Antibodies targeting the Crimean-Congo Hemorrhagic Fever Virus nucleoprotein protect via TRIM21.
Animals
Hemorrhagic Fever Virus, Crimean-Congo
/ immunology
Antibodies, Viral
/ immunology
Mice
Hemorrhagic Fever, Crimean
/ immunology
Nucleoproteins
/ immunology
Ribonucleoproteins
/ immunology
Mice, Knockout
Humans
Female
Mice, Inbred C57BL
Viral Vaccines
/ immunology
Antibodies, Neutralizing
/ immunology
Immunization, Passive
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
25 Oct 2024
25 Oct 2024
Historique:
received:
06
02
2024
accepted:
09
10
2024
medline:
26
10
2024
pubmed:
26
10
2024
entrez:
25
10
2024
Statut:
epublish
Résumé
Crimean-Congo Hemorrhagic Fever Virus (CCHFV) is a negative-sense RNA virus spread by Hyalomma genus ticks across Europe, Asia, and Africa. CCHF disease begins as a non-specific febrile illness which may progress into a severe hemorrhagic disease with no widely approved or highly efficacious interventions currently available. Recently, we reported a self-replicating, alphavirus-based RNA vaccine that expresses the CCHFV nucleoprotein and is protective against lethal CCHFV disease in mice. This vaccine induces high titers of non-neutralizing anti-NP antibodies and we show here that protection does not require Fc-gamma receptors or complement. Instead, vaccinated mice deficient in the intracellular Fc-receptor TRIM21 were unable to control the infection despite mounting robust CCHFV-specific immunity. We also show that passive transfer of NP-immune sera confers significant TRIM21-dependent protection against lethal CCHFV challenge. Together our data identifies TRIM21-mediated mechanisms as the Fc effector function of protective antibodies against the CCHFV NP and provides mechanistic insight into how vaccines against the CCHFV NP confer protection.
Identifiants
pubmed: 39455551
doi: 10.1038/s41467-024-53362-7
pii: 10.1038/s41467-024-53362-7
doi:
Substances chimiques
SS-A antigen
0
Antibodies, Viral
0
Nucleoproteins
0
Ribonucleoproteins
0
Viral Vaccines
0
Antibodies, Neutralizing
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
9236Subventions
Organisme : Division of Intramural Research, National Institute of Allergy and Infectious Diseases (Division of Intramural Research of the NIAID)
ID : N/A
Informations de copyright
© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.
Références
Bente, D. A. et al. Crimean-Congo hemorrhagic fever: history, epidemiology, pathogenesis, clinical syndrome and genetic diversity. Antivir. Res. 100, 159–189 (2013).
pubmed: 23906741
doi: 10.1016/j.antiviral.2013.07.006
Hawman, D. W. & Feldmann, H. Crimean-Congo haemorrhagic fever virus. Nat. Rev. Microbiol. 21, 463–477 (2023).
pubmed: 36918725
doi: 10.1038/s41579-023-00871-9
Hawman, D. W. & Feldmann, H. Recent advances in understanding Crimean-Congo hemorrhagic fever virus. F1000Res. 7 (2018).
Grandi, G. et al. First records of adult Hyalomma marginatum and H. rufipes ticks (Acari: Ixodidae) in Sweden. Ticks Tick. Borne Dis. 11, 101403 (2020).
pubmed: 32037097
doi: 10.1016/j.ttbdis.2020.101403
Egizi, A. et al. First glimpse into the origin and spread of the Asian longhorned tick, Haemaphysalis longicornis, in the United States. Zoonoses Public Health 67, 637–650 (2020).
pubmed: 32638553
doi: 10.1111/zph.12743
Tsergouli, K. et al. Nosocomial infections caused by Crimean-Congo haemorrhagic fever virus. J. Hosp. Infect. 105, 43–52 (2020).
pubmed: 31821852
doi: 10.1016/j.jhin.2019.12.001
Leventhal, S. S. et al. A Look into Bunyavirales Genomes: Functions of Non-Structural (NS) Proteins. Viruses. 13, 314 (2021).
Hawman, D. W. & Feldmann, H. Crimean–Congo haemorrhagic fever virus. Nat. Rev. Microbiol. 21, 463–477 (2023).
Zivcec, M. et al. Nucleocapsid protein-based vaccine provides protection in mice against lethal Crimean-Congo hemorrhagic fever virus challenge. PLOS Neglected Tropical Dis. 12, e0006628 (2018).
doi: 10.1371/journal.pntd.0006628
Appelberg, S. et al. Nucleoside-modified mRNA vaccines protect IFNAR(−/−) mice against Crimean Congo hemorrhagic fever virus infection. J Virol. 96, e0156821 (2022).
Spengler, J. R. et al. Viral replicon particles protect IFNAR(-/)(-) mice against lethal Crimean-Congo hemorrhagic fever virus challenge three days after vaccination. Antivir. Res. 191, 105090 (2021).
pubmed: 34044061
doi: 10.1016/j.antiviral.2021.105090
Hawman, D. W. et al. A DNA-based vaccine protects against Crimean-Congo haemorrhagic fever virus disease in a Cynomolgus macaque model. Nat. Microbiol. 6, 187–195 (2021).
pubmed: 33257849
doi: 10.1038/s41564-020-00815-6
Hawman, D. W. et al. Accelerated DNA vaccine regimen provides protection against Crimean-Congo hemorrhagic fever virus challenge in a macaque model. Mol. Ther. 31, 387–397 (2023).
Sorvillo, T. E. et al. Replicon particle vaccination induces non-neutralizing anti-nucleoprotein antibody-mediated control of Crimean-Congo hemorrhagic fever virus. npj Vaccines 9, 88 (2024).
pubmed: 38782933
doi: 10.1038/s41541-024-00877-1
Bertolotti-Ciarlet, A. et al. Cellular localization and antigenic characterization of crimean-congo hemorrhagic fever virus glycoproteins. J. Virol. 79, 6152–6161 (2005).
pubmed: 15858000
doi: 10.1128/JVI.79.10.6152-6161.2005
Golden, J. W. et al. GP38-targeting monoclonal antibodies protect adult mice against lethal Crimean-Congo hemorrhagic fever virus infection. Sci. Adv. 5, eaaw9535 (2019).
pubmed: 31309159
doi: 10.1126/sciadv.aaw9535
Leventhal, S. S. et al. Replicating RNA vaccination elicits an unexpected immune response that efficiently protects mice against lethal Crimean-Congo hemorrhagic fever virus challenge. EBioMedicine 82, 104188 (2022).
pubmed: 35907368
doi: 10.1016/j.ebiom.2022.104188
Hawman, D. W. et al. A replicating RNA vaccine confers protection in a rhesus macaque model of Crimean-Congo hemorrhagic fever. npj Vaccines 9, 86 (2024).
pubmed: 38769294
doi: 10.1038/s41541-024-00887-z
Lindquist, M. E. et al. Exploring Crimean-Congo hemorrhagic fever virus-induced hepatic injury using antibody-mediated type I interferon blockade in mice. J. Virol. 92, e01083-18 (2018).
Mallery, D. L. et al. Antibodies mediate intracellular immunity through tripartite motif-containing 21 (TRIM21). Proc. Natl Acad. Sci. 107, 19985–19990 (2010).
pubmed: 21045130
doi: 10.1073/pnas.1014074107
Caddy, S. L. et al. Viral nucleoprotein antibodies activate TRIM21 and induce T cell immunity. EMBO J. 40, e106228 (2021).
pubmed: 33258165
doi: 10.15252/embj.2020106228
McEwan, W. A. et al. Regulation of Virus Neutralization and the Persistent Fraction by TRIM21. J. Virol. 86, 8482–8491 (2012).
pubmed: 22647693
doi: 10.1128/JVI.00728-12
Albecka, A. et al. A functional assay for serum detection of antibodies against SARS-CoV-2 nucleoprotein. Embo J. 40, e108588 (2021).
pubmed: 34323299
doi: 10.15252/embj.2021108588
Caddy, S. L. et al. Intracellular neutralisation of rotavirus by VP6-specific IgG. PLoS Pathog. 16, e1008732 (2020).
pubmed: 32750093
doi: 10.1371/journal.ppat.1008732
Hawman, D. W. et al. Immunocompetent mouse model for Crimean-Congo hemorrhagic fever virus. eLife 10, e63906 (2021).
pubmed: 33416494
doi: 10.7554/eLife.63906
Mazzola, L. T. & Kelly-Cirino, C. Diagnostic tests for Crimean-Congo haemorrhagic fever: a widespread tickborne disease. BMJ Glob. Health 4, e001114 (2019).
pubmed: 30899574
doi: 10.1136/bmjgh-2018-001114
McEwan, W. A. et al. Intracellular antibody-bound pathogens stimulate immune signaling via the Fc receptor TRIM21. Nat. Immunol. 14, 327–336 (2013).
pubmed: 23455675
doi: 10.1038/ni.2548
Watkinson, R. E. et al. TRIM21 Promotes cGAS and RIG-I Sensing of Viral Genomes during Infection by Antibody-Opsonized Virus. PLOS Pathog. 11, e1005253 (2015).
pubmed: 26506431
doi: 10.1371/journal.ppat.1005253
Tipih, T. et al. Favipiravir and Ribavirin protect immunocompetent mice from lethal CCHFV infection. Antivir. Res. 218, 105703 (2023).
pubmed: 37611878
doi: 10.1016/j.antiviral.2023.105703
Onomoto, K., Onoguchi, K. & Yoneyama, M. Regulation of RIG-I-like receptor-mediated signaling: interaction between host and viral factors. Cell. Mol. Immunol. 18, 539–555 (2021).
pubmed: 33462384
doi: 10.1038/s41423-020-00602-7
Foss, S. et al. TRIM21—From Intracellular Immunity to Therapy. Front. Immunol. 10, 2049 (2019).
Jones, E. L., Laidlaw, S.M., & Dustin, L.B. TRIM21/Ro52 - Roles in Innate Immunity and Autoimmune Disease. Front. Immunol. 12, 738473 (2021).
Keeble, A. H. et al. TRIM21 is an IgG receptor that is structurally, thermodynamically, and kinetically conserved. Proc. Natl Acad. Sci. 105, 6045–6050 (2008).
pubmed: 18420815
doi: 10.1073/pnas.0800159105
Zhang, K. et al. TRIM21 ameliorates hepatic glucose and lipid metabolic disorders in type 2 diabetes mellitus by ubiquitination of PEPCK1 and FASN. Cell. Mol. Life Sci. 80, 168 (2023).
pubmed: 37249651
doi: 10.1007/s00018-023-04820-w
Yoshimi, R. et al. Gene disruption study reveals a nonredundant role for TRIM21/Ro52 in NF-kappaB-dependent cytokine expression in fibroblasts. J. Immunol. 182, 7527–7538 (2009).
pubmed: 19494276
doi: 10.4049/jimmunol.0804121
Welch, S. R. et al. Fluorescent Crimean-Congo hemorrhagic fever virus illuminates tissue tropism patterns and identifies early mononuclear phagocytic cell targets in Ifnar−/− mice. PLOS Pathog. 15, e1008183 (2019).
pubmed: 31790513
doi: 10.1371/journal.ppat.1008183
Clift, D. et al. A Method for the Acute and Rapid Degradation of Endogenous Proteins. Cell 171, 1692–1706.e18 (2017).
pubmed: 29153837
doi: 10.1016/j.cell.2017.10.033
Hawman, D. W. et al. Favipiravir (T-705) but not ribavirin is effective against two distinct strains of Crimean-Congo hemorrhagic fever virus in mice. Antivir. Res. 157, 18–26 (2018).
pubmed: 29936152
doi: 10.1016/j.antiviral.2018.06.013
Oestereich, L. et al. Evaluation of Antiviral Efficacy of Ribavirin, Arbidol, and T-705 (Favipiravir) in a Mouse Model for Crimean-Congo Hemorrhagic Fever. PLOS Neglected Tropical Dis. 8, e2804 (2014).
doi: 10.1371/journal.pntd.0002804
Garrison, A. R. et al. Nucleocapsid protein-specific monoclonal antibodies protect mice against Crimean-Congo hemorrhagic fever virus. Nat. Commun. 15, 1722 (2024).
pubmed: 38409240
doi: 10.1038/s41467-024-46110-4
Burt, F. J. et al. Human defined antigenic region on the nucleoprotein of Crimean-Congo hemorrhagic fever virus identified using truncated proteins and a bioinformatics approach. J. Virol. Methods 193, 706–712 (2013).
pubmed: 23933073
doi: 10.1016/j.jviromet.2013.07.055
Karaaslan, E. et al. Immune responses in multiple hosts to Nucleocapsid Protein (NP) of Crimean-Congo Hemorrhagic Fever Virus (CCHFV). PLoS Negl. Trop. Dis. 15, e0009973 (2021).
pubmed: 34851958
doi: 10.1371/journal.pntd.0009973
Saksida, A. et al. Interacting roles of immune mechanisms and viral load in the pathogenesis of crimean-congo hemorrhagic fever. Clin. Vaccin. Immunol. 17, 1086–1093 (2010).
doi: 10.1128/CVI.00530-09
Kaya, S. et al. Sequential determination of serum viral titers, virus-specific IgG antibodies, and TNF-alpha, IL-6, IL-10, and IFN-gamma levels in patients with Crimean-Congo hemorrhagic fever. BMC Infect. Dis. 14, 416 (2014).
pubmed: 25066751
doi: 10.1186/1471-2334-14-416
Ergonul, O. et al. Analysis of risk-factors among patients with Crimean-Congo haemorrhagic fever virus infection: severity criteria revisited. Clin. Microbiol Infect. 12, 551–554 (2006).
pubmed: 16700704
doi: 10.1111/j.1469-0691.2006.01445.x
Çevik, M. A. et al. Clinical and laboratory features of Crimean-Congo hemorrhagic fever: predictors of fatality. Int. J. Infect. Dis. 12, 374–379 (2008).
pubmed: 18063402
doi: 10.1016/j.ijid.2007.09.010
Shepherd, A. J., Swanepoel, R. & Leman, P. A. Antibody response in Crimean-Congo hemorrhagic fever. Rev. Infect. Dis. 11, S801–S806 (1989).
pubmed: 2501854
doi: 10.1093/clinids/11.Supplement_4.S801
Ergunay, K. et al. Antibody responses and viral load in patients with Crimean-Congo hemorrhagic fever: a comprehensive analysis during the early stages of the infection. Diagnostic Microbiol. Infect. Dis. 79, 31–36 (2014).
doi: 10.1016/j.diagmicrobio.2013.12.015
Clegg, J. C. S. & Lloyd, G. Vaccinia Recombinant Expressing Lassa-Virus Internal Nucleocapsid Protein Protects Guineapigs Against Lassa Fever. Lancet 330, 186–188 (1987).
doi: 10.1016/S0140-6736(87)90767-7
Boshra, H. et al. A DNA vaccine encoding ubiquitinated Rift Valley fever virus nucleoprotein provides consistent immunity and protects IFNAR(−/−) mice upon lethal virus challenge. Vaccine 29, 4469–4475 (2011).
pubmed: 21549790
doi: 10.1016/j.vaccine.2011.04.043
Jansen van Vuren, P., Tiemessen, C. T. & Paweska, J. T. Anti-Nucleocapsid Protein Immune Responses Counteract Pathogenic Effects of Rift Valley Fever Virus Infection in Mice. PLOS ONE 6, e25027 (2011).
pubmed: 21949840
doi: 10.1371/journal.pone.0025027
Lorenzo, G. et al. Protection against lethal Rift Valley fever virus (RVFV) infection in transgenic IFNAR−/− mice induced by different DNA vaccination regimens. Vaccine 28, 2937–2944 (2010).
pubmed: 20188678
doi: 10.1016/j.vaccine.2010.02.018
Lagerqvist, N. et al. Characterisation of immune responses and protective efficacy in mice after immunisation with Rift Valley Fever virus cDNA constructs. Virol. J. 6, 6 (2009).
pubmed: 19149901
doi: 10.1186/1743-422X-6-6
Boshra, H. et al. A novel Schmallenberg virus subunit vaccine candidate protects IFNAR−/− mice against virulent SBV challenge. Sci. Rep. 10, 18725 (2020).
pubmed: 33230115
doi: 10.1038/s41598-020-73424-2
Saavedra, F. et al. Immune response during hantavirus diseases: implications for immunotherapies and vaccine design. Immunology 163, 262–277 (2021).
pubmed: 33638192
doi: 10.1111/imm.13322
Safronetz, D. et al. Adenovirus vectors expressing hantavirus proteins protect hamsters against lethal challenge with andes virus. J. Virol. 83, 7285–7295 (2009).
pubmed: 19403663
doi: 10.1128/JVI.00373-09
Schmaljohn, C. S. et al. Antigenic subunits of Hantaan virus expressed by baculovirus and vaccinia virus recombinants. J. Virol. 64, 3162–3170 (1990).
pubmed: 1972201
doi: 10.1128/jvi.64.7.3162-3170.1990
Carragher, D. M. et al. A novel role for non-neutralizing antibodies against nucleoprotein in facilitating resistance to influenza virus. J. Immunol. (Baltim., Md.: 1950) 181, 4168–4176 (2008).
doi: 10.4049/jimmunol.181.6.4168
Garrison, A. R. et al. Crimean-Congo hemorrhagic fever virus utilizes a clathrin- and early endosome-dependent entry pathway. Virology 444, 45–54 (2013).
pubmed: 23791227
doi: 10.1016/j.virol.2013.05.030
Mishra, A. K. et al. Structural basis of synergistic neutralization of Crimean-Congo hemorrhagic fever virus by human antibodies. Science 375, 104–109 (2022).
pubmed: 34793197
doi: 10.1126/science.abl6502
Jalali, T. et al. Aptamer based diagnosis of crimean-congo hemorrhagic fever from clinical specimens. Sci. Rep. 11, 12639 (2021).
pubmed: 34135365
doi: 10.1038/s41598-021-91826-8
Hillen, M. R. et al. Autoantigen TRIM21/Ro52 is expressed on the surface of antigen-presenting cells and its enhanced expression in Sjögren’s syndrome is associated with B cell hyperactivity and type I interferon activity. RMD Open 6, e001184 (2020).
Guo, Y.-Y. et al. Viral infection and spread are inhibited by the polyubiquitination and downregulation of TRPV2 channel by the interferon-stimulated gene TRIM21. Cell Rep. 43, 114095 (2024).
Jeeva, S. et al. Crimean-Congo hemorrhagic fever virus nucleocapsid protein has dual RNA binding modes. PLOS ONE 12, e0184935 (2017).
pubmed: 28922369
doi: 10.1371/journal.pone.0184935
Kiss, L. et al. Trim-Away ubiquitinates and degrades lysine-less and N-terminally acetylated substrates. Nat. Commun. 14, 2160 (2023).
pubmed: 37061529
doi: 10.1038/s41467-023-37504-x
Zeng, J. et al. Target-induced clustering activates Trim-Away of pathogens and proteins. Nat. Struct. Mol. Biol. 28, 278–289 (2021).
pubmed: 33633400
doi: 10.1038/s41594-021-00560-2
Golden, J. W. et al. Induced protection from a CCHFV-M DNA vaccine requires CD8(+) T cells. Virus Res. 334, 199173 (2023).
pubmed: 37459918
doi: 10.1016/j.virusres.2023.199173
Erasmus, J. H. et al. An Alphavirus-derived replicon RNA vaccine induces SARS-CoV-2 neutralizing antibody and T cell responses in mice and nonhuman primates. Sci. Transl. Med. 12, eabc9396 (2020).
Glasner, A. et al. NKp46 Receptor-Mediated Interferon-gamma Production by Natural Killer Cells Increases Fibronectin 1 to Alter Tumor Architecture and Control Metastasis. Immunity 48, 396–398 (2018).
pubmed: 29466761
doi: 10.1016/j.immuni.2018.01.010
Mitchell, D. A. et al. Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients. Nature 519, 366–369 (2015).
pubmed: 25762141
doi: 10.1038/nature14320
Haddock, E. et al. A cynomolgus macaque model for Crimean-Congo haemorrhagic fever. Nat. Microbiol. 3, 556–562 (2018).
pubmed: 29632370
doi: 10.1038/s41564-018-0141-7