Russian Journal of Infection and ImmunityRussian Journal of Infection and ImmunityИнфекция и иммунитет2220-76192313-7398SPb RAACI2610.15789/2220-7619-2011-1-29-42REVIEWSОБЗОРЫTHE OUTER MEMBRANE OF PATHOGENIC REPRESENTATIVES OF THE LEPTOSPIRA GENIUSНАРУЖНАЯ МЕМБРАНА ПАТОГЕННЫХ ПРЕДСТАВИТЕЛЕЙ РОДА LEPTOSPIRAVaganovaA. N.ВагановаА. Н.
Russian Federation

научный сотрудник лаборатории зооантропонозных инфекций

197101, Санкт-Петербург, ул. Мира, 14

yersinia@land.ruФГУН «Санкт-Петербургский научно-исследовательский институт эпидемиологии и микробиологии имени Пастера» Роспотребнадзора, Санкт-Петербург240620111129422506201425062014Copyright ©; 2014, Vaganova A.N.Copyright ©; 2014, Ваганова А.Н.2014Vaganova A.N.Ваганова А.Н.https://creativecommons.org/licenses/by/4.0https://iimmun.ru/iimm/article/view/26

Abstract. Pathogenic leptospires can infect wide spectrum of hosts and they can survive in the environment long time. The outer membrane is the cellular component participated in interaction of microorganisms and environment. In present time several proteins located in the outer membrane of leptospires which are responsible for colonization of host organism, protection from influence of immune system of host, transport of substances in to the cell and other processes have been described. The outer membrane contains proteins and lipopolysaccharide molecules which have citotoxic effect. It was shown that regulation of protein composition of membranes depends on several factors of environment such as temperature, osmolarity, presence of certain substances in environment. Lipopolysaccharide and protein molecules of outer membranes have antigenic properties. These molecules can be used in practice as the components of vaccine against leptospiroses and diagnostic tools. Current review summarize information concerning structural organization of the outer membrane of leptospires, diversities of incoming parts of molecules and regulation of their synthesis. Moreover, perspectives of practical using of the outer membrane components in diagnostics and prevention of leptospiroses are presented.

Резюме. Патогенные лептоспиры способны поражать широкий спектр хозяев, и длительно сохраняются в окружающей среде. Наружная мембрана — компонент клетки, участвующий во взаимодействии микроорганизма со средой обитания. В настоящее время описан ряд белков, представленных в наружной мембране лептоспир и отвечающих за колонизацию организма хозяина, защиту от воздействия иммунной системы, поступление веществ в клетку и ряд других процессов. Наружная мембрана содержит белки и молекулы липополисахарида, обладающие цитотоксическим эффектом. Показано, что регуляция белкового состава мембран зависит от ряда факторов окружающей среды, таких как температура, осмолярность, наличие в среде тех или иных веществ. Как липополисахарид, так и белковые молекулы наружной мембраны обладают антигенными свойствами. Препараты таких соединений могут использоваться в практических целях, как компоненты лептоспирозных вакцин и диагностикумов. Настоящий обзор посвящен вопросам структурной организации наружной мембраны лептоспир, разнообразия входящих в ее состав молекул и регуляции их синтеза, а также перспективам практического применения компонентов наружной мембраны в сфере диагностики и профилактики лептоспирозной инфекции.

Leptospiraantigensouter membranelipopolysaccharideLeptospiraантигенынаружная мембраналипополисахарид1. Ананьина Ю.В., Зайцев С.В. Внутривидовая гетерогенность Leptospira interrogans по экологическим признакам // Идеи Пастера в борьбе с инфекциями: Материалы конф. — СПб., 1995. — С. 123.2. Карасева Е.В. Некоторые особенности экологии патогенных лептоспир в естественных условиях природного очага // ЖМЭИ. — 1974. — № 5. — С. 36–40.3. Куликов В.Н., Токаревич Н.К., Стоянова Н.А., Майорова С.О. Получение родоспецифических рекомбинантных антигенов лептоспир и изучение их активности // Идеи Пастера в борьбе с инфекциями: Материалы конф. — СПб., 2008. — С. 95.4. Amutha R., Chaudhuri P., Garg A.P., Cheema P.S., Srivastava S.K. Immunoreactive outer membrane proteins of Leptospira interrogans serovar Canicola strain Hond Utrecht IV // Indian J. Med. Res. — 2006. — Vol. 124, N 5. — P. 569–574.5. Artiushin S., Timoney J. F., Nally J., Verma A. Hostinducible immunogenic sphingomyelinase-like protein, Lk73.5, of Leptospira interrogans // Infect. Immun. — 2004. — Vol. 72, N 2. — P. 742–749.6. Asuthkar S., Velineni S., Stadlmann J., Altmann F., Sritharan M. Expression and characterization of an iron-regulated hemin-binding protein, HbpA, from Leptospira interrogans serovar Lai // Infect. Immun. — 2007. — Vol. 75, N 9. — P. 4582–4591.7. Atzingen M.V., Barbosa A.S., De Brito T., Vasconcellos S.A., de Morais Z.M., Lima D.M., Abreu P.A., Nascimento A.L. Lsa21, a novel leptospiral protein binding adhesive matrix molecules and present during human infection // BMC Microbiol. — 2008. — Vol. 8. — e70.8. Barbosa A.S., Abreu P.A.E., Neves F.O., Atzingen M.V., Watanabe M.M., Vieira M.L., Morais Z.M., Vasconcellos S.A., Nascimento A.L. A newly identified leptospiral adhesin mediates attachment to laminin // Infect. Immun. — 2006. — Vol. 74, N 11. — P. 6356–6364.9. J.K., Barnett D., Bolin C.A., Summers T.A., Wagar E.A., Cheville N.F., Hartskeerl R.A., Haake D.A. Expression and distribution of leptospiral outer membrane components during renal infection of hamsters // Infect. Immun. — 1999. — Vol. 67, N 2. — P. 853–861.10. J.A., LeFebvre R.B., Pan M.J. Protein and antigen profiles of prevalent serovars of Leptospira interrogans // Infect. Immun. — 1991. — Vol. 59, N 5. — P. 1772–1777.11. Braun V., Wolff H. The murein-lipoprotein linkage in the cell wall of Escherichia coli // Eur. J. Biochem. — 1970. — Vol. 14, N 2. — P. 387–391.12. Bulach D.M., Kalambaheti T., de la Pea-Moctezuma A., Adler B. Functional analysis of genes in the rfb locus of Leptospira borgpetersenii serovar Hardjo subtype Hardjobovis // Infect. Immun. — 2000. — Vol. 68, N 7. — P. 3793–3798.13. Cachay E.R., Vinetz J.M. A global research agenda for leptospirosis // J. Postgrad. Med. — 2005. — Vol. 51, N 3. — P. 174–178.14. Carvalho E., Barbosa A.S., Gmez R.M., Cianciarullo A.M., Hauk P., Abreu P.A., Fiorini L.C., Oliveira M.L., Romero E.C., Gon ales A.P., Morais Z.M., Vasconcellos S.A., Ho P.L. Leptospiral TlyC is an extra cellular matrix-binding protein and does not present hemolysin activity // FEBS Lett. — 2009. — Vol. 583, N 8. — P. 1381–1385.15. Cerqueira G.M., McBride A.J., Picardeau M., Ribeiro S.G., Moreira A.N., Morel V., Reis M.G., Ko A.I., Dellagostin O.A. Distribution of the leptospiral immunoglobulin-like (lig) genes in pathogenic Leptospira species and application of ligB to typing leptospiral isolates // J. Med. Microbiol. — 2009. — Vol. 58, N 9. — P. 1173 –1181.16. Chapman A.J., Everard C.O., Faine S., Adler B. Antigens recognized by the human immune response to severe leptospirosis in Barbados // Epidemiol. Infect. — 1991. — Vol. 107, N 1. — P. 143–155.17. Chassin C., Picardeau M., Goujon J.M., Bourhy P., Quellard N., Darche S., Badell E., d'Andon M.F., Winter N., Lacroix-Lamand S., Buzoni-Gatel D., Vandewalle A., Werts C. TLR4- and TLR2-mediated B cell responses control the clearance of the bacterial pathogen, Leptospira interrogans // J. Immunol. — 2009. — Vol. 183, N 4. — P. 2669–2677.18. Choy H.A. Kelley M.M., Chen T.L., Mller A.K., Matsunaga J., Haake D.A. Physiological osmotic induction of Leptospira interrogans adhesion: LigA and LigB bind extracellular matrix proteins and fibrinogen // Infect. Immun. — 2007. — Vol. 5, N 5. — P. 2441–2450.19. Cinco M., Banfi E., Panfili E. Heterogeneity of lipopolysaccharide banding patterns in Leptospira spp // J. Gen. Microbiol. — 1986. — Vol. 132, N 4. — P. 1135–1138.20. Croda J., Ramos J.G., Matsunaga J., Queiroz A., Homma A., Riley L.W., Haake D.A., Reis M.G., Ko A.I. Leptospira immunoglobulin-like proteins as a serodiagnostic marker for acute leptospirosis // J. Clin. Microbiol. — 2007. — Vol. 45, N 5. — P. 1528–1534.21. Cullen P.A., Cordwell S.J., Bulach D.M., Haake D.A., Adler B. Global analysis of outer membrane proteins from Leptospira interrogans serovar Lai // Infect. Immun. — 2002. — Vol. 70, N 5. — P. 2311–2318.22. Cullen P.A., Haake D.A., Bulach D.M., Zuerner R.L., Adler B. LipL21 is a novel surface-exposed lipoprotein of pathogenic Leptospira species // Infect. Immun. — 2003. — Vol. 71, N 5. — P. 2414–2421.23. Dey S., Mohan C.M., Ramadass P., Nachimuthu K. Diagnosis of leptospirosis by recombinant antigen based single serum dilution ELISA // Indian J. Med. Res. — 2008. — Vol. 128, N 2. — P. 172–177.24. Dong H., Hu Y., Xue F., Sun D., Ojcius D.M., Mao Y., Yan J. Characterization of the ompL1 gene of pathogenic Leptospira species in China and cross-immunogenicity of the OmpL1 protein // BMC Microbiol. — 2008. — Vol. 8. — e223.25. Eshghi A., Cullen P.A., Cowen L., Zuerner R.L., Cameron C.E. Global proteome analysis of Leptospira interrogans // J. Proteome Res. — 2009. — Vol. 8, N 10. — P. 456 4 – 4578.26. Faine S., Adler B., Bolin C., Perolat P. Leptospira and Leptospirosis. — Melbourn: MediSci, 1999. — 272 p.27. Feng C.Y., Li Q.T., Zhang X.Y., Dong K., Hu B.Y., Guo X.K. Immune strategies using single-component LipL32 and multi-component recombinant LipL32–41-OmpL1 vaccines against Leptospira // Braz. J. Med. Biol. Res. — 2009. — Vol. 42, N 9. — P. 796–803.28. Flannery B., Costa D., Carvalho F.P., Guerreiro H., Matsunaga J., Da Silva E.D., Ferreira A.G., Riley L.W., Reis M.G., Haake D.A., Ko A.I. Evaluation of recombinant Leptospira antigen-based enzyme-linked immunosorbent assays for the serodiagnosis of leptospirosis // J. Clin. Microbiol. — 2001. — Vol. 39, N 9. — P. 3303–3310.29. Guerreiro H., Croda J., Flannery B., Mazel M., Matsunaga J., Galvão Reis M., Levett P.N., Ko A.I., Haake D.A. Leptospiral proteins recognized during the humoral immune response to leptospirosis in hu mans // Infect. Immun. — 2001. — Vol. 69, N 8. — P. 4958–4968.30. Haake D A. Spirochaetal lipoproteins and pathogenesis // Microbiology. — 2000. — Vol. 146. — P. 1491–1504.31. Haake D.A., Champion C.I., Martinich C., Shang E.S., Blanco D.R., Miller J.N., Lovett M.A. Molecular cloning and sequence analysis of the gene encoding OmpL1, a transmembrane outer membrane protein of pathogenic Leptospira spp. // J. Bacteriol. — 1993. — Vol. 175, N 13. — P. 4225–4234.32. Haake D.A., Chao G., Zuerner R.L. Barnett J.K., Barnett D., Mazel M., Matsunaga J., Levett P.N., Bolin C.A. The leptospiral major outer membrane protein LipL32 is a lipoprotein expressed during mammalian infection // Infect. Immun. — 2000. — Vol. 68, N 4. — P. 2276 –2285.33. Haake D.A., Martinich C., Summers T.A., Shang E.S., Pruetz J.D., McCoy A.M., Mazel M.K., Bolin C.A. Characterization of leptospiral outer membrane lipoprotein LipL36: downregulation associated with late-log-phase growth and mammalian infection // Infect. Immun. — 1998. — Vol. 66, N 4. — P. 1579–1587.34. Haake D.A., Matsunaga J. Leptospira: a spirochaete with a hybrid outer membrane // Mol. Microbiol. — 2010.35. Haake D.A., Mazel M.K., McCoy A.M., Milward F., Chao G., Matsunaga J., Wagar E.A. Leptospiral outer membrane proteins OmpL1 and LipL41 exhibit synergistic immunoprotection // Infect. Immun. — 1999. — Vol. 67, N 12. — P. 6572–6582.36. Haake D.A., Suchard M.A., Kelley M.M., Dundoo M., Alt D.P., Zuerner R.L. Molecular evolution and mosaicism of leptospiral outer membrane proteins involves horizontal DNA transfer // J. Bacteriol. — 2004. — Vol. 186, N 9. — P. 2818–2828.37. Haake D.A., Walker E.M., Blanco D.R., Bolin C.A., Miller M.N., Lovett M.A. Changes in the surface of Leptospira interrogans serovar grippotyphosa during in vitro cultivation // Infect. Immun. — 1991. — Vol. 59, N 3. — P. 1131–1140.38. Hoke D.E., Egan S., Cullen P.A., Adler B. LipL32 is an extracellular matrix-interacting protein of Leptospira spp. and Pseudoalteromonas tunicate // Infect. Immun. — 2008. — Vol. 76, N 5. — P. 2063–2069.39. Hung C.C., Chang C.T., Tian Y.C., Wu M.S., Yu C.C., Pan M.J., Vandewalle A., Yang C.W. Leptospiral membrane proteins stimulate pro-inflammatory chemokines secretion by renal tubule epithelial cells through toll-like receptor 2 and p38 mitogen activated protein kinase // Nephrol. Dial. Transplant. — 2006. — Vol. 21, N 4. — P. 898–910.40. Isogai E., Isogai H., Kubota T., Fujii N., Hayashi S., Indoh T., Takagi S., Miura H., Kimura K. Apoptosis of lymphocytes in mice administered lipopolysaccharide from Leptospira interrogans // Zentralbl. Veterinarmed B. — 1998. — Vol. 45, N 9. — P. 529–537.41. Isogai E., Isogai H., Kurebayashi Y., Ito N. Biological activities of leptospiral lipopolysaccharide // Zentralbl Bakteriol Mikrobiol Hyg A. — 1986. — Vol. 261, N 1. — P. 53 – 64.42. Koizumi N., Watanabe H. Leptospiral immunoglobulin-like proteins elicit protective immunity // Vaccine. — 2004. — Vol. 22, N 11–12. — P. 1545–1552.43. Lee S.H., Kim K.A., Park Y.G., Seong I.W., Kim M.J., Lee Y.J. Identification and partial characterization of a novel hemolysin from Leptospira interrogans serovar lai // Gene. — 2000. — Vol. 254. — P. 19–28.44. Levett P.N. Leptospirosis // Clin. Microbiol. Rev. — 2001. — Vol. 14, N 2. — P. 296–326.45. Lin X., Chen Y., Lu Y., Yan J., Yan J. Application of loop-mediated isothermal amplification method for the detection of pathogenic Leptospira // Diagn. Microbiol. Infect. Dis. — 2009. — Vol. 63, N 3. — P. 237–242.46. Lin X., Chen Y., Yan J., Adler B. Recombinant multiepitope protein for diagnosis of leptospirosis // Clin. Vaccine Immunol. — 2008. — Vol. 15, N 11. — P. 1711–1714.47. Lo M., Cordwell S.J., Bulach D.M., Adler B. Comparative transcriptional and translational analysis of leptospiral outer membrane protein expression in response to temperature // PLoS Negl Trop Dis. — 2009. — Vol. 3, N 12. — e560.48. Longhi M.T., Oliveira T.R., Romero E.C., Gonales A.P., de Morais Z.M., Vasconcellos S.A., Nascimento A.L. A newly identified protein of Leptospira interrogans mediates binding to laminin // J. Med. Microbiol. — 2009. — Vol. 58, N 10. — P. 1275–1282.49. Ludwig W., Euzby J., Whitman W.B. Draft taxonomic outline of the Bacteroidetes, Planctomycetes, Chlamydiae, Spirochaetes, Fibrobacteres, Fusobacteria, Acidobacteria, Verrucomicrobia, Dictyoglomi, and Gemmatimonadetes. Bergey’s Manual Trust, Bergey’s Taxonomic Outlines. — Vol. 4. — P. 16.50. Matsunaga J., Sanchez Y., Xu X, Haake D.A. Osmolarity, a key environmental signal controlling expression of leptospiral proteins LigA and LigB and the extracellular release of LigA // Infect. Immun. — 2005. — Vol. 73, N 1. — P. 70–78.51. Matsunaga J., Young T.A., Barnett J.K., Barnett D., Bolin C.A., Haake D.A. Novel 45-kilodalton leptospiral protein that is processed to a 31-kilodalton growth-phase-regulated peripheral membrane protein // Infect. Immun. — 2002. — Vol. 70, N 1. — P. 323–334.52. Matsunaga J., Barocchi M.A., Croda J., Young T.A., Sanchez Y., Siqueira I., Bolin C.A., Reis M.G., Riley L.W., Haake D.A., Ko A.I. Pathogenic Leptospira species express surface-exposed proteins belonging to the bacterial immunoglobulin superfamily // Mol. Microbiol. — 2003. — Vol. 49, N 4. — P. 929–945.53. Matsunaga J., Werneid K., Zuerner R.L., Frank A., Haake D.A. LipL46 is a novel surface-exposed lipoprotein expressed during leptospiral dissemination in the mammalian host // Microbiology. — 2006. — Vol. 152, N 12. — P. 3777–3786.54. Nahori M.A., Fourni-Amazouz E., Que-Gewirth N.S., Balloy V., Chignard M., Raetz C.R., Saint Girons I., Werts C. Differential TLR recognition of leptospiral lipid A and lipopolysaccharide in murine and human cells // J. Immunol. — 2005. — Vol. 175, N 9. — P. 6022–6031.55. Nally J.E., Chow E., Fishbein M.C., Blanco D.R., Lovett M.A. Changes in lipopolysaccharide O antigen distinguish acute versus chronic Leptospira interrogans infections // Infect. Immun. — 2005. — Vol. 73, N 6. — P. 3251–3260.56. Nally J.E., Timoney J.F., Stevenson B. Temperature-regulated protein synthesis by Leptospira interrogans // Infect. Immun. — 2001. — Vol. 69, N 1. — P. 400–404.57. Nally J.E., Whitelegge J.P., Bassilian S., Blanco D.R., Lovett M.A. Characterization of the outer membrane proteome of Leptospira interrogans expressed during acute lethal infection // Infect. Immun. — 2007. — Vol. 75, N 2. — P. 766–773.58. Nascimento A.L., Verjovski-Almeida S., Van Sluys M.A., Monteiro-Vitorello C.B., Camargo L.E., Digiampietri L.A., Harstkeerl R.A., Ho P.L., Marques M.V., Oliveira M.C., Setubal J.C., Haake D.A., Martins E.A. Genome features of Leptospira interrogans serovar Copenhageni // Braz. J. Med. Biol. Res. — 2004. — Vol. 37, N 4. — P. 459–477.59. Okuda M., Sakai Y., Matsuuchi M., Oikawa T., Watanabe M., Itamoto K., Iwata H., Kano R., Hasegawa A., Onishi T., Inokuma H. Enzyme-linked immunosorbent assay for the detection of canine Leptospira antibodies using recombinant OmpL1 protein // J. Vet. Med. Sci. — 2005. — Vol. 67, N 3. — P. 249 –254.60. Oliveira T.R., Longhi M.T., de Morais Z.M., Romero E.C., Blanco R.M., Kirchgatter K., Vasconcellos S.A., Nascimento A.L. Evaluation of leptospiral recombinant antigens MPL17 and MPL21 for serological diagnosis of leptospirosis by enzyme-linked immunosorbent assays // Clin. Vaccine Immunol. — 2008. — Vol. 15, N 11. — P. 1715–1722.61. Palaniappan R.U.M., Chang Y.-F., Hassan F., McDonough S.P., Pough M., Barr S.C., Simpson K.W., Mohammed H.O., Shin S., McDonough P., Zuerner R.L., Qu J., Roe B. Expression of leptospiral immunoglobulin-like protein by Leptospira interrogans and evaluation of its diagnostic potential in a kinetic ELISA / J. Med. Microbiol. — 2004. — Vol. 53. – P. 975–984.62. Palaniappan R.U., Chang Y.F., Jusuf S.S., Artiushin S., Timoney J.F., McDonough S.P., Barr S.C., Divers T.J., Simpson K.W., McDonough P.L., Mohammed H.O. Cloning and molecular characterization of an immunogenic LigA protein of Leptospira interrogans // Infect. Immun. — 2002. — Vol. 70, N 10. — P. 5924–5930.63. Palaniappan R.U., McDonough S.P., Divers T.J., Chen C.S., Pan M.J., Matsumoto M., Chang Y.F. Immuno protection of recombinant leptospiral immunoglobulin-like protein A against Leptospira interrogans serovar Pomona infection // Infect. Immun. — 2006. — Vol. 74, N 3. — P. 1745–1750.64. Paster B.J., Dewhirst F.E., Weisburg W.G., Tordoff L.A., Fraser G.J., Hespell R.B., Stanton T.B., Zablen L., Mandelco L., Woese C.R. Phylogenetic analysis of the spirochetes // J. Bacteriol. — 1991. — Vol. 173, N 19. — P. 6101– 6109.65. Patarakul K., Lo M., Adler B. Global transcriptomic response of Leptospira interrogans serovar Copenhageni upon exposure to serum // BMC Microbiol. — 2010. — Vol. 10. — e31.66. Peсa-Moctezuma A. de la, Bulach D.M., Kalambaheti T., Adler B. Comparative analysis of the LPS biosynthetic loci of the genetic subtypes of serovar Hardjo: Leptospira interrogans subtype Hardjoprajitno and Leptospira borgpetersenii subtype Hardjobovis // FEMS Microbiol Lett. — 1999. — Vol. 177, N 2. — P. 319–326.67. Picardeau M., Bulach D.M., Bouchier C., Zuerner R.L., Zidane N., Wilson P.J., Creno S., Kuczek E.S., Bommezzadri S., Davis J.C., McGrath A., Johnson M.J., Boursaux-Eude C., Seemann T., Rouy Z., Coppel R.L., Rood J.I., Lajus A., Davies J.K., M digue C., Adler B. Genome sequence of the saprophyte Leptospira biflexa provides insights into the evolution of Leptospira and the pathogenesis of leptospirosis // PLoS One. — 2008. — Vol. 3, N 2. — e1607.68. Pinne M., Haake D.A. A comprehensive approach to identification of surface-exposed, outer membrane-spanning proteins of Leptospira interrogans // PLoS One. — 2009. — Vol. 4, N 6. — e6071.69. Qin J.H., Sheng Y.Y., Zhang Z.M., Shi Y.Z., He P., Hu B.Y., Yang Y., Liu S.G., Zhao G.P., Guo X.K. Genome-wide transcriptional analysis of temperature shift in L. interrogans serovar lai strain 56601 // BMC Microbiol. — 2006. — Vol. 6. — e51.70. Saengjaruk P., Chaicumpa W., Watt G., Bunyaraksyotin G., Wuthiekanun V., Tapchaisri P., Sittinont C., Panaphut T., Tomanakan K., Sakolvaree Y., Chongsa-Nguan M., Mahakunkijcharoen Y., Kalambaheti T., Naigowit P., Wambangco M.A., Kurazono H., Hayashi H. Diagnosis of human leptospirosis by monoclonal antibody-based antigen detection in urine // J. Clin. Microbiol. — 2002. — Vol. 40, N 2.– P. 480–489.71. Shang E.S., Exner M.M., Summers T.A., Martinich C., Champion C.I., Hancock R.E., Haake D.A. The rare outer membrane protein, OmpL1, of pathogenic Leptos pira species is a heat-modifiable porin // Infect. Immun. — 1995. — Vol. 63, N 8. — P. 3174–3181.72. Shang E.S., Summers T.A., Haake D.A. Molecular cloning and sequence analysis of the gene encoding LipL41, a surface-exposed lipoprotein of pathogenic Leptospira species // Infect. Immun. — 1996. — Vol. 64, N 6. — P. 2322–2330.73. Silva E.F., Medeiros M.A., McBride A.J., Matsunaga J., Esteves G.S., Ramos J.G., Santos C.S., Croda J., Homma A., Dellagostin O.A., Haake D.A., Reis M.G., Ko A.I. The terminal portion of leptospiral immunoglobulin-like protein LigA confers protective immunity against lethal infection in the hamster model of leptospirosis // Vaccine. — 2007. — Vol. 25, N 33. — P. 6277–6286.74. Srivastava S.K., Chaudhuri P., Thangapandian E., Mariya R., Amutha R. Evaluation of recombinant Leptospira interrogans serovar canicola outer membrane proteins as diagnostic antigen // Indian J. Med. Microbiol. — 2006. — Vol. 24, N 4. — P. 346–348.75. Stevenson B., Choy H.A., Pinne M., Rotondi M.L., Miller M.C., Demoll E., Kraiczy P., Cooley A.E., Creamer T.P., Suchard M.A., Brissette C.A., Verma A., Haake D.A. Leptospira interrogans endostatin-like outer membrane proteins bind host fibronectin, laminin and regulators of complement // PLoS One. — 2007. — Vol. 14, N 11. — e1188.76. Tahiliani P., Kumar M.M., Chandu D., Kumar A., Nagaraj C., Nandi D. Gel purified lipl32: a prospective antigen for detection of leptospirosis // J. Postgrad. Med. — 2005. — Vol. 51, N 3.– P. 164–168.77. Verma A., Hellwage J., Artiushin S., Zipfel P.F., Kraiczy P., Timoney J.F., Stevenson B. LfhA, a novel factor h-binding protein of Leptospira interrogans // Infect. Immun. — 2007. — Vol. 74, N 5. — P. 2659–2666.78. Vieira M.L., Pimenta D.C., de Morais Z.M., Vasconcellos S.A., Nascimento A.L. Proteome analysis of Leptospira interrogans virulent strain // Open Microbiol. J. — 2009. — Vol. 7, N 3. — P. 69–74.79. Vieira M.L., Atzingen M.V., Oliveira T.R., Oliveira R., Andrade D.M., Vasconcellos S.A., Nascimento A.L. In vitro identification of novel plasminogen-binding receptors of the pathogen Leptospira interrogans // PLoS One. — 2010. — Vol. 5, N 6. — e11259.80. Vijayachari P., Sugunan A.P., Shriram A.N. Leptospiro sis: an emerging global public health problem // J. Biosci. —2008. — Vol. 33, N 4. — P. 557–569.81. Vinh T., Adler B., Faine S. Ultrastructure and chemical composition of lipopolysaccharide extracted from Leptospira interrogans serovar copenhageni // J. Gen. Microbiol. — 1986. — Vol. 132, N 1. — P. 103–109.82. Werts C., Tapping R.I., Mathison J.C., Chuang T.H., Kravchenko V., Saint Girons I., Haake D.A., Godowski P.J., Hayashi F., Ozinsky A., Underhill D.M., Kirschning C.J., Wagner H., Aderem A., Tobias P.S., Ulevitch R.J. Leptospiral lipopolysaccharide activates cells through a TLR2-dependent mechanism // Nat. Immunol. — 2001. — Vol. 4, N 2. — P. 346–352.83. Yang C.W., Wu M.S., Pan M.J., Hsieh W.J., Vandewalle A., Huang C.C. The Leptospira outer membrane protein LipL32 induces tubulointerstitial nephritis-mediated gene expression in mouse proximal tubule cells // J. Am. Soc. Nephrol. — 2002. — Vol. 13, N 8. — P. 2037–2045.84. Yang H.L., Zhu Y.Z., Qin J.H., He P., Jiang X.C., Zhao G.P., Guo X.K. In silico and microarray-based genomic approaches to identifying potential vaccine candidates against Leptospira interrogans // BMC Genomics. — 2006. — Vol. 7. — e293.85. Zhang X.Y., Yu Y., He P., Zhang Y.X., Hu B.Y., Yang Y., Nie Y.X., Jiang X.G., Zhao G.P., Guo X.K. Expression and comparative analysis of genes encoding outer membrane proteins LipL21, LipL32 and OmpL1 in epidemic leptospires // Acta Biochim. Biophys. Sin. (Shanghai). — 2005. — Vol. 37, N 1. — P. 649–656.