Chikungunya virus cell-to-cell transmission is mediated by intercellular extensions in vitro and in vivo.
Journal
Nature microbiology
ISSN: 2058-5276
Titre abrégé: Nat Microbiol
Pays: England
ID NLM: 101674869
Informations de publication
Date de publication:
09 2023
09 2023
Historique:
received:
13
01
2022
accepted:
13
07
2023
medline:
31
8
2023
pubmed:
18
8
2023
entrez:
17
8
2023
Statut:
ppublish
Résumé
Chikungunya virus (CHIKV) has recently emerged to cause millions of human infections worldwide. Infection can induce the formation of long intercellular extensions that project from infected cells and form stable non-continuous membrane bridges with neighbouring cells. The mechanistic role of these intercellular extensions in CHIKV infection was unclear. Here we developed a co-culture system and flow cytometry methods to quantitatively evaluate transmission of CHIKV from infected to uninfected cells in the presence of neutralizing antibody. Endocytosis and endosomal acidification were critical for virus cell-to-cell transmission, while the CHIKV receptor MXRA8 was not. By using distinct antibodies to block formation of extensions and by evaluation of transmission in HeLa cells that did not form extensions, we showed that intercellular extensions mediate CHIKV cell-to-cell transmission. In vivo, pre-treatment of mice with a neutralizing antibody blocked infection by direct virus inoculation, while adoptive transfer of infected cells produced antibody-resistant host infection. Together our data suggest a model in which the contact sites of intercellular extensions on target cells shield CHIKV from neutralizing antibodies and promote efficient intercellular virus transmission both in vitro and in vivo.
Identifiants
pubmed: 37591996
doi: 10.1038/s41564-023-01449-0
pii: 10.1038/s41564-023-01449-0
doi:
Substances chimiques
Antibodies, Neutralizing
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1653-1667Subventions
Organisme : NIAID NIH HHS
ID : R01 AI143673
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI141436
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA013330
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI125462
Pays : United States
Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer Nature Limited.
Références
Kuhn, R. J. in Fields Virology: Emerging Viruses-Volume 1 Vol. 1 (eds Howley, P. M. & Knipe, D. M.) Ch. 5, 170–193 (Lippincott Williams & Wilkins, 2021).
Weaver, S. C., Winegar, R., Manger, I. D. & Forrester, N. L. Alphaviruses: population genetics and determinants of emergence. Antivir. Res 94, 242–257 (2012).
pubmed: 22522323
Silva, L. A. & Dermody, T. S. Chikungunya virus: epidemiology, replication, disease mechanisms, and prospective intervention strategies. J. Clin. Invest. 127, 737–749 (2017).
pubmed: 28248203
pmcid: 5330729
Baxter, V. K. & Heise, M. T. Immunopathogenesis of alphaviruses. Adv. Virus Res. 107, 315–382 (2020).
pubmed: 32711733
pmcid: 8224468
McCarthy, M. K., Davenport, B. J. J. & Morrison, T. E. Chronic chikungunya virus disease. Curr. Top. Microbiol. Immunol. 435, 55–80 (2022).
pubmed: 30656438
Robinson, M. C. An epidemic of virus disease in Southern Province, Tanganyika Territory, in 1952–53. I. Clinical features. Trans. R. Soc. Trop. Med. Hyg. 49, 28–32 (1955).
pubmed: 14373834
Morrison, T. E. Reemergence of chikungunya virus. J. Virol. 88, 11644–11647 (2014).
pubmed: 25078691
pmcid: 4178719
Levi, L. I. & Vignuzzi, M. Arthritogenic alphaviruses: a worldwide emerging threat? Microorganisms 7, 133 (2019).
pubmed: 31091828
pmcid: 6560413
Brown, R. S., Wan, J. J. & Kielian, M. The alphavirus exit pathway: what we know and what we wish we knew. Viruses 10, 89 (2018).
pubmed: 29470397
pmcid: 5850396
Holmes, A. C., Basore, K., Fremont, D. H. & Diamond, M. S. A molecular understanding of alphavirus entry. PLoS Pathog. 16, e1008876 (2020).
pubmed: 33091085
pmcid: 7580943
Kielian, M., Chanel-Vos, C. & Liao, M. Alphavirus entry and membrane fusion. Viruses 2, 796–825 (2010).
pubmed: 21546978
pmcid: 3086016
Cifuentes-Munoz, N., El Najjar, F. & Dutch, R. E. Viral cell-to-cell spread: conventional and non-conventional ways. Adv. Virus Res 108, 85–125 (2020).
pubmed: 33837723
pmcid: 7522014
Zhong, P., Agosto, L. M., Munro, J. B. & Mothes, W. Cell-to-cell transmission of viruses. Curr. Opin. Virol. 3, 44–50 (2013).
pubmed: 23219376
McDonald, D. et al. Recruitment of HIV and its receptors to dendritic cell–T cell junctions. Science 300, 1295–1297 (2003).
pubmed: 12730499
Sowinski, S. et al. Membrane nanotubes physically connect T cells over long distances presenting a novel route for HIV-1 transmission. Nat. Cell Biol. 10, 211–219 (2008).
pubmed: 18193035
Sherer, N. M. et al. Retroviruses can establish filopodial bridges for efficient cell-to-cell transmission. Nat. Cell Biol. 9, 310–315 (2007).
pubmed: 17293854
pmcid: 2628976
Favoreel, H. W., Van Minnebruggen, G., Adriaensen, D. & Nauwynck, H. J. Cytoskeletal rearrangements and cell extensions induced by the US3 kinase of an alphaherpesvirus are associated with enhanced spread. Proc. Natl Acad. Sci. USA 102, 8990–8995 (2005).
pubmed: 15951429
pmcid: 1157013
Hahon, N. & Zimmerman, W. D. Chikungunya virus infection of cell monolayers by cell-to-cell and extracellular transmission. Appl. Microbiol. 19, 389–391 (1970).
pubmed: 4908535
pmcid: 376692
Lee, C. Y. et al. Chikungunya virus neutralization antigens and direct cell-to-cell transmission are revealed by human antibody-escape mutants. PLoS Pathog. 7, e1002390 (2011).
pubmed: 22144891
pmcid: 3228792
Martinez, M. G. & Kielian, M. Intercellular extensions are induced by the alphavirus structural proteins and mediate virus transmission. PLoS Pathog. 12, e1006061 (2016).
pubmed: 27977778
pmcid: 5158078
Jose, J., Taylor, A. B. & Kuhn, R. J. Spatial and temporal analysis of alphavirus replication and assembly in mammalian and mosquito cells. mBio 8, e02294–02216 (2017).
pubmed: 28196962
pmcid: 5312085
Meshram, C. D. et al. Multiple host factors interact with the hypervariable domain of chikungunya virus nsP3 and determine viral replication in cell-specific mode. J. Virol. 92, e00838–18 (2018).
pubmed: 29899097
pmcid: 6069204
Pal, P. et al. Development of a highly protective combination monoclonal antibody therapy against chikungunya virus. PLoS Pathog. 9, e1003312 (2013).
pubmed: 23637602
pmcid: 3630103
Sun, S. et al. Structural analyses at pseudo atomic resolution of chikungunya virus and antibodies show mechanisms of neutralization. eLife 2, e00435 (2013).
pubmed: 23577234
pmcid: 3614025
Jolly, C. & Sattentau, Q. J. Retroviral spread by induction of virological synapses. Traffic 5, 643–650 (2004).
pubmed: 15296489
Zhang, R. et al. Mxra8 is a receptor for multiple arthritogenic alphaviruses. Nature 557, 570–574 (2018).
pubmed: 29769725
pmcid: 5970976
Zhang, R. et al. Expression of the Mxra8 receptor promotes alphavirus infection and pathogenesis in mice and Drosophila. Cell Rep. 28, 2647–2658 e2645 (2019).
pubmed: 31484075
pmcid: 6745702
McCluskey, A. et al. Building a better dynasore: the dyngo compounds potently inhibit dynamin and endocytosis. Traffic 14, 1272–1289 (2013).
pubmed: 24025110
pmcid: 4138991
Stenmark, H. et al. Inhibition of rab5 GTPase activity stimulates membrane fusion in endocytosis. EMBO J. 13, 1287–1296 (1994).
pubmed: 8137813
pmcid: 394944
Hoornweg, T. E. et al. Dynamics of chikungunya virus cell entry unraveled by single-virus tracking in living cells. J. Virol. 90, 4745–4756 (2016).
pubmed: 26912616
pmcid: 4836339
Glomb-Reinmund, S. & Kielian, M. The role of low pH and disulfide shuffling in the entry and fusion of Semliki Forest virus and Sindbis virus. Virology 248, 372–381 (1998).
pubmed: 9721245
Neil, S. J. The antiviral activities of tetherin. Curr. Top. Microbiol. Immunol. 371, 67–104 (2013).
pubmed: 23686232
Ooi, Y. S., Dube, M. & Kielian, M. BST2/tetherin inhibition of alphavirus exit. Viruses 7, 2147–2167 (2015).
pubmed: 25912717
pmcid: 4411694
Wan, J. J., Ooi, Y. S. & Kielian, M. Mechanism of tetherin inhibition of alphavirus release. J. Virol. 93, e02165–18 (2019).
pubmed: 30674629
pmcid: 6430530
Pal, P. et al. Chikungunya viruses that escape monoclonal antibody therapy are clinically attenuated, stable, and not purified in mosquitoes. J. Virol. 88, 8213–8226 (2014).
pubmed: 24829346
pmcid: 4135940
Gorchakov, R. et al. Attenuation of chikungunya virus vaccine strain 181/clone 25 is determined by two amino acid substitutions in the E2 envelope glycoprotein. J. Virol. 86, 6084–6096 (2012).
pubmed: 22457519
pmcid: 3372191
Fox, J. M. et al. Optimal therapeutic activity of monoclonal antibodies against chikungunya virus requires Fc–FcγR interaction on monocytes. Sci. Immunol. 4, eaav5062 (2019).
pubmed: 30796092
pmcid: 6698136
Zhong, P. et al. Cell-to-cell transmission can overcome multiple donor and target cell barriers imposed on cell-free HIV. PLoS ONE 8, e53138 (2013).
pubmed: 23308151
pmcid: 3538641
Jolly, C., Booth, N. J. & Neil, S. J. Cell-cell spread of human immunodeficiency virus type 1 overcomes tetherin/BST-2-mediated restriction in T cells. J. Virol. 84, 12185–12199 (2010).
pubmed: 20861257
pmcid: 2976402
Young, A. R. et al. Dermal and muscle fibroblasts and skeletal myofibers survive chikungunya virus infection and harbor persistent RNA. PLoS Pathog. 15, e1007993 (2019).
pubmed: 31465513
pmcid: 6715174
Hoarau, J. J. et al. Persistent chronic inflammation and infection by chikungunya arthritogenic alphavirus in spite of a robust host immune response. J. Immunol. 184, 5914–5927 (2010).
pubmed: 20404278
Hawman, D. W. et al. Pathogenic chikungunya virus evades B cell responses to establish persistence. Cell Rep. 16, 1326–1338 (2016).
pubmed: 27452455
pmcid: 5003573
Ashbrook, A. W. et al. Residue 82 of the chikungunya virus E2 attachment protein modulates viral dissemination and arthritis in mice. J. Virol. 88, 12180–12192 (2014).
pubmed: 25142598
pmcid: 4248890
Liljeström, P., Lusa, S., Huylebroeck, D. & Garoff, H. In vitro mutagenesis of a full-length cDNA clone of Semliki Forest virus: the small 6,000-molecular-weight membrane protein modulates virus release. J. Virol. 65, 4107–4113 (1991).
pubmed: 2072446
pmcid: 248843
Hardwick, J. M. & Levine, B. Sindbis virus vector system for functional analysis of apoptosis regulators. Methods Enzymol. 322, 492–508 (2000).
pubmed: 10914042
Dube, M., Etienne, L., Fels, M. & Kielian, M. Calcium-dependent rubella virus fusion occurs in early endosomes. J. Virol. 90, 6303–6313 (2016).
pubmed: 27122589
pmcid: 4936153
Poddar, S., Hyde, J. L., Gorman, M. J., Farzan, M. & Diamond, M. S. The interferon-stimulated gene IFITM3 restricts infection and pathogenesis of arthritogenic and encephalitic alphaviruses. J. Virol. 90, 8780–8794 (2016).
pubmed: 27440901
pmcid: 5021394
Crill, W. D. & Chang, G. J. Localization and characterization of flavivirus envelope glycoprotein cross-reactive epitopes. J. Virol. 78, 13975–13986 (2004).
pubmed: 15564505
pmcid: 533943
Quiroz, J. A. et al. Human monoclonal antibodies against chikungunya virus target multiple distinct epitopes in the E1 and E2 glycoproteins. PLoS Pathog. 15, e1008061 (2019).
pubmed: 31697791
pmcid: 6837291
Voss, J. E. et al. Glycoprotein organization of chikungunya virus particles revealed by X-ray crystallography. Nature 468, 709–712 (2010).
pubmed: 21124458
Kielian, M., Jungerwirth, S., Sayad, K. U. & DeCandido, S. Biosynthesis, maturation, and acid-activation of the Semliki Forest virus fusion protein. J. Virol. 64, 4614–4624 (1990).
pubmed: 2118964
pmcid: 247945
Meyer, W. J. & Johnston, R. E. Structural rearrangement of infecting Sindbis virions at the cell surface: mapping of newly accessible epitopes. J. Virol. 67, 5117–5125 (1993).
pubmed: 7688818
pmcid: 237909
Schneider, C. A., Rasband, W. S. & Eliceiri, K. W. NIH Image to ImageJ: 25 years of image analysis. Nat. Methods 9, 671–675 (2012).
pubmed: 22930834
pmcid: 5554542