Identification of a novel infection-enhancing epitope on dengue prM using a dengue cross-reacting monoclonal antibody

BMC Microbiology

Li-Fang Jiang¹  Gu-Cheng Zeng¹  Hui-Jun Yan¹  Dan-Yun Fang¹  Zhi-Zhun Yu¹  Jun-Mei Zhou¹  Jun-Jie Feng¹  Ya-Yan Luo¹ 

[1] Key Laboratory for Tropic Diseases Control, Ministry of Education of China, Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China

关键词: Antibody-dependent enhancement;    Phage display peptide library;    Epitope;    prM protein;    Dengue virus;   

Others  :  1143174
DOI  :  10.1186/1471-2180-13-194

 received in 2013-04-24, accepted in 2013-08-26,  发布年份 2013

【 摘 要 】

Background

Dengue virus (DENV) infection is the most important arthropod- borne viral disease in human, but antiviral therapy and approved vaccines remain unavailable due to antibody-dependent enhancement (ADE) phenomenon. Many studies showed that pre-membrane (prM)-specific antibodies do not efficiently neutralize DENV infection but potently promote ADE infection. However, most of the binding epitopes of these antibodies remain unknown.

Results

In the present study, we characterized a DENV cross-reactive monoclonal antibody (mAb), 4D10, that neutralized poorly but potently enhanced infection of four standard DENV serotypes and immature DENV (imDENV) over a broad range of concentration. In addition, the epitope of 4D10 was successfully mapped to amino acid residues 14 to18 of DENV1-4 prM protein using a phage-displayed peptide library and comprehensive bioinformatics analysis. We found that the epitope was DENV serocomplex cross-reactive and showed to be highly immunogenic in Balb/c mice. Furthermore, antibody against epitope peptide PL10, like 4D10, showed broad cross-reactivity and weak neutralizing activtity with four standard DENV serotypes and imDENV but significantly promoted ADE infection. These results suggested 4D10 and anti-PL10 sera were infection-enhancing antibodies and PL10 was infection-enhancing epitope.

Conclusions

We mapped the epitope of 4D10 to amino acid residues 14 to18 of DENV1-4 prM and found that this epitope was infection-enhancing. These findings may provide significant implications for future vaccine design and facilitate understanding the pathogenesis of DENV infection.

【 授权许可】

   
2013 Luo et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

Figure 7.

Figure 8.

【 参考文献 】

• [1]Bhatt S, Gething PW, Brady OJ, Messina JP, Farlow AW, Moyes CL, Drake JM, Brownstein JS, Hoen AG, Sankoh O, Myers MF, George DB, Jaenisch T, Wint GR, Simmons CP, Scott TW, Farrar JJ, Hay SI: The global distribution and burden of dengue. Nature 2013, 496:504-507.
• [2]Krishnan N, Purswani M, Hagmann S: Severe Dengue Virus Infection in Pediatric Travelers Visiting Friends and Relatives after Travel to the Caribbean. Am J Trop Med Hyg 2012, 86:474-476.
• [3]Coller BG, Clements DE: Dengue vaccines: progress and challenges. Curr Opin Immunol 2011, 23:1-8.
• [4]Miller N: Recent progress in dengue vaccine research and development. Curr Opin Mol Ther 2010, 12:31-38.
• [5]Halstead SB, Lan NT, Myint TT, Shwe TN, Nisalak A, Kalyanarooj S, Nimmannitya S, Soegijanto S, Vaughn DW, Endy TP: Dengue hemorrhagic fever in infants: research opportunities ignored. Emerg Infect Dis 2002, 8:1474-1479.
• [6]Kliks SC, Nisalak A, Brandt WE, Wahl L, Burke DS: Antibody-dependent enhancement of dengue virus growth in human monocytes as a risk factor for dengue hemorrhagic fever. Am J Trop Med Hyg 1989, 40:444-451.
• [7]Halstead SB, O’Rourke EJ: Antibody-enhanced dengue virus infection in primate leukocytes. Nature 1977, 265:739-741.
• [8]Halstead SB: Neutralization and antibody-dependent enhancement of dengue viruses. Adv Virus Res 1977, 60:421-467.
• [9]Guy B, Almond J, Lang J: Dengue vaccine prospects: a step forward. Lancet 2011, 377:381-382.
• [10]Tang Y, Kou Z, Zhang F, Yao X, Liu S, Ma J, Zhou Y, Zhao W, Tang X, Jin X: Both Viremia and Cytokine Levels Associate with the Lack of Severe Disease in Secondary Dengue 1 Infection among Adult Chinese Patients. PLoS One 2010, 5:e15631.
• [11]Libraty DH, Acosta LP, Tallo V, Segubre-Mercado E, Bautista A, Potts JA, Jarman RG, Yoon IK, Gibbons RV, Brion JD, Capeding RZ: A prospective nested case–control study of dengue in infants: rethinking and refining the antibody-dependent enhancement dengue hemorrhagic fever model. PLoS Med 2009, 6:e1000171.
• [12]Mohammed H, Linnen JM, Muñoz-Jordán JL, Tomashek K, Foster G, Broulik AS, Petersen L, Stramer SL: Dengue virus in blood donations, Puerto Rico, 2005. Transfusion 2008, 48:1348-1354.
• [13]Halstead SB: In vivo enhancement of dengue virus infection in rhesus monkeys by passively transferred antibody. J Infect Dis 1979, 140:527-533.
• [14]Goncalvez AP, Engle RE, St Claire M, Purcell RH, Lai CJ: Monoclonal antibody- mediated enhancement of dengue virus infection in vitro and in vivo and strategies for prevention. Proc Natl Acad Sci USA 2007, 104:9422-9427.
• [15]Balsitis SJ, Williams KL, Lachica R, Flores D, Kyle JL, Mehlhop E, Johnson S, Diamond MS, Beatty PR, Harris E: Lethal antibody enhancement of dengue disease in mice is prevented by Fc modification. PLoS Pathog 2010, 6:e1000790.
• [16]Anandarao R, Swaminathan S, Khanna N: The identification of immunodominant linear epitopes of dengue type 2 virus capsid and NS4a proteins using pin-bound peptides. Virus Res 2005, 112:60-68.
• [17]Mukhopadhyay S, Kuhn RJ, Rossmann MG: A structural perspective of the flavivirus life cycle. Nat Rev Microbiol 2005, 3:13-22.
• [18]Lorenz IC, Allison SL, Heinz FX, Helenius A: Folding and dimerization of tick-borne encephalitis virus envelope proteins prM and E in the endoplasmic reticulum. J Virol 2002, 76:5480-5491.
• [19]Mackenzie JM, Westaway EG: Assembly and maturation of the flavivirus Kunjin virus appear to occur in the rough endoplasmic reticulum and along the secretory pathway, respectively. J Virol 2001, 75:10787-10799.
• [20]Yu IM, Zhang W, Holdaway HA, Li L, Kostyuchenko VA, Chipman PR, Kuhn RJ, Rossmann MG, Chen J: Structure of the immature dengue virus at low pH primes proteolytic maturation. Science 2008, 319:1834-1837.
• [21]Bray M, Lai CJ: Dengue virus premembrane and membrane proteins elicit a protective immune response. Virology 1991, 185:505-508.
• [22]Cardosa MJ, Wang SM, Sum MS, Tio PH: Antibodies against prM protein distinguish between previous infection with dengue and Japanese encephalitis viruses. BMC Microbiol 2002, 2:9. BioMed Central Full Text
• [23]Se-Thoe SY, Ng MM, Ling AE: Retrospective study of Western blot profiles in immune sera of natural dengue virus infections. J Med Virol 1999, 57:322-330.
• [24]Dejnirattisai W, Jumnainsong A, Onsirisakul N, Fitton P, Vasanawathana S, Limpitikul W, Puttikhunt C, Edwards C, Duangchinda T, Supasa S, Chawansuntati K, Malasit P, Mongkolsapaya J, Screaton G: Cross-reacting antibodies enhance dengue virus infection in humans. Science 2010, 328:745-748.
• [25]Lai CY, Tsai WY, Lin SR, Kao CL, Hu HP, King CC, Wu HC, Chang GJ, Wang WK: Antibodies to envelope glycoprotein of dengue virus during the natural course of infection are predominantly cross-reactive and recognize epitopes containing highly conserved residues at the fusion loop of domain II. J Virol 2008, 82:6631-6643.
• [26]Beltramello M, Williams KL, Simmons CP, Macagno A, Simonelli L, Quyen NT, Sukupolvi-Petty S, Navarro-Sanchez E, Young PR, de Silva AM, Rey FA, Varani L, Whitehead SS, Diamond MS, Harris E, Lanzavecchia A, Sallusto F: The human immune response to Dengue virus is dominated by highly cross-reactive antibodies endowed with neutralizing and enhancing activity. Cell Host Microbe 2010, 8:271-283.
• [27]Rodenhuis-Zybert IA, van der Schaar HM, da Silva Voorham JM, van der Ende-Metselaar H, Lei HY, Wilschut J, Smit JM: Immature dengue virus: a veiled pathogen? PLoS Pathog 2010, 6:e1000718.
• [28]Chan AH, Tan HC, Chow AY, Lim AP, Lok SM, Moreland NJ, Vasudevan SG, MacAry PA, Ooi EE, Hanson BJ: A human PrM antibody that recognizes a novel cryptic epitope on dengue E glycoprotein. PLoS One 2012, 7:e33451.
• [29]Chau TN, Hieu NT, Anders KL, Wolbers M, Lien LB, Hieu LT, Hien TT, Hung NT, Farrar J, Whitehead S, Simmons CP: Dengue virus infections and maternal antibody decay in a prospective birth cohort study of Vietnamese infants. J Infect Dis 2009, 200:1893-1900.
• [30]Huang KJ, Yang YC, Lin YS, Liu HS, Yeh TM, Chen SH, Liu CC, Lei HY: Flow Cytometric Determination for Dengue Virus-Infected cells: Its application for Antibody-Dependent Enhancement study. Dengue Bulletin 2005, 29:142-150.
• [31]Huang KJ, Yang YC, Lin YS, Huang JH, Liu HS, Yeh TM, Chen SH, Liu CC, Lei HY: The dual-specific binding of dengue virus and target cells for the antibody-dependent enhancement of dengue virus infection. J Immunol 2006, 176:2825-2832.
• [32]Men R, Yamashiro T, Goncalvez AP, Wernly C, Schofield DJ, Emerson SU, Purcell RH, Lai CJ: Identification of chimpanzee Fab fragments by repertoire cloning and production of a full-length humanized immunoglobulin G1 antibody that is highly efficient for neutralization of dengue type 4 virus. J Virol 2004, 78:4665-4674.
• [33]Vanniasinkam T, Barton MD, Heuzenroeder MW: B-Cell epitope mapping of the VapA protein of Rhodococcus equi: implications for early detection of R. equi disease in foals. J Clin Microbiol 2001, 39:1633-1637.
• [34]Viudes A, Perea S, Lopez-Ribot JL: Identification of continuous B cell epitopes on the protein moiety of the 58-kiloDalton cell wall mannoprotein of Candida albicans belonging to a family of immunodominant fungal antigens. Infect Immun 2001, 69:2909-2919.
• [35]Li PC, Liao MY, Cheng PC, Liang JJ, Liu IJ, Chiu CY, Lin YL, Chang GJ, Wu HC: Development of a humanized antibody with high therapeutic potential against dengue virus type 2. PLoS Negl Trop Dis 2012, 6:e1636.
• [36]de Alwis R, Smith SA, Olivarez NP, Messer WB, Huynh JP, Wahala WM, White LJ, Diamond MS, Baric RS, Crowe JE Jr, de Silva AM: Identification of human neutralizing antibodies that bind to complex epitopes on dengue virions. Proc Natl Acad Sci USA 2012, 109:7439-7444.
• [37]Lin HE, Tsai WY, Liu IJ, Li PC, Liao MY, Tsai JJ, Wu YC, Lai CY, Lu CH, Huang JH, Chang GJ, Wu HC, Wang WK: Analysis of Epitopes on Dengue Virus Envelope Protein Recognized by Monoclonal Antibodies and Polyclonal Human Sera by a High Throughput Assay. PLoS Negl Trop Dis 2012, 6:e1447.
• [38]Hughes HR, Crill WD, Chang GJ: Manipulation of immunodominant dengue virus E protein epitopes reduces potential antibody-dependent enhancement. Virol J 2012, 9:115. BioMed Central Full Text
• [39]Wahala WM, Huang C, Butrapet S, White LJ, de Silva AM: Recombinant dengue type 2 viruses with altered E protein domain III epitopes are efficiently neutralized by human immune sera. J Virol 2012, 86:4019-4023.
• [40]Falconar AK: Identification of an epitope on the dengue virus membrane (M) protein defined by cross-protective monoclonal antibodies: design of an improved epitope sequence based on common determinants present in both envelope (E and M) proteins. Arch Virol 1999, 144:2313-2330.
• [41]Huang KJ, Lin YS, Cheng YT, Huang JH, Liu HS, Yeh TM, Liu CC, Lei HY: Anti-prM Antibody as an Autoantibody in Dengue Virus Infection. Am J Infect Dis 2008, 4:59-67.
• [42]Rodenhuis-Zybert IA, van der Ende-Metselaar H, Wilschut J, Smit JM: Functional importance of dengue virus maturation: infectious properties of immature virions. J Gen Virol 2008, 89:3047-3051.
• [43]Kohler G, Milstein C: Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 1975, 256:495-497.
• [44]Yenchitsomanus PT, Sricharoen P, Jaruthasana I, Pattanakitsakul SN, Nitayaphan S, Mongkolsapaya J, Malasit P: Rapid detection and identification of dengue viruses by polymerase chain reaction (PCR). Southeast Asian J Trop Med Public Health 1996, 27:228-236.
• [45]Innis BL, Nisalak A, Nimmannitya S, Kusalerdchariya S, Chongswasdi V, Suntayakorn S, Puttisri P, Hoke CH: An enzyme-linked immunosorbent assay to characterize dengue infections where dengue and Japanese encephalitis co-circulate. Am J Trop Med Hyg 1989, 40:418-427.
• [46]Hoop TP, Woods KR: Prediction of protein antigenic determinants from amino acid sequences. Proc Natl Acad Sci USA 1981, 78:3824-3828.
• [47]Grantham R: Amino acid difference formula to help explain protein evolution. Science 1974, 185:862-864.
• [48]Jameson BA, Wolf H: The anigenic index: a novel algorithm for predicting antigenic determinants. Comput Appl Biosci 1988, 4:181-186.
• [49]Bhaskaran R, Ponnuswamy PK: Positional flexibilities of amino acid residues in globular proteins. Int J Peptide Protein Res 1988, 32:241-255.
• [50]Emini EA, Hughes JV, Perlow DS, Boger J: Induction of hepatitis A virus- neutralizing antibody by a virus specific synthetic peptide. J Virol 1985, 55:836-839.
• [51]Deleage G, Roux B: An algorithm for protein secondary structure prediction based on class prediction. Protein Eng 1987, 1:289-294.
• [52]Luo YY, Feng JJ, Fang DY, Jiang LF: Development of TaqMan MGB probe-based real-time fluorescence quantitative reverse transcription PCR for dengue virus and its application. J Mol Diagn Ther 2012, 4:158-162.
• [53]Lok SM, Kostyuchenko V, Nybakken GE, Holdaway HA, Battisti AJ, Sukupolvi-Petty S, Sedlak D, Fremont DH, Chipman PR, Roehrig JT, Diamond MS, Kuhn RJ, Rossmann MG: Binding of a neutralizing antibody to dengue virus alters the arrangementof surface glycoproteins. Nat Struct Mol Biol 2008, 15:312-317.
• [54]da Silva Voorham JM, Rodenhuis-Zybert IA, Ayala Nuñez NV, Colpitts TM, van der Ende-Metselaar H, Fikrig E, Diamond MS, Wilschut J, Smit JM: Antibodies against the Envelope Glycoprotein Promote Infectivity of Immature Dengue Virus Serotype 2. PLoS One 2012, 7:e29957.
• [55]Kaufman BM, Summers PL, Dubois DR, Cohen WH, Gentry MK: Monoclonal antibodies for dengue virus prM glycoprotein protect mice against lethal DENV infection. Am J Trop Med Hyg 1989, 41:576-580.
• [56]Rodenhuis-Zybert IA, Wilschut J, Smit JM: Partial maturation: an immune-evasion strategy of dengue virus? Trends Microbiol 2011, 19:248-254.
• [57]Lindenbach BD, Thiel HJ, Rice CM: Flaviviridae: the viruses and their replication. In In Fields virology, Volume. 5th edition. Edited by Knipe DM, Howley PM. Philadelphia: Lippincott William and Wilkins; 2001:1101-1152.
• [58]Chiou SS, Crill WD, Chen LK, Chang GJ: Enzyme-linked immunosorbent assays using novel Japanese encephalitis virus antigen improve the accuracy of clinical diagnosis of flavivirus infections. Clin Vaccine Immunol 2008, 15:825-835.
• [59]Vázquez S, Guzmán MG, Guillen G, Chinea G, Pérez AB, Pupo M, Rodriguez R, Reyes O, Garay HE, Delgado I, García G, Alvarez M: Immune response to synthetic peptides of dengue prM protein. Vaccine 2002, 20:1823-1830.
• [60]van der Schaar HM, Rust MJ, Waarts BL, van der Ende-Metselaar H, Kuhn RJ, Wilschut J, Zhuang X, Smit JM: Characterization of the early events in dengue virus cell entry by biochemical assays and single-virus tracking. J Virol 2007, 81:12019-12028.
• [61]Cherrier MV, Kaufmann B, Nybakken GE, Lok SM, Warren JT, Chen BR, Nelson CA, Kostyuchenko VA, Holdaway HA, Chipman PR, Kuhn RJ, Diamond MS, Rossmann MG, Fremont DH: Structural basis for the preferential recognition of immature flaviviruses by a fusion-loop antibody. EMBO J 2009, 28:3269-3276.
• [62]Junjhon J, Edwards TJ, Utaipat U, Bowman VD, Holdaway HA, Zhang W, Keelapang P, Puttikhunt C, Perera R, Chipman PR, Kasinrerk W, Malasit P, Kuhn RJ, Sittisombut N: Influence of pr-M cleavage on the heterogeneity of extracellular dengue virus particles. J Virol 2010, 84:8353-8358.
• [63]Nelson S, Jost CA, Xu Q, Ess J, Martin JE, Oliphant T, Whitehead SS, Durbin AP, Graham BS, Diamond MS, Pierson TC: Maturation of West Nile virus modulates sensitivity to antibody-mediated neutralization. PLoS Pathog 2008, 4:e1000060.
• [64]Halstead SB: Neutralization and antibody-dependent enhancement of dengue viruses. Adv Virus Res 2003, 60:421-467.
• [65]Henchal EA, McCown JM, Burke DS, Seguin MC, Brandt WE: Epitopic analysis of antigenic determinants on the surface of dengue-2 virions using monoclonal antibodies. Am J Trop Med Hyg 1985, 34:162-169.
• [66]Randolph VB, Winkler G, Stollar V: Acidotropic amines inhibit proteolytic processing of flavivirus prM protein. Virology 1990, 174:450-458.