Факторы патогенности Staphylococcus aureus - их роль в инфекционном процессе и в формировании поствакцинального иммунитета

Бурное развитие молекулярно-биологических и генетических методов исследования способствовало расширению и углублению знаний о патогенезе инфекционных заболеваний, структуре факторов патогенности и их роли в развитии постинфекционного и поствакцинального иммунитета. В обзоре представлены данные литературы по этим вопросам применительно к заболеваниям, вызываемым S. aureus, которые приобрели большую социальную и экономическую значимость. Приведен перечень многочисленных факторов патогенности S. aureus, их значимость в развитии инфекционного процесса и возможность применения при создании вакцинных препаратов. Большая часть вакцин, в конструкции которых использованы капсульные полисахариды, токсины, белковые антигены клеточной стенки, находятся на различных стадиях доклинических и клинических испытаний. Предварительные данные свидетельствуют о необходимости использования для создания протективного иммунитета мультиантиген-ного комплекса с направленностью на многочисленные факторы патогенности S. aureus.

Staphylococcus aureus, факторы патогенности, капсульный полисахарид, токсин, вакцина, инфекционный процесс, поствакцинальный иммунитет, экспериментальные модели, Staphylococcus aureus, pathogenicity factors, capsular polysaccharide, toxin, vaccine, infection process, post-vaccination immunity, experimental models

1. Данилов А.И., Алексеева И.В., Аснер Т.В., Власова Е.Е., Данилова Е.М., Дехнич А.В. и др. Этиология инфекционного эндокардита в России. Клин микробиол антимикроб химиотер. 2015; 17(1): 4 - 10.

2. Теплякова О.В., Руднов В.А., Шлыкова Г.И., Доценко Т.Г. Септический артрит у взрослых. Клин микробиол антимикроб химиотер. 2015; 17 (3): 187 - 206.

3. Otto M. Basis of virulence in community-associated methicillin-resistant Staphylococcus aureus. Annu. Rev. Microbiol. 2010; 64: 143 - 162.

4. Laabei M., Recker M., Rudkin J.K., Aldeljawi M., Gulay Z., Sloan T.J. et al. Predicting the virulence of MRSA from its genome sequence. Genome Res. 2014; 24: 839 - 849.

5. Noskin G.A., Rubin R.J., Schentag J.J., Kluytmans J., Hedblom E.C., Smulders M. et al. The burden of Staphylococcus aureus infections on hospitals in the United States: an analysis of the 2000 and 2001 Nationwide Inpatient Sample Database. Arch Intern Med. 2005; 165 (15):1756 - 1761.

6. Carrillo-Marquez M.A., Hulten K.G., Hammerman W., Lamberth L., Mason E.O., Kaplan S.L. Staphylococcus aureus pneumonia in children in the era of community-acquired methicillin-resistance at Texas Children’s Hospital. Pediatr. Infect. Dis. J. 2011; 30 (7): 545 - 550.

7. Del Giudice P, Tattevin P, Etienne J. Community-acquired methicillin-resistant Staphylococcus aureus: Review. Presse Med. 2012; 41 (7 - 8): 713 - 720.

8. Garcia-Romo G.S., Gonzalez-Ibarra M., Donis-Hernandez F.R., Zendejas-Buitron V.M., Pedroza-Gonzalez A. Immunization with heat-inactivated Staphylococcus aureus induced an antibody response mediated by IgG1 and IgG2 in patients with recurrent tonsillitis. Microbiol Immunol. 2015; 59(4):193-201.

9. von Eiff C., Becker K., Machka K., Stammer H., Peters G. Nasal carriage as a source of Staphylococcus aureus bacteremia. N. Engl. J. Med. 2001; 344 (1): 11 - 16.

10. McCarthy A.J., Lindsay J.A. Genetic variation in Staphylococcus aureus surface and immune evasion genes is lineage associated: implications for vaccine design and host-pathogen interactions. BMC Microbiology 2010; 10: 173. PMC 2905362.

11. Broughan J., Anderson R., Anderson A.S. Strategies for and advances in the development of Staphylococcus aureus prophylactic vaccines. Expert Rev. Vaccines 2011; 10: 695 - 708.

12. DeDent A., Kim H.K., Missiakas D., Schneewind O. Exploring Staphylococcus aureus pathways to disease for vaccine development. Semin Immunopathol. 2012; 34: 317 - 333.

13. Daum R.S., Spellberg B. Progress toward a Staphylococcus aureus vaccine. Clin. Infect. Dis. 2012; 54 (4): 560 - 567.

14. Дмитренко О.А. Род Staphylococcus. Руководство по медицинской микробиологии. Книга III. Том первый. Оппортунистические инфекции: возбудители и этиологическая диагностика. Под ред. А.С. Лабинской, Н.Н. Костюковой. Москва: Издательство БИНОМ. 2013; 31 - 87.

15. Scully I.L., Liberator P.A., Jansen K.U., Anderson A.S. Covering all the bases: preclinical development of an effective Staphylococcus aureus vaccine. Frontiers in Immunol. 2014; 5 (art 109): 1 - 7.

16. Lin L., Ibrahim A.S., Xu X., Farber J.M., Avanesian V., Baquir B. et al. Th1-Th17 cells mediate protective adaptive immunity against Staphylococcus aureus and Candida albicans infection in mice. PLoSPathog. 2009; 5 (12): РМС 2792038.

17. Rigby K.M., DeLeo F.R. Neutrophils in innate host defense against Staphylococcus aureus infections. Semin Immunopathol. 2012; 34 (2): 237- 259.

18. DeLeo F.R., Diep B.A., Otto M. Host defense and pathogenesis in Staphylococcus aureus infections. Infect Dis Clin North Am 2009; 23 (1): 17 - 34.

19. Lorenz E., Mira J.P, Cornish K.L., Arbour N.C., Schwartz D.A. A novel polymorphism in the toll-like receptor 2 gene and its potential association with staphylococcal infection. Infect Immun. 2000; 68 (11): 6398 - 6401.

20. Quilty S., Kwok G., Hajkowicz K., Currie B. High incidence of methicillin-resistant Staphylococcus aureus sepsis and death in patients with febrile neutropenia at Royal Darwin Hospital. Intern. Med. J. 2009; 39: 557 - 559.

21. Spellberg B., Ibrahim A.S., Yeaman M.R., Lin L., Fu Y., Avanesian V. et al. The antifungal vaccine derived from the recombinant N terminus of Als3p protects mice against the bacterium Staphylococcus aureus. Infect Immun. 2008; 76 (10): 4574 - 4580.

22. Mar di L., Cypowyj S., T th B., Chernyshova L., Puel A., Casanova J.L. Molecular mechanisms of mucocutaneous immunity against Candida and Staphylococcus species. J. Allergy Clin. Immunol. 2012; 130 (5): 1019 - 1027.

23. Joshi A., Pancari G., Cope L., Bowman E.P, Cua D., Proctor R.A., McNeely T. Immunization with Staphylococcus aureus iron regulated surface determinant B (IsdB) confers protection via Th17/IL17 pathway in a murine sepsis model. Hum Vaccin Immunother. 2012; 8: 336 - 346.

24. Narita K., Hu D.L., Mori F., Wakabayashi K., Iwakura Y., Nakane A. Role of interleukin-17A in cell-mediated protection against Staphylococcus aureus infection in mice immunized with the fibrinogen-binding domain of clumping factor A. Infect Immun. 2010; 78: 4234 - 4242.

25. Hanke M.L., Heim C.E., Angle A., Sanderson S.D., Kielian T. Targeting macrophage activation for the prevention and treatment of Staphylococcus aureus biofilm infections. J Immunol, 2013; 190 : 2159 - 2168.

26. Fournier B. The function of TLR2 during staphylococcal diseases. Front. Cell. Inf. Microbiol. 2013; 2: 167.

27. Fowler V.G., Proctor R.A. Where does a Staphylococcus aureus vaccine stand? Clin. Microbiol. Infect. 2014; 20, Suppl. 5: 66 - 75.

28. Schreiner J., Kretschmer D., Klenk J., Otto M., Buhring H-J, Stevanovic S. et al. Staphylococcus aureus phenol-soluble modulin peptides modulate dendritic cell functions and increase in vitro priming of regulatory T cells. J Immunol. 2013; 190: 3417 - 3426.

29. Bagnoli F., Bertholet S., Grandi G. Inferring reasons for the failure of Staphylococcus aureus vaccines in clinical trials. Front Cell Infect Microbiol. 2012; 2: 1 - 4.

30. Frank K.M., Zhou T., Moreno-Vinasco L., Hollett B., Garcia J.G., Bubeck Wardenburg J. Host response signature to Staphylococcus aureus alpha-hemolysin implicates pulmonary Th17 response. Infect Immun. 2012; 80: 3161 - 3169.

31. Fritz S.A., Tiemann K.M., Hogan P.G., Epplin E.K., Rodriguez M., Al-Zubeidi D.N. et al. A serologic correlate of protective immunity against community-onset Staphylococcus aureus infection. Clin Infect Dis. 2013; 56 (11): 1554 - 1561.

32. Rasigade J.P., Sicot N., Laurent F., Lina G., Vandenesch F., Etienne J. A history of Panton-Valentine leukocidin (PVL)-associated infection protects against death in PVL-associated pneumonia. Vaccine. 2011; 29 (25): 4185 - 4186.

33. Spellberg B., Daum R. Development of vaccine against Staphylococcus aureus. Semin immunopathol. 2012; 34 (2): 335 - 348.

34. Stranger-Jones Y.K., Bae T., Schneewind O. Vaccine assembly from surface proteins of Staphylococcus aureus. Proc Natl Acad Sci USA. 2006; 103: 16942 -16947.

35. Jansen K.U., Girgenti D.Q., Scully I.L., Anderson A.S. Vaccine review: Staphyloccocus aureus vaccines: Problems and prospects. Vaccine. 2013; 31: 2723 - 2730.

36. Bubeck Wardenburg J., Schneewind O. Vaccine protection against Staphylococcus aureus pneumonia. J. Exp. Med. 2008; 205 (2): 287 - 294.

37. Brown E.L., Dumitrescu O., Thomas D., Badiou C., Koers E.M., Choudhury P. et al. The Panton-Valentine leukocidin vaccine protects mice against lung and skin infections caused by Staphylococcus aureus USA300. Clin. Microbiol. Infect. 2009; 15 (2): 156 - 64.

38. Schennings T., Heimdahl A., Coster K., Flock J.I. Immunisation with fibronectin-binding protein from Staphylococcus aureus protects against experimental endocarditis in rats. Microb. Pathogen. 1993; 15: 227 - 236.

39. Que Y.A., Haefliger J.A., Piroth L., Francois P., Widmer E., Entenza J.M. et al. Fibrinogen and fibronectin binding cooperate for valve infection and invasion in Staphylococcus aureus experimental endocarditis. J. Exp. Med. 2005; 201 (10): 1627 - 1635.

40. Gong R., Hu C., Xu H., Guo A., Chen H., Zhang G., Shi L. Clumping factor A binding region A in a subunit vaccine against Staphylococcus aureus-induced mastitis in mice. Clin. Vaccine Immunol. 2010; 17 (11): 1746 - 1752.

41. Josefsson E., Hartford O., O’Brien L., Patti J.M., Foster T. Protection against experimental Staphylococcus aureus arthritis by vaccination with clumping factor A, a novel virulence determinant. J. Infect. Dis. 2001; 184: 1572 - 1580.

42. Cheng A.G., Kim H.K., Burts M.L., Krausz T., Schneewind O., Missiakas D.M. 2009. Genetic requirements for Staphylococcus aureus abscessformation and persistence in host tissues. FASEB J. 2009; 23: 3393 - 3404.

43. Cheng A.G., McAdow M., Kim H.K., Bae T., Missiakas D.M., Schneewind O. Contribution of œagulases towards Staphylococcus aureus disease and protective immunity. PLoS Pathog. 2010; 6 (8): 1 - 18.

44. Kim H.K., Cheng A.G., Kim H-Y, Missiakas D.M., Schneewind O. Nontoxigenic protein A vaccine for methicillin-resistant Staphylococcus aureus infections in mice. J. Exp. Med. 2010; 207 (9): 1863 - 1870.

45. Kim H.K., DeDent A., Cheng A.G., McAdow M., Bagnolib F., Missiakas D.M., Schneewind O. IsdA and IsdB antibodies protect mice against Staphylococcus aureus abscess formation and lethal challenge. Vaccine. 2010; 28: 6382 - 6392.

46. Mazmanian S.K., Scaar E.P., Gaspar A.H., Humayun M., Gornicki P. Passage of geme-iron across the envelope of Staphylococcus.aureus. Science. 2003; 299: 906 - 909.

47. Bjerketorp J., Jacobsson K., Frykberg L. The von Willebrand factor-binding protein (vWbp) of Staphylococcus aureus is a coagulase. FEMS Microbiol Lett. 2004; 234: 309 - 314.

48. McAdow M., Kim H.K., DeDent A.C., Hendrickx A.P.A., Missiakas D.M., Schneewind O. Preventing Staphylococcus aureus sepsis through the inhibition of its agglutination in blood. PLoS Pathog. 2011; 7 (10). PMCID: PMC3197598.

49. Foster T.J., Geoghegan J.A., Ganesh V.K., Hook M. Adhesion, invasion and evasion: the many functions of the surface proteins of Staphylococcus aureus. Nat Rev Microbiol. 2014; 12 (1): 49 - 62.

50. O’Riordan K., Lee J.C. Staphylococcus aureus capsular polysaccharides. Clin. Microbiol. Rev. Jan. 2004; 17 (1): 218 - 234.

51. Fattom A.L., Sarwar J., Ortiz A., Naso R. Staphylococcus aureus capsular polysaccharide vaccine and CP-specific antibodies protect mice against bacterial challenge. Infect. Immun. 1996; 64 (5): 1659 - 1665.

52. Kropec A., Maira-Litran T., Jefferson K.K., Grout M., Cramton S.E., Gotz F. et al. Poly-N-acetylglucosamine production in Staphylococcus aureus is essential for virulence in murine models of systemic infection. Infect. Immun. 2005; 73 (10): 6868 - 6876.

53. Kely-Quintos C., Cavacini L.A., Posner M.R., Goldmann D., Pier G.B. Characterization of the opsonic and protective activity against Staphylococcus aureus of fully human monoclonal antibodies specific for the bacterial surface polysaccharide poly-N-acetylglucosamine. Infect. Immun. 2006; 74 (5): 2742 - 2750.

54. Daum R.S. Staphylococcus aureus vaccines. «Vaccines», Eds.: Plotkin S.A., Orenstein W.A., Offit P.A. Elsevier. 2008; 1307 - 1315.

55. Anderson A.S., Miller A.A., Donald R.G., Scully I.L., Nanra J.S., Cooper D., Jansen K.U. Development of a multicomponent Staphylococcus aureus vaccine designed to counter multiple bacterial virulence factors. Hum. Vaccin. Immunother. 2012; 8 (11): 1585 - 1594.

56. Nanra J.S., Buitrago S.M., Crawford S., Ng J., Fink P.S., Hawkins J. et al. Capsular polysaccharides are an important immune evasion mechanism for Staphylococcus aureus. Hum. Vaccin. Immunother. 2013; 9 (3): 480 - 487.

57. Matalon A.M., Buerkert J., Block G., Hohenboken M., Fattom A., Horwirth G. et al. Efficacy profile of a bivalent Staphylococcus aureus glycoconjugate investigational vaccine in adults on haemodialysis: phase III randomized study. International symposium on staphylococci and staphylococcal infections. Lyon France; 2012; 9 - 114.

58. Moustafa M., Aronoff G.R., Chandran C., Hartzel J.S., Smugar S.S., Galphin C.M. et al. Phase IIa study of the immunogenicity and safety of the novel Staphylococcus aureus vaccine V710 in adults with end-stage renal disease receiving hemodialysis. Clin. Vaccine Immunol. 2012; 19 (9):1509 - 1516.

59. Fowler V.G., Allen K.B., Moreira E.D., Moustafa M., Isgro F., Boucher H.W. et al. Effect of an investigational vaccine for preventing Staphylococcus aureus infections after cardiothoracic surgery: a randomized trial. J. Am. Med. Assoc. 2013; 309 (13): 1368 - 1378.

60. Ohlsen K., Lorenz U. Immunotherapeutic strategies to combat staphylococcal infections. Intern. J. of Med. Microbiol. 2010; 300: 402 - 410.

61. Vaccines in development. Medicine in development for vaccines. 2013; 22 - 27.

62. Nissen M., Marshall H., Richmond P., Shakib S., Jiang Q., Cooper D.et al. A randomized phase I study of the safety and immunogenicity ofthree ascending dose levels of a 3-antigen Staphylococcus aureus vaccine (SA3Ag) in healthy adults. Vaccine. 2015; 33 (15): 1846 - 1854.

63. denReijer P.M., Lemmens-denToom N., Kant S., Snijders S.V., Boelens H., Tavakol M., et al. Characterization of the humoral immune response during Staphylococcus aureus bacteremia and global gene expression by Staphylococcus aureus in humanblood. PLoSOne. 2013; 8 (1): e53391.

64. Rozemeijer W., Fink P., Rojas E., Jones C.H., Pavliakova D., Giardina P et al. Evaluation of approaches to monitor Staphylococcus aureus virulence factor expression during human disease. PLoS ONE. 2015; 10 (2): e0116945.

65. Gening M.L., Maira-Litran T., Kropec A., Skurnik D., Grout M., Tsvetkov Y.E. et al. Synthetic ß-(1 6)-linked N-acetylated and nonacetylated oligoglucosamines used to produce conjugate vaccines for bacterial pathogens. Infect Immun. 2010; 78 (2): 764 - 772.

66. Cywes-Bentley C., Skurnik D., Zaidi T., Rouxa D., Rosane B., DeOliveira et al. Antibody to a conserved antigenic target is protective against diverse prokaryotic and eukaryotic pathogens. PNAS. 2013; 110 (24): E2209 - 2218.

67. Pozzi C., Wilk K., Lee J.C., Gening M., Nifantiev N., Pier G.B. Opsonic and protective properties of antibodies raised to conjugate vaccines targeting six Staphylococcus aureus antigens. PLoS One. 2012; 7 (10). PMID 23077517.

68. Skurnik D., Merighi M., Grout M., Gadjeva M., Maira-Litran T., Ericsson M. et al. Animal and human antibodies to distinct Staphylococcus aureus antigens mutually neutralize opsonic killing and protection in mice. J. Clin. Invest. 2010; 120 (9): 3220 - 3233.

69. Ефремова В.Н., Егорова Н.Б., Масюкова С.А. Бесклеточная антистафилококковая вакцина для лечения хронической стафилококковой инфекции. Патент РФ на изобретение, № 2122862 от 10.12.1998.

70. Егорова Н.Б., Ефремова В.Н., Курбатова Е.А., Грубер И.М. Экспериментальная и клинико-иммунологическая оценка бесклеточной стафилококковой вакцины Стафиловак. Журн микробиол. 2008; 6: 102 - 108.

71. Кузьменко О.М., Злыгостев С.А., Михайлова Н.А., Грубер И.М., Ахматова Н.К., Егорова Н.Б. и др. Характеристика комплексов антигенов вакцинных штаммов Staphylococcus aureus, полученных в различных условиях культивирования. Журн микробиол. 2010; 2: 51 - 54.

72. Грубер И.М., Егорова Н.Б., Михайлова Н.А., Черкасова Л.С., Тарасова О.Е., Асташкина Е.А. и др. Исследование протективной активности стафилококковой вакцины «Стафиловак-2». Журн микробиол. 2014; 6: 54 - 58.

73. Черкасова Л.С., Плеханова Н.Г., Тарасова О.Е., Асташкина Е.А., Мельников Н.В., Грубер И.М. и др. Иммуногенные свойства экспериментально производственных серий вакцины вакцины «Стафиловак-2». Журн. микробиол. 2014; 5: 86 - 90.

74. Грубер И.М., Егорова Н.Б., Курбатова Е.А., Михайлова Н.А. Стратегия разработки противостафилококковых иммунопрофилактических и иммунотерапевтических препаратов. Эпидемиол инфекцион болезни. Актуал вопр. 2013; 4: 31 - 38.