T-cell Responses in Individuals Infected with Zika Virus and in Those Vaccinated Against Dengue Virus

Dominic Paquin-Proulx, Fabio E. Leal, Cassia G. Terrassani Silveira, Alvino Maestri, Claudia Brockmeyer, Shannon M. Kitchen, Vinicius D. Cabido, Esper G. Kallas, Douglas F. Nixon

Abstract


Background: The outbreak of Zika virus (ZIKV) infection in Brazil has raised concerns that infection during pregnancy could cause microcephaly and other severe neurodevelopmental malformations in the fetus. The mechanisms by which ZIKV causes fetal abnormalities are largely unknown. The importance of pre-infection with dengue virus (DENV), or other flaviviruses endemic to Brazil, remains to be investigated. It has been reported that antibodies directed against DENV can increase ZIKV infectivity by antibody dependent enhancement (ADE), suggesting that a history of prior DENV infection might worsen the outcome of ZIKV infection.

Methods: We used bioinformatics tools to design 18 peptides from the ZIKV envelope containing predicted HLA-I T-cell epitopes and investigated T-cell cross-reactivity between ZIKV-infected individuals and DENV-vaccinated subjects by IFNg ELISPOT.

Results: Three peptides induced IFNg production in both ZIKV-infected subjects and in DENV-vaccinated individuals. Flow cytometry indicated that 1 ZIKV peptide induced a CD4+ T-cell response in DENV-vaccinated subjects.

Conclusions: We demonstrated that vaccination against DENV induced a T-cell response against ZIKV and identified one such CD4+ T-cell epitope. The ZIKV-reactive CD4+ T cells induced by DENV vaccination and identified in this study could contribute to the appearance of cross-reactive antibodies mediating ADE.


Keywords


zika virus; dengue virus; T cell; IFNg; ELISPOT; CD4; antibody dependent enhancement

Full Text:

HTML PDF

References


1. Dick GW, Kitchen SF, Haddow AJ. Zika virus. I. Isolations and serological specificity. Trans R Soc Trop Med Hyg. 1952;46(5):509-20. PubMed PMID: 12995440.

2. Driggers RW, Ho CY, Korhonen EM, Kuivanen S, Jaaskelainen AJ, Smura T, Rosenberg A, Hill DA, DeBiasi RL, Vezina G, Timofeev J, Rodriguez FJ, Levanov L, Razak J, Iyengar P, Hennenfent A, Kennedy R, Lanciotti R, du Plessis A, Vapalahti O. Zika Virus Infection with Prolonged Maternal Viremia and Fetal Brain Abnormalities. N Engl J Med. 2016. PubMed PMID: 27028667. doi: 10.1056/NEJMoa1601824

3. Calvet G, Aguiar RS, Melo AS, Sampaio SA, de Filippis I, Fabri A, Araujo ES, de Sequeira PC, de Mendonca MC, de Oliveira L, Tschoeke DA, Schrago CG, Thompson FL, Brasil P, Dos Santos FB, Nogueira RM, Tanuri A, de Filippis AM. Detection and sequencing of Zika virus from amniotic fluid of fetuses with microcephaly in Brazil: a case study. Lancet Infect Dis. 2016. PubMed PMID: 26897108. doi: 10.1016/S1473-3099(16)00095-5

4. Kleber de Oliveira W, Cortez-Escalante J, De Oliveira WT, do Carmo GM, Henriques CM, Coelho GE, Araujo de Franca GV. Increase in Reported Prevalence of Microcephaly in Infants Born to Women Living in Areas with Confirmed Zika Virus Transmission During the First Trimester of Pregnancy - Brazil, 2015. MMWR Morb Mortal Wkly Rep. 2016;65(9):242-7. PubMed PMID: 26963593. doi: 10.15585/mmwr.mm6509e2

5. Martines RB, Bhatnagar J, Keating MK, Silva-Flannery L, Muehlenbachs A, Gary J, Goldsmith C, Hale G, Ritter J, Rollin D, Shieh WJ, Luz KG, Ramos AM, Davi HP, Kleber de Oliveria W, Lanciotti R, Lambert A, Zaki S. Notes from the Field: Evidence of Zika Virus Infection in Brain and Placental Tissues from Two Congenitally Infected Newborns and Two Fetal Losses - Brazil, 2015. MMWR Morb Mortal Wkly Rep. 2016;65(6):159-60. PubMed PMID: 26890059. doi: 10.15585/mmwr.mm6506e1

6. Mlakar J, Korva M, Tul N, Popovic M, Poljsak-Prijatelj M, Mraz J, Kolenc M, Resman Rus K, Vesnaver Vipotnik T, Fabjan Vodusek V, Vizjak A, Pizem J, Petrovec M, Avsic Zupanc T. Zika Virus Associated with Microcephaly. N Engl J Med. 2016;374(10):951-8. PubMed PMID: 26862926. doi: 10.1056/NEJMoa1600651

7. Cugola FR, Fernandes IR, Russo FB, Freitas BC, Dias JL, Guimaraes KP, Benazzato C, Almeida N, Pignatari GC, Romero S, Polonio CM, Cunha I, Freitas CL, Brandao WN, Rossato C, Andrade DG, Faria Dde P, Garcez AT, Buchpigel CA, Braconi CT, Mendes E, Sall AA, Zanotto PM, Peron JP, Muotri AR, Beltrao-Braga PC. The Brazilian Zika virus strain causes birth defects in experimental models. Nature. 2016;534(7606):267-71. PubMed PMID: 27279226. Pubmed Central PMCID: PMC4902174. doi: 10.1038/nature18296

8. Yockey LJ, Varela L, Rakib T, Khoury-Hanold W, Fink SL, Stutz B, Szigeti-Buck K, Van den Pol A, Lindenbach BD, Horvath TL, Iwasaki A. Vaginal Exposure to Zika Virus during Pregnancy Leads to Fetal Brain Infection. Cell. 2016;166(5):1247-56 e4. PubMed PMID: 27565347. Pubmed Central PMCID: PMC5006689. doi: 10.1016/j.cell.2016.08.004

9. Adams Waldorf KM, Stencel-Baerenwald JE, Kapur RP, Studholme C, Boldenow E, Vornhagen J, Baldessari A, Dighe MK, Thiel J, Merillat S, Armistead B, Tisoncik-Go J, Green RR, Davis MA, Dewey EC, Fairgrieve MR, Gatenby JC, Richards T, Garden GA, Diamond MS, Juul SE, Grant RF, Kuller L, Shaw DW, Ogle J, Gough GM, Lee W, English C, Hevner RF, Dobyns WB, Gale M, Jr., Rajagopal L. Fetal brain lesions after subcutaneous inoculation of Zika virus in a pregnant nonhuman primate. Nat Med. 2016;22(11):1256-9. PubMed PMID: 27618651. doi: 10.1038/nm.4193

10. Cauchemez S, Besnard M, Bompard P, Dub T, Guillemette-Artur P, Eyrolle-Guignot D, Salje H, Van Kerkhove MD, Abadie V, Garel C, Fontanet A, Mallet HP. Association between Zika virus and microcephaly in French Polynesia, 2013-15: a retrospective study. Lancet. 2016. PubMed PMID: 26993883. doi: 10.1016/S0140-6736(16)00651-6

11. Brasil P, Pereira JP, Jr., Raja Gabaglia C, Damasceno L, Wakimoto M, Ribeiro Nogueira RM, Carvalho de Sequeira P, Machado Siqueira A, Abreu de Carvalho LM, Cotrim da Cunha D, Calvet GA, Neves ES, Moreira ME, Rodrigues Baiao AE, Nassar de Carvalho PR, Janzen C, Valderramos SG, Cherry JD, Bispo de Filippis AM, Nielsen-Saines K. Zika Virus Infection in Pregnant Women in Rio de Janeiro - Preliminary Report. N Engl J Med. 2016. PubMed PMID: 26943629. doi: 10.1056/NEJMoa1602412

12. Johansson MA, Mier YT-RL, Reefhuis J, Gilboa SM, Hills SL. Zika and the Risk of Microcephaly. N Engl J Med. 2016. PubMed PMID: 27222919. doi: 10.1056/NEJMp1605367

13. Brasil P, Pereira JP, Jr., Moreira ME, Ribeiro Nogueira RM, Damasceno L, Wakimoto M, Rabello RS, Valderramos SG, Halai UA, Salles TS, Zin AA, Horovitz D, Daltro P, Boechat M, Raja Gabaglia C, Carvalho de Sequeira P, Pilotto JH, Medialdea-Carrera R, Cotrim da Cunha D, Abreu de Carvalho LM, Pone M, Machado Siqueira A, Calvet GA, Rodrigues Baiao AE, Neves ES, Nassar de Carvalho PR, Hasue RH, Marschik PB, Einspieler C, Janzen C, Cherry JD, Bispo de Filippis AM, Nielsen-Saines K. Zika Virus Infection in Pregnant Women in Rio de Janeiro. N Engl J Med. 2016;375(24):2321-34. PubMed PMID: 26943629. doi: 10.1056/NEJMoa1602412

14. Honein MA, Dawson AL, Petersen EE, Jones AM, Lee EH, Yazdy MM, Ahmad N, Macdonald J, Evert N, Bingham A, Ellington SR, Shapiro-Mendoza CK, Oduyebo T, Fine AD, Brown CM, Sommer JN, Gupta J, Cavicchia P, Slavinski S, White JL, Owen SM, Petersen LR, Boyle C, Meaney-Delman D, Jamieson DJ, Collaboration USZPR. Birth Defects Among Fetuses and Infants of US Women With Evidence of Possible Zika Virus Infection During Pregnancy. JAMA. 2017;317(1):59-68. PubMed PMID: 27960197. doi: 10.1001/jama.2016.19006

15. Cuevas EL, Tong VT, Rozo N, Valencia D, Pacheco O, Gilboa SM, Mercado M, Renquist CM, Gonzalez M, Ailes EC, Duarte C, Godoshian V, Sancken CL, Turca AM, Calles DL, Ayala M, Morgan P, Perez EN, Bonilla HQ, Gomez RC, Estupinan AC, Gunturiz ML, Meaney-Delman D, Jamieson DJ, Honein MA, Martinez ML. Preliminary Report of Microcephaly Potentially Associated with Zika Virus Infection During Pregnancy - Colombia, January-November 2016. MMWR Morb Mortal Wkly Rep. 2016;65(49):1409-13. PubMed PMID: 27977645. doi: 10.15585/mmwr.mm6549e1

16. Dejnirattisai W, Supasa P, Wongwiwat W, Rouvinski A, Barba-Spaeth G, Duangchinda T, Sakuntabhai A, Cao-Lormeau VM, Malasit P, Rey FA, Mongkolsapaya J, Screaton GR. Dengue virus sero-cross-reactivity drives antibody-dependent enhancement of infection with zika virus. Nat Immunol. 2016. PubMed PMID: 27339099. doi: 10.1038/ni.3515

17. Priyamvada L, Quicke KM, Hudson WH, Onlamoon N, Sewatanon J, Edupuganti S, Pattanapanyasat K, Chokephaibulkit K, Mulligan MJ, Wilson PC, Ahmed R, Suthar MS, Wrammert J. Human antibody responses after dengue virus infection are highly cross-reactive to Zika virus. Proc Natl Acad Sci U S A. 2016. PubMed PMID: 27354515. doi: 10.1073/pnas.1607931113

18. Castanha PM, Nascimento EJ, Cynthia B, Cordeiro MT, de Carvalho OV, de Mendonca LR, Azevedo EA, Franca RF, Rafael D, Marques ET, Jr. Dengue virus (DENV)-specific antibodies enhance Brazilian Zika virus (ZIKV) infection. J Infect Dis. 2016. PubMed PMID: 28039355. doi: 10.1093/infdis/jiw638

19. Paul LM, Carlin ER, Jenkins MM, Tan AL, Barcellona CM, Nicholson CO, Michael SF, Isern S. Dengue virus antibodies enhance Zika virus infection. Clin Transl Immunology. 2016;5(12):e117. PubMed PMID: 28090318. Pubmed Central PMCID: PMC5192063. doi: 10.1038/cti.2016.72

20. Halstead SB. Biologic Evidence Required for Zika Disease Enhancement by Dengue Antibodies. Emerg Infect Dis. 2017;23(4):569-73. PubMed PMID: 28322690. doi: 10.3201/eid2304.161879

21. Weiskopf D, Cerpas C, Angelo MA, Bangs DJ, Sidney J, Paul S, Peters B, Sanches FP, Silvera CG, Costa PR, Kallas EG, Gresh L, de Silva AD, Balmaseda A, Harris E, Sette A. Human CD8+ T-Cell Responses Against the 4 Dengue Virus Serotypes Are Associated With Distinct Patterns of Protein Targets. J Infect Dis. 2015;212(11):1743-51. PubMed PMID: 25980035. Pubmed Central PMCID: PMC4633759. doi: 10.1093/infdis/jiv289

22. Wen J, Tang WW, Sheets N, Ellison J, Sette A, Kim K, Shresta S. Identification of Zika virus epitopes reveals immunodominant and protective roles for dengue virus cross-reactive CD8+ T cells. Nat Microbiol. 2017;2:17036. PubMed PMID: 28288094. doi: 10.1038/nmicrobiol.2017.36

23. Larsen MV, Lundegaard C, Lamberth K, Buus S, Lund O, Nielsen M. Large-scale validation of methods for cytotoxic T-lymphocyte epitope prediction. BMC Bioinformatics. 2007;8:424. PubMed PMID: 17973982. Pubmed Central PMCID: PMC2194739. doi: 10.1186/1471-2105-8-424

24. Wang P, Sidney J, Dow C, Mothe B, Sette A, Peters B. A systematic assessment of MHC class II peptide binding predictions and evaluation of a consensus approach. PLoS Comput Biol. 2008;4(4):e1000048. PubMed PMID: 18389056. Pubmed Central PMCID: PMC2267221. doi: 10.1371/journal.pcbi.1000048

25. Wang P, Sidney J, Kim Y, Sette A, Lund O, Nielsen M, Peters B. Peptide binding predictions for HLA DR, DP and DQ molecules. BMC Bioinformatics. 2010;11:568. PubMed PMID: 21092157. Pubmed Central PMCID: PMC2998531. doi: 10.1186/1471-2105-11-568

26. Li W, Cowley A, Uludag M, Gur T, McWilliam H, Squizzato S, Park YM, Buso N, Lopez R. The EMBL-EBI bioinformatics web and programmatic tools framework. Nucleic Acids Res. 2015;43(W1):W580-4. PubMed PMID: 25845596. Pubmed Central PMCID: PMC4489272. doi: 10.1093/nar/gkv279

27. McWilliam H, Li W, Uludag M, Squizzato S, Park YM, Buso N, Cowley AP, Lopez R. Analysis Tool Web Services from the EMBL-EBI. Nucleic Acids Res. 2013;41(Web Server issue):W597-600. PubMed PMID: 23671338. Pubmed Central PMCID: PMC3692137. doi: 10.1093/nar/gkt376

28. Bardi MS, Jarduli LR, Jorge AJ, Camargo RB, Carneiro FP, Gelinski JR, Silva RA, Lavado EL. HLA-A, B and DRB1 allele and haplotype frequencies in volunteer bone marrow donors from the north of Parana State. Rev Bras Hematol Hemoter. 2012;34(1):25-30. PubMed PMID: 23049380. Pubmed Central PMCID: PMC3459602. doi: 10.5581/1516-8484.20120010

29. Ayo CM, da Silveira Camargo AV, Xavier DH, Batista MF, Carneiro OA, Brandao de Mattos CC, Ricci O, Jr., de Mattos LC. Frequencies of allele groups HLA-A, HLA-B and HLA-DRB1 in a population from the northwestern region of Sao Paulo State, Brazil. Int J Immunogenet. 2015;42(1):19-25. PubMed PMID: 25418108. doi: 10.1111/iji.12159

30. UniProt C. UniProt: a hub for protein information. Nucleic Acids Res. 2015;43(Database issue):D204-12. PubMed PMID: 25348405. Pubmed Central PMCID: PMC4384041. doi: 10.1093/nar/gku989

31. Kirkpatrick BD, Whitehead SS, Pierce KK, Tibery CM, Grier PL, Hynes NA, Larsson CJ, Sabundayo BP, Talaat KR, Janiak A, Carmolli MP, Luke CJ, Diehl SA, Durbin AP. The live attenuated dengue vaccine TV003 elicits complete protection against dengue in a human challenge model. Sci Transl Med. 2016;8(330):330ra36. PubMed PMID: 27089205. doi: 10.1126/scitranslmed.aaf1517

32. Zehn D, Turner MJ, Lefrancois L, Bevan MJ. Lack of original antigenic sin in recall CD8(+) T cell responses. J Immunol. 2010;184(11):6320-6. PubMed PMID: 20439913. Pubmed Central PMCID: PMC2982183. doi: 10.4049/jimmunol.1000149

33. Mongkolsapaya J, Dejnirattisai W, Xu XN, Vasanawathana S, Tangthawornchaikul N, Chairunsri A, Sawasdivorn S, Duangchinda T, Dong T, Rowland-Jones S, Yenchitsomanus PT, McMichael A, Malasit P, Screaton G. Original antigenic sin and apoptosis in the pathogenesis of dengue hemorrhagic fever. Nat Med. 2003;9(7):921-7. PubMed PMID: 12808447. doi: 10.1038/nm887

34. Rivino L, Lim MQ. CD4+ and CD8+ T-cell immunity to Dengue - lessons for the study of Zika virus. Immunology. 2017;150(2):146-54. PubMed PMID: 27763656. Pubmed Central PMCID: PMC5214511. doi: 10.1111/imm.12681

35. Hadinegoro SR, Arredondo-Garcia JL, Capeding MR, Deseda C, Chotpitayasunondh T, Dietze R, Muhammad Ismail HI, Reynales H, Limkittikul K, Rivera-Medina DM, Tran HN, Bouckenooghe A, Chansinghakul D, Cortes M, Fanouillere K, Forrat R, Frago C, Gailhardou S, Jackson N, Noriega F, Plennevaux E, Wartel TA, Zambrano B, Saville M, Group C-TDVW. Efficacy and Long-Term Safety of a Dengue Vaccine in Regions of Endemic Disease. N Engl J Med. 2015;373(13):1195-206. PubMed PMID: 26214039. doi: 10.1056/NEJMoa1506223

36. Angelo MA, Grifoni A, O'Rourke PH, Sidney J, Paul S, Peters B, de Silva AD, Phillips E, Mallal S, Diehl SA, Kirkpatrick BD, Whitehead SS, Durbin AP, Sette A, Weiskopf D. Human CD4+ T Cell Responses to an Attenuated Tetravalent Dengue Vaccine Parallel Those Induced by Natural Infection in Magnitude, HLA Restriction, and Antigen Specificity. J Virol. 2017;91(5). PubMed PMID: 27974563. Pubmed Central PMCID: PMC5309943. doi: 10.1128/JVI.02147-16


Figure legends

Figure 1. Alignment of ZIKV and DENV Sequences. The ZIKV amino acid sequences of selected peptides were aligned to the corresponding DENV-1, DENV-2, DENV-3, and DENV-4 sequences using EMBL-EBI bioinformatics framework. * indicates positions with a single, fully conserved residue; : indicates conservation between groups of strongly similar properties—roughly equivalent to scoring > 0.5 in the Gonnet PAM 250 matrix; . indicates conservation between groups of weakly similar properties—roughly equivalent to scoring ≤ 0.5 and > 0 in the Gonnet PAM 250 matrix.

Figure 2. Identification of ZIKV Epitope. PBMCs from ZIKV-infected subjects were stimulated with peptides 1-18 and IFNg production was evaluated by ELISPOT. The dashed line represents the background level of IFNg in the absence of stimulation multiplied by 2.

Figure 3. Identification of DENV-ZIKV Cross-reactive Peptides. PBMCs from DENV-vaccinated subjects were stimulated with peptides 1-18 and IFNg production was evaluated by ELISPOT. The dashed line represents the background level of IFNg in the absence of stimulation multiplied by 2.

Figure 4. Fine Mapping of Peptide 1. IFNg spots per million PBMCs after stimulation with peptides 1, A, B, and C for DENV 1038 and 1049. The dashed line represents the background level of IFNg in the absence of stimulation multiplied by 2 (A). CellTrace Violet labeled PBMCs were stimulated for 6 days with peptide 1 in the presence of IL-2 (20 U/ml) before re-stimulation with peptide 1 for 12 hours in the presence of monensin. As a negative control, PBMCs were cultured with IL-2 in absence of peptide stimulation. Cells were then stained for CD3, CD4, CD8, and IFNγ. Representative flow plots (B).


Article Level Metrics

Refbacks

  • There are currently no refbacks.




Copyright (c) 2017 Dominic Paquin-Proulx

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

© Pathogens and Immunity 2017

Case Western Reserve University; Division of Infectious Diseases

10900 Euclid Ave.; Mailstop 4984; Cleveland, OH 44106

(216) 368-6317; ISSN: 2469-2964; info@paijournal.com