During the last decade, the epidemiology of WNV in humans has changed in the southern regions of Europe, with high incidence of West Nile fever (WNF) cases, but also of West Nile neuroinvasive disease (WNND). The lack of human vaccine or specific treatment against WNV infection imparts a pressing need to characterize indicators associated with neurological involvement. By its intimacy with central nervous system (CNS) structures, modifications in the cerebrospinal fluid (CSF) composition could accurately reflect CNS pathological process. Until now, few studies investigated the association between imbalance of CSF elements and severity of WNV infection. The aim of the present study was to apply the iTRAQ technology in order to identify the CSF proteins whose abundances are modified in patients with WNND. Forty-seven proteins were found modified in the CSF of WNND patients as compared to control groups, and most of them are reported for the first time in the context of WNND. On the basis of their known biological functions, several of these proteins were associated with inflammatory response. Among them, Defensin-1 alpha (DEFA1), a protein reported with anti-viral effects, presented the highest increasing fold-change (FC>12). The augmentation of DEFA1 abundance in patients with WNND was confirmed at the CSF, but also in serum, compared to the control individual groups. Furthermore, the DEFA1 serum level was significantly elevated in WNND patients compared to subjects diagnosed for WNF. The present study provided the first insight into the potential CSF biomarkers associated with WNV neuroinvasion. Further investigation in larger cohorts with kinetic sampling could determine the usefulness of measuring DEFA1 as diagnostic or prognostic biomarker of detrimental WNND evolution.
References
[1]
Weissenbock H, Hubalek Z, Bakonyi T, Nowotny N (2010) Zoonotic mosquito-borne flaviviruses: worldwide presence of agents with proven pathogenicity and potential candidates of future emerging diseases. Vet Microbiol 140: 271–280. doi: 10.1016/j.vetmic.2009.08.025
[2]
Jeffrey Root J (2013) West Nile virus associations in wild mammals: a synthesis. Arch Virol 158: 735–752. doi: 10.1007/s00705-012-1516-3
[3]
Rossi SL, Ross TM, Evans JD (2010) West Nile virus. Clin Lab Med 30: 47–65. doi: 10.1016/j.cll.2009.10.006
[4]
Omalu BI, Shakir AA, Wang G, Lipkin WI, Wiley CA (2003) Fatal fulminant pan-meningo-polioencephalitis due to West Nile virus. Brain Pathol 13: 465–472. doi: 10.1111/j.1750-3639.2003.tb00477.x
[5]
De Filette M, Ulbert S, Diamond M, Sanders NN (2012) Recent progress in West Nile virus diagnosis and vaccination. Vet Res 43: 16. doi: 10.1186/preaccept-1716579776622450
[6]
Sambri V, Capobianchi M, Charrel R, Fyodorova M, Gaibani P, et al.. (2013) West Nile virus in Europe: emergence, epidemiology, diagnosis, treatment, and prevention. Clin Microbiol Infect.
[7]
Papa A, Danis K, Baka A, Bakas A, Dougas G, et al.. (2010) Ongoing outbreak of West Nile virus infections in humans in Greece, July-August 2010. Euro Surveill 15.
[8]
Danis K, Papa A, Theocharopoulos G, Dougas G, Athanasiou M, et al. (2011) Outbreak of West Nile virus infection in Greece, 2010. Emerg Infect Dis 17: 1868–1872. doi: 10.3201/eid1710.110525
[9]
Rizzo C, Salcuni P, Nicoletti L, Ciufolini MG, Russo F, et al.. (2012) Epidemiological surveillance of West Nile neuroinvasive diseases in Italy, 2008 to 2011. Euro Surveill 17.
[10]
Papa A (2012) West Nile virus infections in Greece: an update. Expert Rev Anti Infect Ther 10: 743–750. doi: 10.1586/eri.12.59
[11]
Neghina AM, Neghina R (2011) Reemergence of human infections with West Nile virus in Romania, 2010: an epidemiological study and brief review of the past situation. Vector Borne Zoonotic Dis 11: 1289–1292. doi: 10.1089/vbz.2010.0206
[12]
Paz S, Semenza JC (2013) Environmental drivers of west nile Fever epidemiology in europe and Western Asia-a review. Int J Environ Res Public Health 10: 3543–3562. doi: 10.3390/ijerph10083543
[13]
Beasley DW, Barrett AD, Tesh RB (2013) Resurgence of West Nile neurologic disease in the United States in 2012: What happened? What needs to be done? Antiviral Res.
[14]
Hamdan A, Green P, Mendelson E, Kramer MR, Pitlik S, et al. (2002) Possible benefit of intravenous immunoglobulin therapy in a lung transplant recipient with West Nile virus encephalitis. Transpl Infect Dis 4: 160–162. doi: 10.1034/j.1399-3062.2002.01014.x
[15]
Shimoni Z, Niven MJ, Pitlick S, Bulvik S (2001) Treatment of West Nile virus encephalitis with intravenous immunoglobulin. Emerg Infect Dis 7: 759. doi: 10.3201/eid0704.017432
[16]
Loginova S, Borisevich SV, Pashchenko Iu A, Bondarev VP (2009) [Ribavirin prophylaxis and therapy of experimental West Nile fever]. Antibiot Khimioter 54: 17–20.
[17]
Jordan I, Briese T, Fischer N, Lau JY, Lipkin WI (2000) Ribavirin inhibits West Nile virus replication and cytopathic effect in neural cells. J Infect Dis 182: 1214–1217. doi: 10.1086/315847
[18]
Kalil AC, Devetten MP, Singh S, Lesiak B, Poage DP, et al. (2005) Use of interferon-alpha in patients with West Nile encephalitis: report of 2 cases. Clin Infect Dis 40: 764–766. doi: 10.1086/427945
[19]
Sayao AL, Suchowersky O, Al-Khathaami A, Klassen B, Katz NR, et al. (2004) Calgary experience with West Nile virus neurological syndrome during the late summer of 2003. Can J Neurol Sci 31: 194–203.
[20]
Dauphin G, Zientara S (2007) West Nile virus: recent trends in diagnosis and vaccine development. Vaccine 25: 5563–5576. doi: 10.1016/j.vaccine.2006.12.005
[21]
Lim SM, Koraka P, Osterhaus AD, Martina BE (2011) West Nile virus: immunity and pathogenesis. Viruses 3: 811–828. doi: 10.3390/v3060811
[22]
Miller F, Afonso PV, Gessain A, Ceccaldi PE (2012) Blood-brain barrier and retroviral infections. Virulence 3: 222–229. doi: 10.4161/viru.19697
[23]
Shahim P, Mansson JE, Darin N, Zetterberg H, Mattsson N (2013) Cerebrospinal fluid biomarkers in neurological diseases in children. Eur J Paediatr Neurol 17: 7–13. doi: 10.1016/j.ejpn.2012.09.005
[24]
Colpitts TM, Conway MJ, Montgomery RR, Fikrig E (2012) West Nile Virus: biology, transmission, and human infection. Clin Microbiol Rev 25: 635–648. doi: 10.1128/cmr.00045-12
[25]
Kapoor H, Signs K, Somsel P, Downes FP, Clark PA, et al. (2004) Persistence of West Nile Virus (WNV) IgM antibodies in cerebrospinal fluid from patients with CNS disease. J Clin Virol 31: 289–291. doi: 10.1016/j.jcv.2004.05.017
[26]
Carson PJ, Steidler T, Patron R, Tate JM, Tight R, et al. (2003) Plasma cell pleocytosis in cerebrospinal fluid in patients with West Nile virus encephalitis. Clin Infect Dis 37: e12–15. doi: 10.1086/375692
[27]
Tyler KL, Pape J, Goody RJ, Corkill M, Kleinschmidt-DeMasters BK (2006) CSF findings in 250 patients with serologically confirmed West Nile virus meningitis and encephalitis. Neurology 66: 361–365. doi: 10.1212/01.wnl.0000195890.70898.1f
[28]
Crichlow R, Bailey J, Gardner C (2004) Cerebrospinal fluid neutrophilic pleocytosis in hospitalized West Nile virus patients. J Am Board Fam Pract 17: 470–472. doi: 10.3122/jabfm.17.6.470
[29]
Jordan M, Nagpal A, Newman W, Thompson PA, Carson PJ (2012) Plasma cell cerebrospinal fluid pleocytosis does not predict West Nile virus infection. J Biomed Biotechnol 2012: 697418. doi: 10.1155/2012/697418
[30]
Petzold A, Groves M, Leis AA, Scaravilli F, Stokic DS (2010) Neuronal and glial cerebrospinal fluid protein biomarkers are elevated after West Nile virus infection. Muscle Nerve 41: 42–49. doi: 10.1002/mus.21448
[31]
Leis AA, Stokic DS, Petzold A (2012) Glial S100B is elevated in serum across the spectrum of West Nile virus infection. Muscle Nerve 45: 826–830. doi: 10.1002/mus.23241
[32]
Abdi F, Quinn JF, Jankovic J, McIntosh M, Leverenz JB, et al. (2006) Detection of biomarkers with a multiplex quantitative proteomic platform in cerebrospinal fluid of patients with neurodegenerative disorders. J Alzheimers Dis 9: 293–348.
[33]
Schutzer SE, Angel TE, Liu T, Schepmoes AA, Clauss TR, et al. (2011) Distinct cerebrospinal fluid proteomes differentiate post-treatment lyme disease from chronic fatigue syndrome. PLoS One 6: e17287. doi: 10.1371/journal.pone.0017287
[34]
Gonzalez H, Ottervald J, Nilsson KC, Sjogren N, Miliotis T, et al. (2009) Identification of novel candidate protein biomarkers for the post-polio syndrome - implications for diagnosis, neurodegeneration and neuroinflammation. J Proteomics 71: 670–681. doi: 10.1016/j.jprot.2008.11.014
[35]
Laspiur JP, Anderson ER, Ciborowski P, Wojna V, Rozek W, et al. (2007) CSF proteomic fingerprints for HIV-associated cognitive impairment. J Neuroimmunol 192: 157–170. doi: 10.1016/j.jneuroim.2007.08.004
[36]
Unwin RD, Griffiths JR, Whetton AD (2010) Simultaneous analysis of relative protein expression levels across multiple samples using iTRAQ isobaric tags with 2D nano LC-MS/MS. Nat Protoc 5: 1574–1582. doi: 10.1038/nprot.2010.123
[37]
Briolant S, Almeras L, Belghazi M, Boucomont-Chapeaublanc E, Wurtz N, et al. (2010) Plasmodium falciparum proteome changes in response to doxycycline treatment. Malar J 9: 141. doi: 10.1186/1475-2875-9-141
[38]
Fraisier C, Rodrigues R, Hai VV, Belghazi M, Bourdon S, et al.. (2013) Hepatocyte pathway alterations in response to in vitro Crimean Congo hemorrhagic fever virus infection. Virus Res (in press).
[39]
Fraisier C, Camoin L, Lim S, Bakli M, Belghazi M, et al. (2013) Altered protein networks and cellular pathways in severe west nile disease in mice. PLoS One 8: e68318. doi: 10.1371/journal.pone.0068318
[40]
Diamond MS, Shrestha B, Marri A, Mahan D, Engle M (2003) B cells and antibody play critical roles in the immediate defense of disseminated infection by West Nile encephalitis virus. J Virol 77: 2578–2586. doi: 10.1128/jvi.77.4.2578-2586.2003
[41]
Prince HE, Lape-Nixon M (2005) Evaluation of a West Nile virus immunoglobulin A capture enzyme-linked immunosorbent assay. Clin Diagn Lab Immunol 12: 231–233. doi: 10.1128/cdli.12.1.231-233.2005
[42]
Nixon ML, Prince HE (2006) West Nile virus immunoglobulin A (WNV IgA) detection in cerebrospinal fluid in relation to WNV IgG and IgM reactivity. J Clin Virol 37: 174–178. doi: 10.1016/j.jcv.2006.07.005
[43]
Busch MP, Kleinman SH, Tobler LH, Kamel HT, Norris PJ, et al. (2008) Virus and antibody dynamics in acute west nile virus infection. J Infect Dis 198: 984–993. doi: 10.1086/591467
[44]
Shores KS, Knapp DR (2007) Assessment approach for evaluating high abundance protein depletion methods for cerebrospinal fluid (CSF) proteomic analysis. J Proteome Res 6: 3739–3751. doi: 10.1021/pr070293w
[45]
Agerberth B, Charo J, Werr J, Olsson B, Idali F, et al. (2000) The human antimicrobial and chemotactic peptides LL-37 and alpha-defensins are expressed by specific lymphocyte and monocyte populations. Blood 96: 3086–3093.
[46]
Ganz T, Lehrer RI (1994) Defensins. Curr Opin Immunol 6: 584–589. doi: 10.1016/0952-7915(94)90145-7
[47]
Niyonsaba F, Nagaoka I, Ogawa H (2006) Human defensins and cathelicidins in the skin: beyond direct antimicrobial properties. Crit Rev Immunol 26: 545–576. doi: 10.1615/critrevimmunol.v26.i6.60
[48]
Jarczak J, Kosciuczuk EM, Lisowski P, Strzalkowska N, Jozwik A, et al. (2013) Defensins: Natural component of human innate immunity. Hum Immunol 74: 1069–1079. doi: 10.1016/j.humimm.2013.05.008
[49]
Daher KA, Selsted ME, Lehrer RI (1986) Direct inactivation of viruses by human granulocyte defensins. J Virol 60: 1068–1074.
[50]
Salvatore M, Garcia-Sastre A, Ruchala P, Lehrer RI, Chang T, et al. (2007) alpha-Defensin inhibits influenza virus replication by cell-mediated mechanism(s). J Infect Dis 196: 835–843. doi: 10.1086/521027
[51]
Flores Anticona EM, Zainah H, Ouellette DR, Johnson LE (2012) Two case reports of neuroinvasive west nile virus infection in the critical care unit. Case Rep Infect Dis 2012: 839458. doi: 10.1155/2012/839458
[52]
Lee S, Kim JH, Seo JW, Han HS, Lee WH, et al. (2011) Lipocalin-2 Is a chemokine inducer in the central nervous system: role of chemokine ligand 10 (CXCL10) in lipocalin-2-induced cell migration. J Biol Chem 286: 43855–43870. doi: 10.1074/jbc.m111.299248
[53]
Bi F, Huang C, Tong J, Qiu G, Huang B, et al. (2013) Reactive astrocytes secrete lcn2 to promote neuron death. Proc Natl Acad Sci U S A 110: 4069–4074. doi: 10.1073/pnas.1218497110
[54]
Berard JL, Zarruk JG, Arbour N, Prat A, Yong VW, et al. (2012) Lipocalin 2 is a novel immune mediator of experimental autoimmune encephalomyelitis pathogenesis and is modulated in multiple sclerosis. Glia 60: 1145–1159. doi: 10.1002/glia.22342
[55]
Marques F, Mesquita SD, Sousa JC, Coppola G, Gao F, et al. (2012) Lipocalin 2 is present in the EAE brain and is modulated by natalizumab. Front Cell Neurosci 6: 33. doi: 10.3389/fncel.2012.00033
[56]
Marques F, Rodrigues AJ, Sousa JC, Coppola G, Geschwind DH, et al. (2008) Lipocalin 2 is a choroid plexus acute-phase protein. J Cereb Blood Flow Metab 28: 450–455. doi: 10.1038/sj.jcbfm.9600557
[57]
Chakraborty S, Kaur S, Guha S, Batra SK (2012) The multifaceted roles of neutrophil gelatinase associated lipocalin (NGAL) in inflammation and cancer. Biochim Biophys Acta 1826: 129–169. doi: 10.1016/j.bbcan.2012.03.008
[58]
Gasche Y, Soccal PM, Kanemitsu M, Copin JC (2006) Matrix metalloproteinases and diseases of the central nervous system with a special emphasis on ischemic brain. Front Biosci 11: 1289–1301. doi: 10.2741/1883
[59]
Thibert KA, Raymond GV, Nascene DR, Miller WP, Tolar J, et al. (2012) Cerebrospinal fluid matrix metalloproteinases are elevated in cerebral adrenoleukodystrophy and correlate with MRI severity and neurologic dysfunction. PLoS One 7: e50430. doi: 10.1371/journal.pone.0050430
[60]
Sathyanesan M, Girgenti MJ, Banasr M, Stone K, Bruce C, et al. (2012) A molecular characterization of the choroid plexus and stress-induced gene regulation. Transl Psychiatry 2: e139. doi: 10.1038/tp.2012.64
[61]
Sharma A, Bhomia M, Honnold SP, Maheshwari RK (2011) Role of adhesion molecules and inflammation in Venezuelan equine encephalitis virus infected mouse brain. Virol J 8: 197. doi: 10.1186/1743-422x-8-197
[62]
Srikrishna G (2012) S100A8 and S100A9: new insights into their roles in malignancy. J Innate Immun 4: 31–40. doi: 10.1159/000330095
[63]
Nacken W, Roth J, Sorg C, Kerkhoff C (2003) S100A9/S100A8: Myeloid representatives of the S100 protein family as prominent players in innate immunity. Microsc Res Tech 60: 569–580. doi: 10.1002/jemt.10299
[64]
Markowitz J, Carson WE 3rd (2013) Review of S100A9 biology and its role in cancer. Biochim Biophys Acta 1835: 100–109. doi: 10.1016/j.bbcan.2012.10.003
[65]
Poynton RA, Hampton MB (2013) Peroxiredoxins as biomarkers of oxidative stress. Biochim Biophys Acta.
[66]
Bayer SB, Maghzal G, Stocker R, Hampton MB, Winterbourn CC (2013) Neutrophil-mediated oxidation of erythrocyte peroxiredoxin 2 as a potential marker of oxidative stress in inflammation. FASEB J 27: 3315–3322. doi: 10.1096/fj.13-227298
[67]
Botia B, Seyer D, Ravni A, Benard M, Falluel-Morel A, et al. (2008) Peroxiredoxin 2 is involved in the neuroprotective effects of PACAP in cultured cerebellar granule neurons. J Mol Neurosci 36: 61–72. doi: 10.1007/s12031-008-9075-5
