microbeПроблемы особо опасных инфекцийProblems of Particularly Dangerous Infections0370-10692658-719XRussian Research Anti-Plague Institute “Microbe”10.21055/0370-1069-2015-3-89-93microbe-252Research ArticleМИКРОБИОЛОГИЯMICROBIOLOGYМолекулярные механизмы проникновения вируса Эбола в пермиссивные клеткиMolecular Mechanisms of Ebola Virus Entry into Permissive CellsСизиковаТ. Е.SizikovaT. E.noemail@neicon.ruЛебедевВ. Н.LebedevV. N.noemail@neicon.ruПантюховВ. Б.PantyukhovV. B.noemail@neicon.ruБорисевичС. В.BorisevichS. V.noemail@neicon.ru48 Центральный научно-исследовательский институт Министерства обороныРоссияThe 48th Central Research Institute of the RF Ministry of DefenseRussian Federation201520092015038993Copyright © Сизикова Т.Е., Лебедев В.Н., Пантюхов В.Б., Борисевич С.В., 20152015Сизикова Т.Е., Лебедев В.Н., Пантюхов В.Б., Борисевич С.В.Sizikova T.E., Lebedev V.N., Pantyukhov V.B., Borisevich S.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://journal.microbe.ru/jour/article/view/252

Вирус Эбола, являющийся представителем рода Еbolavirus семейства Filoviridae, вызывает у человека лихорадку с летальностью до 90 %. Представители рода Еbolavirus инфицируют многие виды клеток млекопитающих. Недавно проведенные исследования показали, что при проникновении вируса Эбола в клетку задействованы многочисленные белковые взаимодействия и молекулярные механизмы, часть из которых являются уникальными для филовирусов, а некоторые используются всеми вирусными гликопротеинами. Клеточные факторы, используемые филовирусами при их проникновении в пермиссивные клетки, полностью не изучены. Целью данного обзора является анализ особенности проникновения вируса Эбола в пермиссивные клетки на молекулярном уровне. Проникновение вируса Эбола в клетки инициируется взаимодействием вирусного гликопротеина с одним или несколькими рецепторами на поверхности клетки-хозяина. Главные клеточные факторы, задействованные в процессе проникновения филовирусов в клетки, это факторы прикрепления (клеточные лектины и Т-клеточный муцин 1 (TIM-1) человека), сигнальные факторы (рецепторы тирозинкиназы и α5β1-интегрин), эндолизосомальные факторы клетки-хозяина (катепсины B и L, а также белок Неймана-Пика C1). Изучение особенностей проникновения вируса в клетки открывает потенциальные подходы к созданию средств профилактики и лечения болезни, вызванной вирусом Эбола.

Ebola virus, representative of the Ebolavirus genus, Filoviridae family, causes severe hemorrhagic fever in humans, with lethality rates amounting up to 90 %. The members of Ebolavirus genus infect a broad range of mammalian cells. Recent studies indicate that entry of Ebola virus into cells requires a series of cellular protein interactions and molecular mechanisms, some of which are unique to filoviruses, while others are commonly used by all viral glycoproteins. The cellular factors deployed by filoviruses for their entry into permissive cells are defined incompletely. The aim of this review is to analyze peculiarity of the Ebola virus penetration into permissive cells at molecular level. The Ebola virus entry into cells is initiated by the interaction of viral glycoprotein with one or more receptors on the surface of host-cell. The main host-cell factors, involved in filovirus entry, are: attachment factors (cell lectins and human T-cell mucin 1 (TIM-1)), signaling factors (tyrosinkinase receptors and α5β1-integrin), and endolisosomal host-cell factors (cathepsins B and L and Niemann-Pick C1 protein. The study of the complex set of virus entry events provides potential avenues for the development of antiviral therapies against Ebola fever.

вирус Эболафиловирусыпроникновение вирусаэндоцитозфакторы присоединениясигнальные факторыэндолизосомальные факторыклетка-хозяинEbola virushemorrhagic feverfilovirusvirus entryendocytosisattachment factorssignaling factorsendolisosomal factorshost-cellReferencesAlbarino C.G., Shoemaker T., Khristova M.L., Wamala J.F., Muyembe J.J., Balinandi S., Tumusiime A., Campbell S., Cannon D., Gibbons A., Bergeron E., Bird B., Dodd K., Spiropoulou C., Erickson B.R., Guerrero L., Knust B., Nichol S.T., Rollin P.E., Stroher U. Genomic analysis of filoviruses associated with four viral hemorrhagic fever outbreaks in Uganda and the Democratic Republic of the Congo in 2012. Virology. 2013; 442:97-100.Albarino C.G., Shoemaker T., Khristova M.L., Wamala J.F., Muyembe J.J., Balinandi S., Tumusiime A., Campbell S., Cannon D., Gibbons A., Bergeron E., Bird B., Dodd K., Spiropoulou C., Erickson B.R., Guerrero L., Knust B., Nichol S.T., Rollin P.E., Stroher U. Genomic analysis of filoviruses associated with four viral hemorrhagic fever outbreaks in Uganda and the Democratic Republic of the Congo in 2012. Virology. 2013; 442:97–100.Baize S., Pannetier D., Oestereich L., Rieger T., Koivogui L. Emergence of Zaire Ebola Virus Disease in Guinea. N. Engl. J. Med. 2014; 371(15):1418-25.Baize S., Pannetier D., Oestereich L., Rieger T., Koivogui L. Emergence of Zaire Ebola Virus Disease in Guinea. N. Engl. J. Med. 2014; 371(15):1418–25.Barrientos L.G., O'Keefe B.R., Bray M., Sanches A., Gronenborn A.M., Boyd M.R. Cyanovirin-N binds to viral surface glycoprotein, G 1,2 and inhibits infectivity of Ebola virus. Antivirus Res. 2003; 58:47-56.Barrientos L.G., OKeefe B.R., Bray M., Sanches A., Gronenborn A.M., Boyd M.R. Cyanovirin-N binds to viral surface glycoprotein, G 1,2 and inhibits infectivity of Ebola virus. Antivirus Res. 2003; 58:47–56.Basu A., Li B., Mills D.M., Panchal R.G., Cardinale S.C., Butler M.M., Peet N.P. Identification of small molecule entry inhibitor for filoviruses. J. Virol. 2011; 85:3106-19.Basu A., Li B., Mills D.M., Panchal R.G., Cardinale S.C., Butler M.M., Peet N.P. Identification of small molecule entry inhibitor for filoviruses. J. Virol. 2011; 85:3106–19.Cote M., Misasi J., Ren T., Bruches A., Lee K., Filone C.M., Hensley L., Li Q., Ory D., Chandran K. Small molecule inhibitors reveal Niemann-Pick C1 is essential for Ebola virus infection. Nature. 2011; 477:344-8.Cote M., Misasi J., Ren T., Bruches A., Lee K., Filone C.M., Hensley L., Li Q., Ory D., Chandran K. Small molecule inhibitors reveal Niemann-Pick C1 is essential for Ebola virus infection. Nature. 2011; 477:344–8.Empig C.J., Goldsmith M.A. Associacion of the calveola vesicular system with cellular entry by filoviruses. J. Virol. 2003; 76:5266-70.Empig C.J., Goldsmith M.A. Associacion of the calveola vesicular system with cellular entry by filoviruses. J. Virol. 2003; 76:5266–70.Feldmann H., Geisbert T.W. Ebola hemorrhagic fever. Lancet. 2011; 377:849-62.Feldmann H., Geisbert T.W. Ebola hemorrhagic fever. Lancet. 2011; 377:849–62.Geisbert T.W., Hensley L.E., Gibb T.R., Steele K.E., Jaax N.K., Jahrling P.B. Apoptosis induced in vitro and in vivo during infection by Ebola and Marburg viruses. Lab. Invest. 2000; 80:171-86.Geisbert T.W., Hensley L.E., Gibb T.R., Steele K.E., Jaax N.K., Jahrling P.B. Apoptosis induced in vitro and in vivo during infection by Ebola and Marburg viruses. Lab. Invest. 2000; 80:171–86.Geisbert T.W., Hensley L.E., Larsen T., Young H.A., Reed D.S., Geisbert J.B., Scott D.P., Kagan E., Jahrling P.B., Davis K.J. Pathogenesis of Ebola hemorrhagic fever in cynomolgus macaques: evidence that dendritic cells are early and sustained targets of infection. Am. J. Pathol. 2003; 163:2347-70.Geisbert T.W., Hensley L.E., Larsen T., Young H.A., Reed D.S., Geisbert J.B., Scott D.P., Kagan E., Jahrling P.B., Davis K.J. Pathogenesis of Ebola hemorrhagic fever in cynomolgus macaques: evidence that dendritic cells are early and sustained targets of infection. Am. J. Pathol. 2003; 163:2347–70.Hartman A.L., Towner J.S., Nichol S.T. Ebola and Marburg hemorrhagic fever. Clin. Lab. Med. 2010; 30:161-77.Hartman A.L., Towner J.S., Nichol S.T. Ebola and Marburg hemorrhagic fever. Clin. Lab. Med. 2010; 30:161–77.Hofmann-Winkler H., Kaup F., Pohlman S. Host cell factors in filovirus entry; novel players, new insights. Viruses. 2012; 4:3336-62.Hofmann-Winkler H., Kaup F., Pohlman S. Host cell factors in filovirus entry; novel players, new insights. Viruses. 2012; 4:3336–62.Hunt C.L., Lennenmann N.J., Maury W. Filovirus entry: a novelty in the viiralfusion world. Viruses. 2012; 4:258-75.Hunt C.L., Lennenmann N.J., Maury W. Filovirus entry: a novelty in the viiralfusion world. Viruses. 2012; 4:258–75.Коnduru K., Bradfute S.B., Jasquess J., Manangeeswaran M., Nakamura S., Morshed S., Wood S.C., Bavary S., Kaplan G.G. Ebola virus glycoprotein Fc fusion protein confer protection against lethal challenge in vaccinated mice. Vaccine. 2011; 29:2968-77.К оnduru K., Bradfute S.B., Jasquess J., Manangeeswaran M., Nakamura S., Morshed S., Wood S.C., Bavary S., Kaplan G.G. Ebola virus glycoprotein Fc fusion protein confer protection against lethal challenge in vaccinated mice. Vaccine. 2011; 29:2968–77.Kuhn J.H., Radoshitzky S.R., Guth A.C., Warfield K.L., Li W., Vincent M.J., Towner J.S., Nichol S.T., Bavary S., Choe H. Conserved receptor-binding domains of Lake Victoria marburgvirus and Zaire ebolavirus bind a common receptor. J. Biol. Chem. 2006; 281:15951-8.Kuhn J.H., Radoshitzky S.R., Guth A.C., Warfield K.L., Li W., Vincent M.J., Towner J.S., Nichol S.T., Bavary S., Choe H. Conserved receptor-binding domains of Lake Victoria marburgvirus and Zaire ebolavirus bind a common receptor. J. Biol. Chem. 2006; 281:15951–8.Kuhn J.H., Becker S., Ebihara H., Geisbert T.W., Johnson K.M., Kawaoka Y., Lipkin W.I., Negredo A.I., Netesov S.V., Nichol S.T., Palacios G., Peters C.J., Tenorio A., Volchkov V.E., Jahrling P.B. Proposal for a revised taxonomy of the family Filoviridae: Classification, names of taxa and viruses, and virus abbreviations. Arch. Virol. 2010; 155:2083-103.Kuhn J.H., Becker S., Ebihara H., Geisbert T.W., Johnson K.M., Kawaoka Y., Lipkin W.I., Negredo A.I., Netesov S.V., Nichol S.T., Palacios G., Peters C.J., Tenorio A., Volchkov V.E., Jahrling P.B. Proposal for a revised taxonomy of the family Filoviridae: Classification, names of taxa and viruses, and virus abbreviations. Arch. Virol. 2010; 155:2083–103.Kuhn J.H., Bao Y., Bavari S., Becker S., Bradfute S., Brauburger K., Rodney Brister J., Bukreyev A.A., Cai Y., Chandran K., Davey R.A., Dolnik O., Dye J.M., Enterlein S., Gonzalez J.P., Formenty P., Freiberg A.N., Hensley L.E., Hoenen T., Honko A.N., Ignatyev G.M., Jahrling P.B., Johnson K.M., Klenk H.D., Kobinger G., Lackemeyer M.G., Leroy E.M., Lever M.S., Mühlberger E., Netesov S.V., Olinger G.G., Palacios G., Patterson J.L., Paweska J.T., Pitt L., Radoshitzky S.R., Ryabchikova E.I., Saphire E.O., Shestopalov A.M., Smither S.J., Sullivan N.J., Swanepoel R., Takada A., Towner J.S., van der Groen G., Volchkov V.E., Volchkova V.A., Wahl-Jensen V., Warren T.K., Warfield K.L., Weidmann M., Nichol S.T. Virus nomenclature below the species level: a standardized nomenclature for filovirus strains and variants rescued from cDNA. Arch. Virol. 2014; 159(5):1229-37.Kuhn J.H., Bao Y., Bavari S., Becker S., Bradfute S., Brauburger K., Rodney Brister J., Bukreyev A.A., Cai Y., Chandran K., Davey R.A., Dolnik O., Dye J.M., Enterlein S., Gonzalez J.P., Formenty P., Freiberg A.N., Hensley L.E., Hoenen T., Honko A.N., Ignatyev G.M., Jahrling P.B., Johnson K.M., Klenk H.D., Kobinger G., Lackemeyer M.G., Leroy E.M., Lever M.S., Mühlberger E., Netesov S.V., Olinger G.G., Palacios G., Patterson J.L., Paweska J.T., Pitt L., Radoshitzky S.R., Ryabchikova E.I., Saphire E.O., Shestopalov A.M., Smither S.J., Sullivan N.J., Swanepoel R., Takada A., Towner J.S., van der Groen G., Volchkov V.E., Volchkova V.A., Wahl-Jensen V., Warren T.K., Warfield K.L., Weidmann M., Nichol S.T. Virus nomenclature below the species level: a standardized nomenclature for filovirus strains and variants rescued from cDNA. Arch. Virol. 2014; 159(5):1229–37.Lee J.E., Fusco M.L., Hessell A.J., Oswald W.B., Burton D.R., Saphire E.O. Structure of Ebola virus glycoprotein bound to an antibody from a human survivor. Nature. 2008; 454:177-82.Lee J.E., Fusco M.L., Hessell A.J., Oswald W.B., Burton D.R., Saphire E.O. Structure of Ebola virus glycoprotein bound to an antibody from a human survivor. Nature. 2008; 454:177–82.Lee J.E., Saphire E.O. Ebolavirus glycoprotein structure and mechanism of entry. Future Virol. 2009; 4:621-35.Lee J.E., Saphire E.O. Ebolavirus glycoprotein structure and mechanism of entry. Future Virol. 2009; 4:621–35.Martinez O., Ndungo E., Tantral L., Miller E.H., Leung L.W., Chandran K., Basler C.F. A mutation in the Ebola virus envelope glycoprotein restricts viral entry in a host species- and cell-type - specific manner. J. Virol. 2013; 87:3324-34.Martinez O., Ndungo E., Tantral L., Miller E.H., Leung L.W., Chandran K., Basler C.F. A mutation in the Ebola virus envelope glycoprotein restricts viral entry in a host species- and cell-type – specific manner. J. Virol. 2013; 87:3324–34.Marzi A., Reinheckel T., Feldmann H. Cathepsis B and L are not required for Ebola virus replication. PLoS Negl. Trop. Dis. 2012; 6:1-9.Marzi A., Reinheckel T., Feldmann H. Cathepsis B and L are not required for Ebola virus replication. PLoS Negl. Trop. Dis. 2012; 6:1–9.Muller E.H., Harrison J.S., Radoshitzky S.R., Huggins C.D., Chi X., Dong L., Kuhn J.H., Bavari S., Lai J.R., Chanran K. Inhibition of Ebola virus entry by a C-peptide targeted to endosomes. J. Biol. Chem. 2011; 286:15854-61.Muller E.H., Harrison J.S., Radoshitzky S.R., Huggins C.D., Chi X., Dong L., Kuhn J.H., Bavari S., Lai J.R., Chanran K. Inhibition of Ebola virus entry by a C-peptide targeted to endosomes. J. Biol. Chem. 2011; 286:15854–61.Muller E.H., Obernoster G., Raaben M., Herbert A.S., Deffieu M.S., Krishnan A., Ndungo E., Sandesara R.G., Carette J.E., Kuehne A.I., Ruthel G., Pfeffer S.R., Due J.R., Whelan S.P., Brummelkamp T.R., Chandran K. Ebola virus entry requires the host-programmed recognition of an intracellular recognition of an intracellular receptor. EMBO J. 2012; 31:1947-60.Muller E.H., Obernoster G., Raaben M., Herbert A.S., Deffieu M.S., Krishnan A., Ndungo E., Sandesara R.G., Carette J.E., Kuehne A.I., Ruthel G., Pfeffer S.R., Due J.R., Whelan S.P., Brummelkamp T.R., Chandran K. Ebola virus entry requires the host-programmed recognition of an intracellular recognition of an intracellular receptor. EMBO J. 2012; 31:1947–60.Sanchez A., Geisbert T.W., Feldmann H. Filoviridae: Marburg and Ebola Viruses. In: Fields virology. Philadelphia, PA, USA: Lippincott Williams and Wilkins; 2007. Р. 1279-304.Sanchez A., Geisbert T.W., Feldmann H. Filoviridae: Marburg and Ebola Viruses. In: Fields virology. Philadelphia, PA, USA: Lippincott Williams and Wilkins; 2007. Р. 1279–304.Saseed M.F., Kolokoltsov A.A., Freiberg A.N., Holbrook M.R., Davey R.A. Phosphoinositide-3 kinase -act pathway controls cellular entry of Ebola virus. PLoS Pathog. 2008; 4(8):1-11.Saseed M.F., Kolokoltsov A.A., Freiberg A.N., Holbrook M.R., Davey R.A. Phosphoinositide-3 kinase -act pathway controls cellular entry of Ebola virus. PLoS Pathog. 2008; 4(8):1–11.Saseed M.F., Kolokoltsov A.A., Albrecht T., Davey R.A. Cellular entry of Ebola virus involves uptake by macropinocytosis-like mechanism and subsequent trafficking through early and late endosomes. PLoS Pathog. 2010; 6(9):1-15.Saseed M.F., Kolokoltsov A.A., Albrecht T., Davey R.A. Cellular entry of Ebola virus involves uptake by macropinocytosis-like mechanism and subsequent trafficking through early and late endosomes. PLoS Pathog. 2010; 6(9):1–15.Simmons G., Rennekamp A.J., Chai N., Vandenberghe L.H., Riley J.L., Bates P. Folate receptor alpha and calveola are not required for Ebola virus glycoprotein-mediated virus infection. J. Virol. 2003; 77:13433-8.Simmons G., Rennekamp A.J., Chai N., Vandenberghe L.H., Riley J.L., Bates P. Folate receptor alpha and calveola are not required for Ebola virus glycoprotein-mediated virus infection. J. Virol. 2003; 77:13433–8.Stroher U., West E., Bugany H., Klenk H.D., Schnittler H.J., Feldman H. Infection and activation of monocytes by Marburg and Ebola viruses. J. Virol. 2001; 75:11025-33.Stroher U., West E., Bugany H., Klenk H.D., Schnittler H.J., Feldman H. Infection and activation of monocytes by Marburg and Ebola viruses. J. Virol. 2001; 75:11025–33.Takada A., Robinson G., Goto H., Sanchez A., Murty R.G., Whitt M.A., Kawaoka Y.A. A system for functional analysis of Ebola virus glycoprotein. Proc. Natl. Acad. Sci USA. 1997; 94:14764-9.Takada A., Robinson G., Goto H., Sanchez A., Murty R.G., Whitt M.A., Kawaoka Y.A. A system for functional analysis of Ebola virus glycoprotein. Proc. Natl. Acad. Sci USA. 1997; 94:14764–9.Volchkov V.E., Feldmann H., Volchkova V.A., Klenk H.D. Processing of Ebola virus glycoprotein be polyprotein convertase furin. Proc. Natl. Acad. Sci USA. 1998; 95:5762-7.Volchkov V.E., Feldmann H., Volchkova V.A., Klenk H.D. Processing of Ebola virus glycoprotein be polyprotein convertase furin. Proc. Natl. Acad. Sci USA. 1998; 95:5762–7.Wool-Lewis R.J., Bates P. Characterization of Ebola virus entry bu using pseudotyped viruses: identification of receptor - deficient cell lines. J. Virol. 1998; 72(4):3155-60.Wool-Lewis R.J., Bates P. Characterization of Ebola virus entry bu using pseudotyped viruses: identification of receptor – deficient cell lines. J. Virol. 1998; 72(4):3155–60.Yang Z.Y., Duckers H.J., Sullivan N.J., Sanchez A., Nabel E.G., Nabel G.J. Identification of the Ebola virus glycoprotein as main viral determinant of vascular cell cytotoxicity and injury. Nat. Med. 2000; 6:886-9.Yang Z.Y., Duckers H.J., Sullivan N.J., Sanchez A., Nabel E.G., Nabel G.J. Identification of the Ebola virus glycoprotein as main viral determinant of vascular cell cytotoxicity and injury. Nat. Med. 2000; 6:886–9.

The authors declare that there are no conflicts of interest present.