5):6115–22. https://doi.org/10.3892/ol.2018.8117.CrossRefPubMedPubMedCentral

20.

Cohen A, Combes V, Grau GE. MicroRNAs and malaria—a dynamic interaction still incompletely understood. J Neuroinfect Dis. 2015;6(1):165.PubMed

21.

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(1):272. https://doi.org/10.1186/1756-3305-6-272.CrossRefPubMedPubMedCentral

22.

Tiwari N, Kumar V, Gedda MR, Singh AK, Singh VK, Gannavaram S, et al. Identification and characterization of miRNAs in response to Leishmania donovani infection: delineation of their roles in macrophage dysfunction. Front Microbiol. 2017;8:314. https://doi.org/10.3389/fmicb.2017.00314/full.CrossRefPubMedPubMedCentral

23.

Jia B, Chang Z, Wei X, Lu H, Yin J, Jiang N, et al. Plasma microRNAs are promising novel biomarkers for the early detection of Toxoplasma gondii infection. Parasit Vectors. 2014;7(1):433. https://doi.org/10.1186/1756-3305-7-433.CrossRefPubMedPubMedCentral

24.

Judice CC, Bourgard C, Kayano ACAV, Albrecht L, Costa FTM. MicroRNAs in the host-apicomplexan parasites interactions: a review of immunopathological aspects. Front Cell Infect Microbiol. 2016;6:5. https://doi.org/10.3389/fcimb.2016.00005/abstract.CrossRefPubMedPubMedCentral

25.

Thirugnanam S, Rout N, Gnanasekar M. Possible role of Toxoplasma gondii in brain cancer through modulation of host microRNAs. Infect Agents Cancer. 2013;8(1):8. https://doi.org/10.1186/1750-9378-8-8.CrossRefPubMedPubMedCentral

26.

Singh B, Bobogare A, Cox-Singh J, Snounou G, Abdullah MS, Rahman HA. A genus- and species-specific nested polymerase chain reaction malaria detection assay for epidemiologic studies. Am J Trop Med Hyg. 1999;60(4):687–92.CrossRef

27.

Han ETET, Watanabe R, Sattabongkot J, Khuntirat B, Sirichaisinthop J, Iriko H, et al. Detection of four Plasmodium species by genus- and species-specific loop-mediated isothermal amplification for clinical diagnosis. J Clin Microbiol. 2007;45(8):2521–8.CrossRef

28.

World Health Organization (WHO). Management of severe malaria—a practical handbook, 3th edition. WHO; 2012. http://www.who.int/malaria/publications/atoz/9789241548526/en/. Accessed 9 Jul 2018.

29.

Parsi S, Soltani BM, Hosseini E, Tousi SE, Mowla SJ. Experimental verification of a predicted intronic microRNA in human NGFR gene with a potential pro-apoptotic function. PloS ONE. 2012;7(4):e35561. https://doi.org/10.1371/journal.pone.0035561.CrossRefPubMedPubMedCentral

30.

McDermott AM, Kerin MJ, Miller N. Identification and validation of miRNAs as endogenous controls for RQ-PCR in blood specimens for breast cancer studies. PloS ONE. 2013;8(12):e83718. https://doi.org/10.1371/journal.pone.0083718.CrossRefPubMedPubMedCentral

31.

Zhao H, Ma T-F, Lin J, Liu L-L, Sun W-J, Guo L-X, et al. Identification of valid reference genes for mRNA and microRNA normalisation in prostate cancer cell lines. Scientific Rep. 2018;8(1):1949. http://www.nature.com/articles/s41598-018-19458-z. Accessed 3 Jul 2018.

32.

Agarwal V, Bell GW, Nam J-W, Bartel DP. Predicting effective microRNA target sites in mammalian mRNAs. eLife. 2015;4:e05005. https://elifesciences.org/articles/05005. Accessed 3 Jul 2018.

33.

Jiao X, Sherman BT, Huang DW, Stephens R, Baseler MW, Lane HC, et al. DAVID-WS: a stateful web service to facilitate gene/protein list analysis. Bioinformatics. 2012;28(13):1805–6.CrossRef

34.

Szklarczyk D, Morris JH, Cook H, Kuhn M, Wyder S, Simonovic M, et al. The STRING database in 2017: quality-controlled protein-protein association networks, made broadly accessible. Nucleic Acids Res. 2017;45(D1):D362–8. https://doi.org/10.1093/nar/gkw937.CrossRef

35.

Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003;13(11):2498–504.CrossRef

36.

Price RN, Tjitra E, Guerra CA, Yeung S, White NJ, Anstey NM. Vivax malaria: neglected and not benign. Am J Trop Med Hyg. 2007;77(6 Suppl):79–87.CrossRef

37.

Naing C, Whittaker MA, Nyunt Wai V, Mak JW. Is Plasmodium vivax malaria a severe malaria? A systematic review and meta-analysis. PLoS Negl Trop Dis. 2014;8(8):e3071. https://doi.org/10.1371/journal.pntd.0003071.CrossRefPubMedPubMedCentral

38.

Ray S, Patel SK, Venkatesh A, Bhave A, Kumar V, Singh V, et al. Clinicopathological analysis and multipronged quantitative proteomics reveal oxidative stress and cytoskeletal proteins as possible markers for severe vivax malaria. Scientific Rep. 2016;6(1):24557. http://www.nature.com/articles/srep24557. Accessed 4 Jul 2018.

39.

Rubio M, Bassat Q, Estivill X, Mayor A. Tying malaria and microRNAs: from the biology to future diagnostic perspectives. Malar J. 2016;15(1):167.CrossRef

40.

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(4):e0005365. https://doi.org/10.1371/journal.pntd.0005365.CrossRefPubMedPubMedCentral

41.

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. http://linkinghub.elsevier.com/retrieve/pii/S0014489415001022. Accessed 3 Jul 2018.CrossRef

42.

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(2):187–99.CrossRef

43.

Delić D, Dkhil M, Al-Quraishy S, Wunderlich F. Hepatic miRNA expression reprogrammed by Plasmodium chabaudi malaria. Parasitol Res. 2011;108(5):1111–21. https://doi.org/10.1007/s00436-010-2152-z.CrossRefPubMed

44.

El-Assaad F, Hempel C, Combes V, Mitchell AJ, Ball HJ, Kurtzhals JAL, et al. Differential microRNA expression in experimental cerebral and noncerebral malaria. Infect Immun. 2011;79(6):2379–84. https://doi.org/10.1128/iai.01136-10.CrossRefPubMedPubMedCentral

45.

Wang Z, Xi J, Hao X, Deng W, Liu J, Wei C, et al. Red blood cells release microparticles containing human argonaute 2 and miRNAs to target genes of Plasmodium falciparum. Emerg Microbes Infect. 2017;6(8):e75.CrossRef

46.

Barker KR, Lu Z, Kim H, Zheng Y, Chen J, Conroy AL, et al. miR-155 modifies inflammation, endothelial activation and blood-brain barrier dysfunction in cerebral malaria. Mol Med. 2017;23(1):1. http://www.molmed.org/content/pdfstore/16_139_Barker.pdf. Accessed 4 Jul 2018.

47.

Burel JG, Apte SH, Groves PL, Boyle MJ, Langer C, Beeson JG, et al. Dichotomous miR expression and immune responses following primary blood-stage malaria. JCI Insight. 2017;2(15). https://insight.jci.org/articles/view/93434. Accessed 4 Jul 2018.

48.

Chamnanchanunt S, Fucharoen S, Umemura T. Circulating microRNAs in malaria infection: bench to bedside. Malaria J. 2017;16(1):334. https://doi.org/10.1186/s12936-017-1990-x.CrossRef

49.

Oturai DB, Søndergaard HB, Börnsen L, Sellebjerg F, Christensen JR. Identification of suitable reference genes for peripheral blood mononuclear cell subset studies in multiple sclerosis. Scand J Immunol. 2016;83(1):72–80. https://doi.org/10.1111/sji.12391.CrossRefPubMed

50.

Panichakul T, Ponnikorn S, Roytrakul S, Paemanee A, Kittisenachai S, Hongeng S, et al. Plasmodium vivax inhibits erythroid cell growth through altered phosphorylation of the cytoskeletal protein ezrin. Malaria J. 2015;14(1):138. http://www.malariajournal.com/content/14/1/138. Accessed 4 Jul 2018.

51.

Wickramasinghe SN, Looareesuwan S, Nagachinta B, White NJ. Dyserythropoiesis and ineffective erythropoiesis in Plasmodium vivax malaria. Br J Haematol. 1989;72(1):91–9.CrossRef

52.

Panichakul T, Payuhakrit W, Panburana P, Wongborisuth C, Hongeng S, Udomsangpetch R. Suppression of erythroid development in vitro by Plasmodium vivax. Malaria J. 2012;11(1):173. https://doi.org/10.1186/1475-2875-11-173.CrossRef

53.

Horiguchi H, Kobune M, Kikuchi S, Yoshida M, Murata M, Murase K, et al. Extracellular vesicle miR-7977 is involved in hematopoietic dysfunction of mesenchymal stromal cells via poly(rC) binding protein 1 reduction in myeloid neoplasms. Haematologica. 2016;101(4):437–47. https://doi.org/10.3324/haematol.2015.134932.CrossRefPubMedPubMedCentral

54.

Wahl SM, McCartney-Francis N, Mergenhagen SE. Inflammatory and immunomodulatory roles of TGF-beta. Immunol Today. 1989;10(8):258–61.CrossRef

55.

Omer FM, Riley EM. Transforming growth factor beta production is inversely correlated with severity of murine malaria infection. J Exp Med. 1998;188(1):39–48.CrossRef

56.

Chaves YO, da Costa AG, Pereira MLM, de Lacerda MVG, Coelho-Dos-Reis JG, Martins-Filho OA, et al. Immune response pattern in recurrent Plasmodium vivax malaria. Malaria J. 2016;15(1):445. https://doi.org/10.1186/s12936-016-1501-5.CrossRef

57.

Wenisch C, Parschalk B, Burgmann H, Looareesuwan S, Graninger W. Decreased serum levels of TGF-beta in patients with acute Plasmodium falciparum malaria. J Clin Immunol. 1995;15(2):69–73.CrossRef

58.

Perkins DJ, Weinberg JB, Kremsner PG. Reduced interleukin-12 and transforming growth factor-beta1 in severe childhood malaria: relationship of cytokine balance with disease severity. J Infect Dis. 2000;182(3):988–92. https://doi.org/10.1086/315762.CrossRefPubMed

59.

Coulson RMR, Hall N, Ouzounis CA. Comparative genomics of transcriptional control in the human malaria parasite Plasmodium falciparum. Genome Res. 2004;14(8):1548–54.CrossRef

60.

Hall N, Carlton J. Comparative genomics of malaria parasites. Curr Opin Genet Dev. 2005;15(6):609–13.CrossRef

61.

Kobayashi M, Oshima S, Maeyashiki C, Nibe Y, Otsubo K, Matsuzawa Y, et al. The ubiquitin hybrid gene UBA52 regulates ubiquitination of ribosome and sustains embryonic development. Scientific Rep. 2016;6(1):36780. http://www.nature.com/articles/srep36780. Accessed 4 Jul 2018.

62.

Venny. Venny 2.1.0. http://bioinfogp.cnb.csic.es/tools/venny/. Accessed 3 Jul 2018.

Title: Screening and identification of potential novel biomarker for diagnosis of complicated Plasmodium vivax malaria
Authors: Hargobinder Kaur
Rakesh Sehgal
Archit Kumar
Alka Sehgal
Devendra Bansal
Ali A. Sultan
Publication date: 01-12-2018
Publisher: BioMed Central
Published in: Journal of Translational Medicine / Issue 1/2018
Electronic ISSN: 1479-5876
DOI: https://doi.org/10.1186/s12967-018-1646-9

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