Flaviviruses such as dengue virus (DENV), Zika virus (ZIKV), and yellow fever virus (YFV) are spread by mosquitoes and cause human disease and mortality in tropical areas. In contrast, Powassan virus (POWV), which causes severe neurologic illness, is a flavivirus transmitted by ticks in temperate regions of the Northern hemisphere. We find serologic neutralizing activity against POWV in individuals living in Mexico and Brazil. Monoclonal antibodies P002 and P003, which were derived from a resident of Mexico (where POWV is not reported), neutralize POWV lineage I by recognizing an epitope on the virus envelope domain III (EDIII) that is shared with a broad range of tick- and mosquito-borne flaviviruses. Our findings raise the possibility that POWV, or a flavivirus closely related to it, infects humans in the tropics.

Department of Psychiatry Columbia University and New York State Psychiatric Institute New York NY 10027 USA

Division of Biology and Biological Engineering California Institute of Technology Pasadena CA 91125 USA

Gonçalo Moniz Institute Oswaldo Cruz Foundation Ministry of Health Salvador BA 40296 Brazil; Department of Epidemiology of Microbial Diseases Yale School of Public Health New Haven CT 06511 USA

Gonçalo Moniz Institute Oswaldo Cruz Foundation Ministry of Health Salvador BA 40296 Brazil; Department of Epidemiology of Microbial Diseases Yale School of Public Health New Haven CT 06511 USA; Faculty of Medicine of Bahia Federal University of Bahia Salvador 40025 Brazil

Institute for Research in Biomedicine Università della Svizzera italiana 6500 Bellinzona Switzerland

Institute of Collective Health Federal University of Bahia Salvador BA 40025 Brazil; Gonçalo Moniz Institute Oswaldo Cruz Foundation Ministry of Health Salvador BA 40296 Brazil; Department of Epidemiology of Microbial Diseases Yale School of Public Health New Haven CT 06511 USA

Laboratory of Molecular Immunology The Rockefeller University New York NY 10065 USA

Laboratory of Molecular Immunology The Rockefeller University New York NY 10065 USA; Howard Hughes Medical Institute The Rockefeller University New York NY 10065 USA

Laboratory of Virology and Infectious Disease The Rockefeller University New York NY 10065 USA

National Institute of Respiratory Diseases Mexico City CP 14080 Mexico

National Institute of Respiratory Diseases Mexico City CP 14080 Mexico; Coordination of the National Institutes of Health and High Specialty Hospitals Ministry of Health Mexico City CP 14610 Mexico

Veterinary Research Institute Brno Czech Republic; Institute of Parasitology Biology Centre of the Czech Academy of Sciences Ceske Budejovice Czech Republic; Institute of Experimental Biology Faculty of Science Masaryk University Brno Czech Republic

Veterinary Research Institute Brno Czech Republic; Institute of Parasitology Biology Centre of the Czech Academy of Sciences Ceske Budejovice Czech Republic; Institute of Experimental Biology Faculty of Science Masaryk University Brno Czech Republic; Department of Pharmacology and Pharmacy Faculty of Veterinary Medicine University of Veterinary Sciences Brno Czech Republic

Zobrazit více v PubMed

Gould EA, and Solomon T (2008). Pathogenic flaviviruses. Lancet 371, 500–509. 10.1016/S0140-6736(08)60238-X. PubMed DOI

Postler TS, Beer M, Blitvich BJ, Bukh J, de Lamballerie X, Drexler JF, Imrie A, Kapoor A, Karganova GG, Lemey P, et al. (2023). Renaming of the genus Flavivirus to Orthoflavivirus and extension of binomial species names within the family Flaviviridae. Arch Virol 168, 224. 10.1007/s00705-023-05835-1. PubMed DOI

Kemenesi G, and Banyai K (2019). Tick-Borne Flaviviruses, with a Focus on Powassan Virus. Clin Microbiol Rev 32. 10.1128/CMR.00106-17. PubMed DOI PMC

Halstead SB (2014). Dengue Antibody-Dependent Enhancement: Knowns and Unknowns. Microbiol Spectr 2. 10.1128/microbiolspec.AID-0022-2014. PubMed DOI

Katzelnick LC, Gresh L, Halloran ME, Mercado JC, Kuan G, Gordon A, Balmaseda A, and Harris E (2017). Antibody-dependent enhancement of severe dengue disease in humans. Science 358, 929–932. 10.1126/science.aan6836. PubMed DOI PMC

Katzelnick LC, Narvaez C, Arguello S, Lopez Mercado B, Collado D, Ampie O, Elizondo D, Miranda T, Bustos Carillo F, Mercado JC, et al. (2020). Zika virus infection enhances future risk of severe dengue disease. Science 369, 1123–1128. 10.1126/science.abb6143. PubMed DOI PMC

Kuno G, Chang GJ, Tsuchiya KR, Karabatsos N, and Cropp CB (1998). Phylogeny of the genus Flavivirus. J Virol 72, 73–83. 10.1128/JVI.72.1.73-83.1998. PubMed DOI PMC

Ebel GD (2010). Update on Powassan virus: emergence of a North American tick-borne flavivirus. Annu Rev Entomol 55, 95–110. 10.1146/annurev-ento-112408-085446. PubMed DOI

Heinz FX, and Stiasny K (2012). Flaviviruses and their antigenic structure. J Clin Virol 55, 289–295. 10.1016/j.jcv.2012.08.024. PubMed DOI

Gaunt MW, Sall AA, Lamballerie X, Falconar AKI, Dzhivanian TI, and Gould EA (2001). Phylogenetic relationships of flaviviruses correlate with their epidemiology, disease association and biogeography. J Gen Virol 82, 1867–1876. 10.1099/0022-1317-82-8-1867. PubMed DOI

Kapoor T, Murray L, Kuvaldina M, Jiang CS, Peace AA, Agudelo M, Jurado A, Robbiani DF, Klemens O, Lattwein E, et al. (2024). Prevalence of Powassan Virus Seropositivity Among People with History of Lyme Disease and Non-Lyme Community Controls in the Northeastern United States. Vector Borne Zoonotic Dis. 10.1089/vbz.2022.0030. PubMed DOI PMC

Ruzek D, Avsic Zupanc T, Borde J, Chrdle A, Eyer L, Karganova G, Kholodilov I, Knap N, Kozlovskaya L, Matveev A, et al. (2019). Tick-borne encephalitis in Europe and Russia: Review of pathogenesis, clinical features, therapy, and vaccines. Antiviral Res 164, 23–51. 10.1016/j.antiviral.2019.01.014. PubMed DOI

Pierson TC, Sanchez MD, Puffer BA, Ahmed AA, Geiss BJ, Valentine LE, Altamura LA, Diamond MS, and Doms RW (2006). A rapid and quantitative assay for measuring antibody-mediated neutralization of West Nile virus infection. Virology 346, 53–65. 10.1016/j.virol.2005.10.030. PubMed DOI

Robbiani DF, Bozzacco L, Keeffe JR, Khouri R, Olsen PC, Gazumyan A, Schaefer-Babajew D, Avila-Rios S, Nogueira L, Patel R, et al. (2017). Recurrent Potent Human Neutralizing Antibodies to Zika Virus in Brazil and Mexico. Cell 169, 597–609 e511. 10.1016/j.cell.2017.04.024. PubMed DOI PMC

Van Rompay KKA, Coffey LL, Kapoor T, Gazumyan A, Keesler RI, Jurado A, Peace A, Agudelo M, Watanabe J, Usachenko J, et al. (2020). A combination of two human monoclonal antibodies limits fetal damage by Zika virus in macaques. Proc Natl Acad Sci U S A 117, 7981–7989. 10.1073/pnas.2000414117. PubMed DOI PMC

Simonelli L, Beltramello M, Yudina Z, Macagno A, Calzolai L, and Varani L (2010). Rapid structural characterization of human antibody-antigen complexes through experimentally validated computational docking. J Mol Biol 396, 1491–1507. 10.1016/j.jmb.2009.12.053. PubMed DOI

Simonelli L, Pedotti M, Beltramello M, Livoti E, Calzolai L, Sallusto F, Lanzavecchia A, and Varani L (2013). Rational engineering of a human anti-dengue antibody through experimentally validated computational docking. PLoS One 8, e55561. 10.1371/journal.pone.0055561. PubMed DOI PMC

Bardelli M, Livoti E, Simonelli L, Pedotti M, Moraes A, Valente AP, and Varani L (2015). Epitope mapping by solution NMR spectroscopy. J Mol Recognit 28, 393–400. 10.1002/jmr.2454. PubMed DOI

Wang J, Bardelli M, Espinosa DA, Pedotti M, Ng TS, Bianchi S, Simonelli L, Lim EXY, Foglierini M, Zatta F, et al. (2017). A Human Bi-specific Antibody against Zika Virus with High Therapeutic Potential. Cell 171, 229–241 e215. 10.1016/j.cell.2017.09.002. PubMed DOI PMC

Simonelli L, Pedotti M, Bardelli M, Jurt S, Zerbe O, and Varani L (2018). Mapping Antibody Epitopes by Solution NMR Spectroscopy: Practical Considerations. Methods Mol Biol 1785, 29–51. 10.1007/978-1-4939-7841-0_3. PubMed DOI

Frontzek K, Bardelli M, Senatore A, Henzi A, Reimann RR, Bedir S, Marino M, Hussain R, Jurt S, Meisl G, et al. (2022). A conformational switch controlling the toxicity of the prion protein. Nat Struct Mol Biol 29, 831–840. 10.1038/s41594-022-00814-7. PubMed DOI PMC

Keeffe JR, Van Rompay KKA, Olsen PC, Wang Q, Gazumyan A, Azzopardi SA, Schaefer-Babajew D, Lee YE, Stuart JB, Singapuri A, et al. (2018). A Combination of Two Human Monoclonal Antibodies Prevents Zika Virus Escape Mutations in Non-human Primates. Cell Rep 25, 1385–1394 e1387. 10.1016/j.celrep.2018.10.031. PubMed DOI PMC

Aliota MT, Dupuis AP 2nd, Wilczek MP, Peters RJ, Ostfeld RS, and Kramer LD (2014). The prevalence of zoonotic tick-borne pathogens in Ixodes scapularis collected in the Hudson Valley, New York State. Vector Borne Zoonotic Dis 14, 245–250. 10.1089/vbz.2013.1475. PubMed DOI PMC

Nelder MP, Russell CB, Sheehan NJ, Sander B, Moore S, Li Y, Johnson S, Patel SN, and Sider D (2016). Human pathogens associated with the blacklegged tick Ixodes scapularis: a systematic review. Parasit Vectors 9, 265. 10.1186/s13071-016-1529-y. PubMed DOI PMC

Tokarz R, Mishra N, Tagliafierro T, Sameroff S, Caciula A, Chauhan L, Patel J, Sullivan E, Gucwa A, Fallon B, et al. (2018). A multiplex serologic platform for diagnosis of tick-borne diseases. Sci Rep 8, 3158. 10.1038/s41598-018-21349-2. PubMed DOI PMC

Maeda A, and Maeda J (2013). Review of diagnostic plaque reduction neutralization tests for flavivirus infection. Vet J 195, 33–40. 10.1016/j.tvjl.2012.08.019. PubMed DOI

Heinz FX, and Stiasny K (2017). The Antigenic Structure of Zika Virus and Its Relation to Other Flaviviruses: Implications for Infection and Immunoprophylaxis. Microbiol Mol Biol Rev 81. 10.1128/MMBR.00055-16. PubMed DOI PMC

Calisher CH, Karabatsos N, Dalrymple JM, Shope RE, Porterfield JS, Westaway EG, and Brandt WE (1989). Antigenic relationships between flaviviruses as determined by cross-neutralization tests with polyclonal antisera. J Gen Virol 70 ( Pt 1), 37–43. 10.1099/0022-1317-70-1-37. PubMed DOI

Holbrook MR, Shope RE, and Barrett AD (2004). Use of recombinant E protein domain III-based enzyme-linked immunosorbent assays for differentiation of tick-borne encephalitis serocomplex flaviviruses from mosquito-borne flaviviruses. J Clin Microbiol 42, 4101–4110. 10.1128/JCM.42.9.4101-4110.2004. PubMed DOI PMC

United-States-Mexico Border Public-Health-Association. (1962). Public Health Rep 77, 140–146. PubMed PMC

Gritsun TS, Nuttall PA, and Gould EA (2003). Tick-borne flaviviruses. Adv Virus Res 61, 317–371. 10.1016/s0065-3527(03)61008-0. PubMed DOI

Anderson JF, and Magnarelli LA (2008). Biology of ticks. Infect Dis Clin North Am 22, 195–215, v. 10.1016/j.idc.2007.12.006. PubMed DOI

De Madrid AT, and Porterfield JS (1974). The flaviviruses (group B arboviruses): a cross-neutralization study. J Gen Virol 23, 91–96. 10.1099/0022-1317-23-1-91. PubMed DOI

Maeki T, Tajima S, Ikeda M, Kato F, Taniguchi S, Nakayama E, Takasaki T, Lim CK, and Saijo M (2019). Analysis of cross-reactivity between flaviviruses with sera of patients with Japanese encephalitis showed the importance of neutralization tests for the diagnosis of Japanese encephalitis. J Infect Chemother 25, 786–790. 10.1016/j.jiac.2019.04.003. PubMed DOI

Maeki T, Tajima S, Ando N, Wakimoto Y, Hayakawa K, Kutsuna S, Kato F, Taniguchi S, Nakayama E, Lim CK, and Saijo M (2023). Analysis of cross-reactivity among flaviviruses using sera of patients with dengue showed the importance of neutralization tests with paired serum samples for the correct interpretations of serological test results for dengue. J Infect Chemother 29, 469–474. 10.1016/j.jiac.2023.01.015. PubMed DOI

Agudelo M, Palus M, Keeffe JR, Bianchini F, Svoboda P, Salat J, Peace A, Gazumyan A, Cipolla M, Kapoor T, et al. (2021). Broad and potent neutralizing human antibodies to tick-borne flaviviruses protect mice from disease. J Exp Med 218. 10.1084/jem.20210236. PubMed DOI PMC

Mouquet H, Scharf L, Euler Z, Liu Y, Eden C, Scheid JF, Halper-Stromberg A, Gnanapragasam PN, Spencer DI, Seaman MS, et al. (2012). Complex-type N-glycan recognition by potent broadly neutralizing HIV antibodies. Proc Natl Acad Sci U S A 109, E3268–3277. 10.1073/pnas.1217207109. PubMed DOI PMC

Bianchini F, Crivelli V, Abernathy ME, Guerra C, Palus M, Muri J, Marcotte H, Piralla A, Pedotti M, De Gasparo R, et al. (2023). Human neutralizing antibodies to cold linear epitopes and subdomain 1 of the SARS-CoV-2 spike glycoprotein. Sci Immunol 8, eade0958. 10.1126/sciimmunol.ade0958. PubMed DOI PMC

Shi PY, Tilgner M, Lo MK, Kent KA, and Bernard KA (2002). Infectious cDNA clone of the epidemic west nile virus from New York City. J Virol 76, 5847–5856. 10.1128/jvi.76.12.5847-5856.2002. PubMed DOI PMC

Blight KJ, McKeating JA, and Rice CM (2002). Highly permissive cell lines for subgenomic and genomic hepatitis C virus RNA replication. J Virol 76, 13001–13014. 10.1128/jvi.76.24.13001-13014.2002. PubMed DOI PMC

Tiller T, Meffre E, Yurasov S, Tsuiji M, Nussenzweig MC, and Wardemann H (2008). Efficient generation of monoclonal antibodies from single human B cells by single cell RT-PCR and expression vector cloning. J Immunol Methods 329, 112–124. 10.1016/j.jim.2007.09.017. PubMed DOI PMC

Van Der Spoel D, Lindahl E, Hess B, Groenhof G, Mark AE, and Berendsen HJ (2005). GROMACS: fast, flexible, and free. J Comput Chem 26, 1701–1718. 10.1002/jcc.20291. PubMed DOI

Ye J, Ma N, Madden TL, and Ostell JM (2013). IgBLAST: an immunoglobulin variable domain sequence analysis tool. Nucleic Acids Res 41, W34–40. 10.1093/nar/gkt382. PubMed DOI PMC

Sircar A, Kim ET, and Gray JJ (2009). RosettaAntibody: antibody variable region homology modeling server. Nucleic Acids Res 37, W474–479. 10.1093/nar/gkp387. PubMed DOI PMC

Gray JJ, Moughon S, Wang C, Schueler-Furman O, Kuhlman B, Rohl CA, and Baker D (2003). Protein-protein docking with simultaneous optimization of rigid-body displacement and side-chain conformations. J Mol Biol 331, 281–299. 10.1016/s0022-2836(03)00670-3. PubMed DOI

Cheung AM, Yip EZ, Ashbrook AW, Goonawardane N, Quirk C, Rice CM, MacDonald MR, and Hoffmann HH (2023). Characterization of Live-Attenuated Powassan Virus Vaccine Candidates Identifies an Efficacious Prime-Boost Strategy for Mitigating Powassan Virus Disease in a Murine Model. Vaccines (Basel) 11. 10.3390/vaccines11030612. PubMed DOI PMC

Kenney JL, Anishchenko M, Hermance M, Romo H, Chen CI, Thangamani S, and Brault AC (2018). Generation of a Lineage II Powassan Virus (Deer Tick Virus) cDNA Clone: Assessment of Flaviviral Genetic Determinants of Tick and Mosquito Vector Competence. Vector Borne Zoonotic Dis 18, 371–381. 10.1089/vbz.2017.2224. PubMed DOI PMC

Pospisil L, Jandasek L, and Pesek J (1954). [Isolation of new strains of meningoencephalitis virus in the Brno region during the summer of 1953]. Lek List 9, 3–5. PubMed

Kozuch O, and Mayer V (1975). Pig kidney epithelial (PS) cells: a perfect tool for the study of flaviviruses and some other arboviruses. Acta Virol 19, 498. PubMed

Felzemburgh RD, Ribeiro GS, Costa F, Reis RB, Hagan JE, Melendez AX, Fraga D, Santana FS, Mohr S, dos Santos BL, et al. (2014). Prospective study of leptospirosis transmission in an urban slum community: role of poor environment in repeated exposures to the Leptospira agent. PLoS Negl Trop Dis 8, e2927. 10.1371/journal.pntd.0002927. PubMed DOI PMC

Esswein SR, Gristick HB, Jurado A, Peace A, Keeffe JR, Lee YE, Voll AV, Saeed M, Nussenzweig MC, Rice CM, et al. (2020). Structural basis for Zika envelope domain III recognition by a germline version of a recurrent neutralizing antibody. Proc Natl Acad Sci U S A 117, 9865–9875. 10.1073/pnas.1919269117. PubMed DOI PMC

Li MZ, and Elledge SJ (2012). SLIC: a method for sequence- and ligation-independent cloning. Methods Mol Biol 852, 51–59. 10.1007/978-1-61779-564-0_5. PubMed DOI

Pedotti M, Simonelli L, Livoti E, and Varani L (2011). Computational docking of antibody-antigen complexes, opportunities and pitfalls illustrated by influenza hemagglutinin. Int J Mol Sci 12, 226–251. 10.3390/ijms12010226. PubMed DOI PMC

Katoh K, and Standley DM (2013). MAFFT multiple sequence alignment software version 7: improvements in performance and usability. Mol Biol Evol 30, 772–780. 10.1093/molbev/mst010. PubMed DOI PMC

simonemoro/MA2consensus: v1.0.0 (v1.0.0). (2024). 10.5281/zenodo.11125547. DOI