Protein Vaccines

James C. Paton; John W. Boslego

doi:10.1128/9781555815820.ch28

Chapter 28 : Protein Vaccines

Authors: James C. Paton¹, John W. Boslego²

VIEW AFFILIATIONS HIDE AFFILIATIONS

Affiliations: 1: School of Molecular and Biomedical Science, University of Adelaide, Adelaide, S.A. 5005, Australia; 2: PATH, Washington, DC 20006

Content Type: Monograph

Publication Year: 2008

Category: Bacterial Pathogenesis; Immunology

Book DOI: 10.1128/9781555815820

Chapter DOI: 10.1128/9781555815820.ch28

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Preview this chapter:

Protein Vaccines, Page 1 of 2

< Previous page | Next page > /docserver/preview/fulltext/10.1128/9781555815820/9781555814083_Chap28-1.gif /docserver/preview/fulltext/10.1128/9781555815820/9781555814083_Chap28-2.gif

Abstract:

The development, manufacture, and administration of pneumococcal polysaccharide vaccine (PPSV) and pneumococcal conjugate vaccine (PCV) have provided significant public health benefit, and these vaccines continue to be important tools in the battle against the pneumococcus. The serotypes that are weak immunogens are also more often associated with antibiotic resistance. If such common-protein vaccines are successfully developed, they could have a number of advantages over the currently available capsular polysaccharide (PS)-based vaccines. The injection of purified pneumolysin (Ply) into rat lungs induces severe lobar pneumonia, indistinguishable histologically from that seen when virulent pneumococci are injected. Pneumococcal surface protein A (PspA) is one of the best-characterized members of the choline-binding protein (CBP) family and has strong credentials as a vaccine antigen. It is found on the surfaces of all pneumococci and has a proven role in the pathogenesis of disease, as evidenced by the significantly reduced virulence of defined PspA-negative pneumococci in animal models. Studies of the vaccine potential of PspA have extended to human trials, and immune sera from volunteers immunized with a family 1 PspA fragment reacted with 37 different Streptococcus pneumoniae strains belonging to diverse capsular and PspA types. The immunization of mice with pneumococcal surface protein C (PspC) is highly protective against intravenous or intraperitoneal challenge with S. pneumoniae. One study has shown that parenteral immunization of mice with purified PsaA in the presence of strong adjuvants elicits significant protection against systemic challenge with S. pneumoniae.

Citation: Paton J, Boslego J. 2008. Protein Vaccines, p 421-435. In Siber G, Klugman K, Mäkelä P (ed), Pneumococcal Vaccines. ASM Press, Washington, DC. doi: 10.1128/9781555815820.ch28

Key Concept Ranking

Tumor Necrosis Factor alpha: 0.43307644

0.43307644

Highlighted Text: Show | Hide

Full text loading...

References

/content/book/10.1128/9781555815820.ch28

1. Adamou, J. E.,, J. H. Heinrichs,, A. L. Erwin,, W. Walsh,, T. Gayle,, M. Dormitzer,, R. Dagan,, Y. A. Brewah,, P. Barren,, R. Lathigra,, S. Langermann,, S. Koenig, and, S. Johnson. 2001. Identification and characterization of a novel family of pneumococcal proteins that are protective against sepsis. Infect. Immun. 69:949–958.

2. Alexander, J. E.,, R. A. Lock,, C. C. A. M. Peeters,, J. T. Poolman,, P. W. Andrew,, T. J. Mitchell,, D. Hansman, and, J. C. Paton. 1994. Immunization of mice with pneumolysin toxoid confers a significant degree of protection against at least nine serotypes of Streptococcus pneumoniae. Infect. Immun. 62:5683–5688.

3. Balachandran, P.,, S. K. Hollingshead,, J. C. Paton, and, D. E. Briles. 2001. The autolytic enzyme LytA of Streptococcus pneumoniae is not responsible for releasing pneumolysin. J. Bacteriol. 183:3108–3116.

4. Balachandran, P.,, A. Brooks-Walter,, A. Virolainen-Julkunen,, S. K. Hollingshead, and, D. E. Briles. 2002. Role of pneumococcal surface protein C in nasopharyngeal carriage and pneumonia and its ability to elicit protection against carriage of Streptococcus pneumoniae. Infect. Immun. 70:2526–2534.

5. Bender, M. H., and, J. N. Weiser. 2006. The atypical amino-terminal LPNTG-containing domain of the pneumococcal human IgA1-specific protease is required for proper enzyme localization and function. Mol. Microbiol. 61:526–543.

6. Bergmann, S.,, M. Rohde,, G. S. Chhatwal, and, S. Hammerschmidt. 2001. α-Enolase of Streptococcus pneumoniae is a plasmin(ogen)-binding protein displayed on the bacterial cell surface. Mol. Microbiol. 40:1273–1287.

7. Berry, A. M.,, J. Yother,, D. E. Briles,, D. Hansman, and, J. C. Paton. 1989. Reduced virulence of a defined pneumolysin-negative mutant of Streptococcus pneumoniae. Infect. Immun. 57:2037–2042.

8. Berry, A. M.,, R. A. Lock,, D. Hansman, and, J. C. Paton. 1989. Contribution of autolysin to the virulence of Streptococcus pneumoniae. Infect. Immun. 57:2324–2330.

9. Berry, A. M.,, J. C. Paton, and, D. Hansman. 1992. Effect of insertional inactivation of the genes encoding pneumolysin and autolysin on the virulence of Streptococcus pneumoniae type 3. Microb. Pathog. 45:87–93.

10. Berry, A. M.,, J. E. Alexander,, T. J. Mitchell,, P. W. Andrew,, D. Hansman, and, J. C. Paton. 1995. Effect of defined point mutations in the pneumolysin gene on the virulence of Streptococcus pneumoniae. Infect. Immun. 63:1969–1974.

11. Berry, A. M., and, J. C. Paton. 1996. Sequence heterogeneity of PsaA, a 37-kilodalton putative adhesin essential for virulence of Streptococcus pneumoniae. Infect. Immun. 64:5255–5262.

12. Berry, A. M., and, J. C. Paton. 2000. Additive attenuation of virulence of Streptococcus pneumoniae by mutation of the genes encoding pneumolysin and other putative pneumococcal virulence proteins. Infect. Immun. 68:133–140.

13. Blander, J. M., and, R. Medzhitov. 2006. Toll-dependent selection of microbial antigens for presentation by dendritic cells. Nature 440:808–812.

14. Boulnois, G. J.,, J. C. Paton,, T. J. Mitchell, and, P. W. Andrew. 1991. Structure and function of pneumolysin, the multifunctional, thioactivated toxin of Streptococcus pneumoniae. Mol. Microbiol. 5:2611–2616.

15. Braun, J. S.,, R. Novak,, G. Gao,, P. J. Murray, and, J. L. Shenep. 1999. Pneumolysin, a protein toxin of Streptococcus pneumoniae, induces nitric oxide production from macrophages. Infect. Immun. 67:3750–3756.

16. Briles, D. E.,, S. K. Hollingshead,, J. King,, A. Swift,, P. A. Braun,, M. K. Park,, L. M. Ferguson,, M. H. Nahm, and, G. S. Nabors. 2000. Immunization of humans with recombinant pneumococcal surface protein A (rPspA) elicits antibodies that passively protect mice from fatal infection with Streptococcus pneumoniae bearing heterologous PspA. J. Infect. Dis. 182:1694–1701.

17. Briles, D. E.,, E. Ades,, J. C. Paton,, J. S. Sampson,, G. M. Carlone,, R. C. Huebner,, A. Virolainen,, E. Swiatlo, and, S. K. Hollingshead. 2000. Intranasal immunization of mice with a mixture of the pneumococcal proteins PsaA and PspA is highly protective against nasopharyngeal carriage of Streptococcus pneumoniae. Infect. Immun. 68:796–800.

18. Briles, D. E.,, S. K. Hollingshead,, J. C. Paton,, E. W. Ades,, L. Novak,, F. W. van Ginkel, and, W. H. Benjamin, Jr. 2003. Immunizations with pneumococcal surface protein A and pneumolysin are protective against pneumonia in a murine model of pulmonary infection with Streptococcus pneumoniae. J. Infect. Dis. 188:339–348.

19. Brooks-Walter, A.,, R. C. Tart,, D. E. Briles, and, S. K. Hollingshead. 1997. The pspC gene encodes a second pneumococcal surface protein homologous to the gene encoding the protection-eliciting PspA protein of Streptococcus pneumoniae. 97th Gen. Meet. Am. Soc. Microbiol. American Society for Microbiology, Washington, DC.

20. Brooks-Walter, A.,, D. E. Briles, and, S. K. Hollingshead. 1999. The pspC gene of Streptococcus pneumoniae encodes a polymorphic protein PspC, which elicits cross-reactive antibodies to PspA and provides immunity to pneumococcal bacteremia. Infect. Immun. 67:6533–6542.

21. Brown, J. S.,, S. M. Gilliland, and, D. W. Holden. 2001. A Streptococcus pneumoniae pathogenicity island encoding an ABC transporter involved in iron uptake and virulence. Mol. Microbiol. 40:572–585.

22. Brown, J. S.,, A. D. Ogunniyi,, M. C. Woodrow,, D. W. Holden, and, J. C. Paton. 2001. Immunization with components of two iron-uptake ABC transporters protects mice against systemic Streptococcus pneumoniae infection. Infect. Immun. 69:6702–6706.

23. Canvin, J. R.,, A. P. Marvin,, M. Sivakumaran,, J. C. Paton,, G. J. Boulnois,, P. W. Andrew, and, T. J. Mitchell. 1995. The role of pneumolysin and autolysin in the pathology of pneumonia and septicemia in mice infected with a type 2 pneumococcus. J. Infect. Dis. 172:119–123.

24. Cheng, Q.,, D. Finkel, and, M. K. Hostetter. 2000. Novel purification scheme and functions for a C3-binding protein from Streptococcus pneumoniae. Biochemistry 39:5450–5457.

25. Crain, M. J.,, W. D. Waltman II,, J. S. Turner,, J. Yother,, D. F. Talkington,, L. S. McDaniel,, B. M. Gray, and, D. E. Briles. 1990. Pneumococcal surface protein A (PspA) is serologically highly variable and is expressed by all clinically important capsular serotypes of Streptococcus pneumoniae. Infect. Immun. 58:3293–3299.

26. Daniels, C. C.,, T. C. Briles,, S. Mirza,, A. P. Hakansson, and, D. E. Briles. 2006. Capsule does not block antibody binding to PspA, a surface virulence protein of Streptococcus pneumoniae. Microb. Pathog. 40:228–233.

27. Daniely, D.,, M. Portnoi,, M. Shagan,, A. Porgador,, N. Givon-Lavi,, E. Ling,, R. Dagan, and, Y. Mizrachi Nebenzahl. 2006. Pneumococcal 6-phosphogluconate-dehydrogenase, a putative adhesin, induces protective immune response in mice. Clin. Exp. Immunol. 144:254–263.

28. Dave, S.,, A. Brooks-Walter,, M. K. Pangburn, and, L. S. McDaniel. 2001. PspC, a pneumococcal surface protein, binds human factor H. Infect. Immun. 69:3435–3437.

29. De, B. K.,, J. S. Sampson,, E. W. Ades,, R. C. Huebner,, D. L. Jue,, S. E. Johnson,, M. Espina,, A. R. Stinson,, D. E. Briles, and, G. M. Carlone. 2000. Purification and characterization of Streptococcus pneumoniae palmitoylated pneumococcal surface adhesion A expressed in Escherichia coli. Vaccine 18:1811–1821.

30. Dintilhac, A.,, G. Alloing,, C. Granadel, and, J. P. Claverys. 1997. Competence and virulence of S. pneumoniae: Adc and PsaA mutants exhibit a requirement for Zn and Mn resulting from inactivation of metal permeases. Mol. Microbiol. 25:727–739.

31. Duthy, T. G.,, R. J. Ormsby,, E. Giannakis,, A. D. Ogunniyi,, U. H. Stroeher,, J. C. Paton, and, D. L. Gordon. 2002. The human complement regulator factor H binds pneumococcal surface protein PspC via short consensus repeat domains 13 to 15. Infect. Immun. 70:5604–5611.

32. Feldman, C.,, N. C. Munro,, P. K. Jeffery,, T. J. Mitchell,, P. W. Andrew,, G. J. Boulnois,, D. Guerreiro,, J. A. Rohde,, H. C. Todd,, P. J. Cole, and, R. Wilson. 1991. Pneumolysin induces the salient histological features of pneumococcal infection in the rat lung in vivo. Am. J. Respir. Cell Mol. Biol. 5:416–423.

33. Gor, D. O.,, X. Ding,, Q. Li,, J. R. Schreiber,, M. Dubinsky, and, N. S. Greenspan. 2002. Enhanced immunogenicity of pneumococcal surface adhesion A by genetic fusion to cytokines and evaluation of protective immunity in mice. Infect. Immun. 70:5589–5595.

34. Gor, D. O.,, X. Ding,, D. E. Briles,, M. R. Jacobs, and, N. S. Greenspan. 2005. Relationship between surface accessibility for PpmA, PsaA, and PspA and antibody-mediated immunity to systemic infection by Streptococcus pneumoniae. Infect. Immun. 73:1304–1312.

35. Gosink, K. K.,, E. R. Mann,, C. Guglielmo,, E. I. Tuomanen, and, H. R. Masure. 2000. Role of novel choline binding proteins in virulence of Streptococcus pneumoniae. Infect. Immun. 68:5690–5695.

36. Hakansson, A.,, H. Roche,, S. Mirza,, L. S. McDaniel,, A. Brooks-Walter, and, D. E. Briles. 2001. Characterization of the binding of human lactoferrin to pneumococcal surface protein A (PspA). Infect. Immun. 69:3372–3381.

37. Hamel, J.,, N. Charland,, I. Pineau,, C. Ouellet,, S. Rioux,, D. Martin, and, B. R. Brodeur. 2004. Prevention of pneumococcal disease in mice immunized with conserved surface-accessible proteins. Infect. Immun. 72:2659–2670.

38. Hammerschmidt, S.,, S. Talay,, P. Brandtzaeg, and, G. S. Chhatwal. 1997. SpsA, a novel pneumococcal surface protein with specific binding to secretory immunoglobulin A and secretory component. Mol. Microbiol. 25:1113–1124.

39. Hammerschmidt, S.,, G. Bethe,, P. Remanen, and, G. S. Chhatwal. 1999. Identification of pneumococcal surface protein A as a lactoferrin-binding protein of Streptococcus pneumoniae. Infect. Immun. 67:1683–1687.

40. Hammerschmidt, S.,, M. P. Tillig,, S. Wolff,, J. P. Vaerman, and, G. S. Chhatwal. 2000. Species-specific binding of human secretory component to SpsA protein of Streptococcus pneumoniae via a hexapeptide motif. Mol. Microbiol. 36:726–736.

41. Hill, J.,, P. W. Andrew, and, T. J. Mitchell. 1994. Amino acids in pneumolysin important for hemolytic activity identified by random mutagenesis. Infect. Immun. 62:757–758.

42. Hollingshead, S. K.,, R. S. Becker, and, D. E. Briles. 2000. Diversity of PspA: mosaic genes and evidence for past recombination in Streptococcus pneumoniae. Infect. Immun. 68:5889–5900.

43. Houldsworth, S.,, P. W. Andrew, and, T. J. Mitchell. 1994. Pneumolysin stimulates production of tumor necrosis factor alpha and interleukin-1β by human mononuclear phagocytes. Infect. Immun. 62:1501–1503.

44. Iannelli, E,, M. R. Oggioni, and, G. Pozzi. 2002. Allelic variation in the highly polymorphic locus pspC of Streptococcus pneumoniae. Gene 284:63–71.

45. Janulczyk, R.,, F. Iannelli,, A. G. Sjoholm,, G. Pozzi, and, L. Bjorck. 2000. Hic, a novel surface protein of Streptococcus pneumoniae that interferes with complement function. J. Biol. Cbem. 275:37257–37263.

46. Jarva, H.,, R. Janulczyk,, J. Hellwage,, P. F. Zipfel,, L. Bjorck, and, S. Meri. 2002. Streptococcus pneumoniae evades complement attack and opsonophagocytosis by expressing the pspC locus-encoded Hic protein that binds to short consensus repeats 8-11 of factor H. J. Immunol. 168:1886–1894.

47. Jedrzejas, M. J.,, S. K. Hollingshead,, J. Lebowitz,, L. Chantalat,, D. E. Briles, and, E. J. Lamani. 2000. Production and characterization of the functional fragment of pneumococcal surface protein A. Arch. Biochem. Biophys. 373:116–125.

48. Johnson, S. E.,, J. K. Dykes,, D. L. Jue,, J. S. Sampson,, G. M. Carlone, and, E. W. Ades. 2002. Inhibition of pneumococcal carriage in mice by subcutaneous immunization with peptides from the common surface protein pneumococcal surface adhesion. J. Infect. Dis. 185:489–496.

49. Jomaa, M.,, J. Yuste,, J. C. Paton,, C. Jones,, G. Dougan, and, J. S. Brown. 2005. Antibodies to the iron uptake ABC transporter lipoproteins PiaA and PiuA promote opsonophagocytosis of Streptococcus pneumoniae. Infect. Immun. 73:6852–6859.

50. Jomaa, M.,, S. Terry,, C. Hale,, C. Jones,, G. Dougan, and, J. Brown. 2006. Immunization with the iron uptake ABC transporter proteins PiA and PiuA prevents respiratory infection with Streptococcus pneumoniae. Vaccine 24:5133–5139.

51. Kharat, A. S., and, A. Tomasz. 2003. Inactivation of the srtA gene affects localization of surface proteins and decreases adhesion of Streptococcus pneumoniae to human pharyngeal cells in vitro. Infect. Immun. 71:2758–2765.

52. Kirkham, L. A.,, A. R. Kerr,, G. R. Douce,, G. K. Paterson,, D. A. Dilts,, D. F. Liu, and, T. J. Mitchell. 2006. Construction and immunological characterization of a novel non-toxic protective pneumolysin mutant for use in future pneumococcal vaccines. Infect. Immun. 74:586–593.

53. Kwon, H. Y.,, A. D. Ogunniyi,, M. H. Choi,, S. N. Pyo,, D. K. Rhee, and, J. C. Paton. 2004. The ClpP protease of Streptococcus pneumoniae modulates virulence gene expression and protects against fatal pneumococcal challenge. Infect. Immun. 72:5646–5653.

54. Lawrence, M. C.,, P. A. Pilling,, A. D. Ogunniyi,, A. M. Berry, and, J. C. Paton. 1998. The crystal structure of pneumococcal surface antigen PsaA reveals a metal-binding site and a novel structure for a putative ABC-type binding protein. Structure 6:1553–1561.

55. Lee, C. J.,, R. A. Lock,, T. J. Mitchell,, P. W. Andrew,, G. J. Boulnois, and, J. C. Paton. 1994. Protection of infant mice from challenge with Streptococcus pneumoniae type 19F by immunization with a type 19F polysaccharide-pneumolysoid conjugate. Vaccine 12:875–878.

56. Ling, E.,, G. Feldman,, M. Portnoi,, R. Dagan,, K. Overweg,, F. Mulholland,, V. Chalifa-Caspi,, J. Wells, and, Y. Mizrachi Nebenzahl. 2004. Glycolytic enzymes associated with the cell surface of Streptococcus pneumoniae are antigenic in humans and elicit protective immune responses in the mouse. Clin. Exp. Immunol. 138:290–298.

57. Lipsitch, M.,, C. G. Whitney,, E. Zell,, T. Kaijalainen,, R. Dagan, and, R. Malley. 2005. Are anticapsular antibodies the primary mechanism of protection against invasive pneumococcal disease? PLoS Med. 2:e15.

58. Lock, R. A.,, J. C. Paton, and, D. Hansman. 1988. Comparative efficacy of pneumococcal neuraminidase and pneumolysin as immunogens protective against Streptococcus pneumoniae. Microb. Pathog. 5:461–467.

59. Lock, R. A.,, D. Hansman, and, J. C. Paton. 1992. Comparative efficacy of autolysin and pneumolysin as immunogens protecting mice against infection by Streptococcus pneumoniae. Microb. Pathog. 12:137–143.

60. Lock, R. A.,, Q. Y. Zhang,, A. M. Berry, and, J. C. Paton. 1996. Sequence variation in the Streptococcus pneumoniae pneumolysin gene affecting haemolytic activity and electrophoretic mobility of the toxin. Microb. Pathog. 21:71–83.

61. Long, J. P.,, H. H. Tong, and, T. F. DeMaria. 2004. Immunization with native or recombinant Streptococcus pneumoniae neuraminidase affords protection in the chinchilla otitis media model. Infect. Immun. 72:4309–4313.

62. Lopez, R.,, M. P. Gonzalez,, E. Garcia,, J. L. Garcia, and, P. Garcia. 2000. Biological roles of two new murein hydrolases of Streptococcus pneumoniae representing examples of module shuffling. Res. Microbiol. 151:437–443.

63. Lopez, R.,, E. Garcia,, P. Garcia, and, J. L. Garcia. 2004. Cell wall hydrolases, p. 75–88. In E. Tuomanen (ed.), The Pneumococcus. ASM Press, Washington, DC.

64. Malley, R.,, M. Lipsitch,, A. Stack,, R. Saladino,, G. Fleisher,, S. Pelton,, C. Thompson,, D. Briles, and, P. Anderson. 2001. Intranasal immunization with killed unencapsulated whole cells prevents colonization and invasive disease by capsulated pneumococci. Infect. Immun. 69:4870–4873.

65. Malley, R.,, P. Henneke,, S. C. Morse,, M. J. Cieslewicz,, M. Lipsitch,, C. M. Thompson,, E. Kurt-Jones,, J. C. Paton,, M. R. Wessels, and, D. Golenbock. 2003. Recognition of pneumolysin by Toll-like receptor (TLR) 4 confers resistence to pneumococcal infection. Proc. Nat. Acad. Sci. USA 100:1966–1971.

66. Malley, R.,, S. C. Morse,, L. C. Leite,, A. P. Mattos Areas,, P. L. Ho,, F. S. Kubrusly,, I. C. Almeida, and, P. Anderson. 2004. Multi-serotype protection of mice against pneumococcal colonization of the nasopharynx and middle ear by killed nonencapsulated cells given intranasally with a non-toxic adjuvant. Infect. Immun. 72:4290–4292.

67. Malley, R.,, K. Trzcinski,, A. Srivastava,, C. M. Thompson,, P. W. Anderson, and, M. Lipsitch. 2005. CD4+ T cells mediate antibody-independent acquired immunity to pneumococcal colonization. Proc. Natl. Acad. Sci. USA 102:4848–4853.

68. Malley, R.,, A. Srivastava,, M. Lipsitch,, C. M. Thompson,, C. Watkins,, A. Tzianabos, and, P. W. Anderson. 2006. Antibody-independent, interleukin-17A-mediated, cross-serotype immunity to pneumococci in mice immunized intranasally with the cell wall polysaccharide. Infect. Immun. 74:2187–2195.

69. Manco, S.,, F. Hernon,, H. Yesilkaya,, J. C. Paton,, P. W. Andrew, and, A. Kadioglu. 2006. Pneumococcal neuramini-dases A and B both have essential roles during infection of the respiratory tract and sepsis. Infect. Immun. 74:4014–4020.

70. McAllister, L. J.,, H. Tseng,, A. D. Ogunniyi,, M. P. Jennings,, A. G. McEwan, and, J. C. Paton. 2004. Molecular analysis of the psa permease complex of Streptococcus pneumoniae. Mol. Microbiol. 53:889–901.

71. McCool, T. L.,, T. R. Cate,, G. Moy, and, J. N. Weiser. 2002. The immune response to pneumococcal proteins during experimental human carriage. J. Exp. Med. 195:359–365.

72. McDaniel, L. S.,, J. Yother,, M. Vijayakumar,, L. McGarry,, W. R. Guild, and, D. E. Briles. 1987. Use of insertional in-activation to facilitate studies of biological properties of pneumococcal surface protein A (PspA). J. Exp. Med. 165:381–394.

73. McDaniel, L. S.,, B. A. Ralph,, D. O. McDaniel, and, D. E. Briles. 1994. Localization of protection-eliciting epitopes on PspA of Streptococcus pneumoniae between amino acid residues 192 and 260. Microb. Pathog. 17:323–337.

74. Michon, F.,, P. C. Fusco,, C. A. Minetti,, M. Laude-Sharp,, C. Uitz,, C. H. Huang,, A. J. D'Ambra,, S. Moore,, D. P. Remeta,, I. Heron, and, M. S. Blake. 1998. Multivalent pneumococcal capsular polysaccharide conjugate vaccines employing genetically detoxified pneumolysin as a carrier protein. Vaccine 16:1732–1741.

75. Mitchell, T. J.,, P. W. Andrew,, F. K. Saunders,, A. N. Smith, and, G. J. Boulnois. 1991. Complement activation and antibody binding by pneumolysin via a region of the toxin homologous to a human acute-phase protein. Mol. Microbiol. 5:1883–1888.

76. Mitchell, T. J. 2004. Pneumolysin and other virulence proteins, p. 61–74. In E. Tuomanen (ed.), The pneumococcus. ASM Press, Washington, DC.

77. Musher, D. M.,, H. M. Phan, and, R. E. Baughn. 2001. Protection against bacteremic pneumococcal infection by antibody to pneumolysin. J. Infect. Dis. 183:827–830.

78. Nabors, G. S.,, P. A. Braun,, D. J. Herrmann,, M. L. Heise,, D. J. Pyle,, S. Gravenstein,, M. Schilling,, L. M. Ferguson,, S. K. Hollingshead,, D. E. Briles, and, R. S. Becker. 2000. Immunization of healthy adults with a single recombinant pneumococcal surface protein A (PspA) variant stimulates broadly cross-reactive antibodies. Vaccine 18:1743–1754.

79. Ogunniyi, A. D.,, R. L. Folland,, S. Hollingshead,, D. E. Briles, and, J. C. Paton. 2000. Immunization of mice with combinations of pneumococcal virulence proteins elicits enhanced protection against challenge with Streptococcus pneumoniae. Infect. Immun. 68:3028–3033.

80. Ogunniyi, A. D.,, M. C. Woodrow,, J. T. Poolman, and, J. C. Paton. 2001. Protection against Streptococcus pneumoniae elicited by immunization with pneumolysin and CbpA. Infect. Immun. 69:5997–6003.

81. Ogunniyi, A. D.,, P. Giammarinaro, and, J. C. Paton. 2002. The genes encoding virulence-associated proteins and the capsule of Streptococcus pneumoniae are upregulated and differentially expressed in vivo. Microbiology 148:2045–2053.

82. Ogunniyi, A. D.,, P. Giammarinaro, and, J. C. Paton. 2007. Development of a vaccine against invasive pneumococcal disease based on combinations of virulence proteins of Streptococcus pneumoniae. Infect. Immun. 75:350–357.

83. Ogunniyi, A. D.,, K. S. LeMessurier,, R. M. A. Graham,, J. M. Watt,, D. E. Briles,, U. H. Stroeher, and, J. C. Paton. 2007. Contributions of pneumolysin, pneumococcal surface protein A (PspA), and PspC to pathogenicity of Streptococcus pneumoniae D39 in a mouse model. Infect. Immun. 75:1843–1851.

84. Orihuela, C. J.,, G. Gao,, K. P. Francis,, J. Yu, and, E. I. Tuomanen. 2004. Tissue-specific contributions of pneumococcal virulence factors to pathogenesis. J. Infect. Dis. 190:1661–1669.

85. Overweg, K.,, A. Kerr,, M. Sluijter,, M. H. Jackson,, T. J. Mitchell,, A. P. de Jong,, R. de Groot, and, P. W. Hermans. 2000. The putative proteinase maturation protein A of Streptococcus pneumoniae is a conserved surface protein with potential to elicit protective immune responses. Infect. Immun. 68:4180–4188.

86. Paton, J. C.,, R. A. Lock, and, D. J. Hansman. 1983. Effect of immunization with pneumolysin on survival time of mice challenged with Streptococcus pneumoniae. Infect. Immun. 40:548–552.

87. Paton, J. C.,, B. Rowan-Kelly, and, A. Ferrante. 1984. Activation of human complement by the pneumococcal toxin pneumolysin. Infect. Immun. 43:1085–1087.

88. Paton, J. C.,, R. A. Lock,, C. J. Lee,, J. P. Li,, A. M. Berry,, T. J. Mitchell,, P. W. Andrew,, D. Hansman, and, G. J. Boulnois. 1991. Purification and immunogenicity of genetically obtained pneumolysin toxoids and their conjugation to Streptococcus pneumoniae type 19F polysaccharide. Infect. Immun. 59:2297–2304.

89. Paton, J. C. 1996. The contribution of pneumolysin to the pathogenicity of Streptococcus pneumoniae. Trends Microbiol. 4:103–106.

90. Paton, J. C.,, A. M. Berry, and, R. A. Lock. 1997. Molecular analysis of putative pneumococcal virulence proteins. Microb. Drug Resist. 3:1–10.

91. Paton, J. C., and, P. Giammarinaro. 2001. Genome-based analysis of pneumococcal virulence factors: the quest for novel vaccine antigens and drug targets. Trends Microbiol. 9:515–518.

92. Pimenta, F. C.,, E. N. Miyaji,, A. P. Areas,, M. L. Oliveira,, A. L. de Andrade,, P. L. Ho,, S. K. Hollingshead, and, L. C. Leite. 2006. Intranasal immunization with the cholera toxin B subunit-pneumococcal surface antigen A fusion protein induces protection against colonization with Streptococcus pneumoniae and has negligible impact on the nasopharyngeal and oral microbiota of mice. Infect. Immun. 74:4939–4944.

93. Ren, B,, A. J. Szalai,, O. Thomas,, S. K. Hollingshead, and, D. E. Briles. 2003. Both family 1 and family 2 PspA proteins can inhibit complement deposition and confer virulence to a capsular serotype 3 strain on Streptococcus pneumoniae. Infect. Immun. 71:75–85.

94. Riboldi-Tunnicliffe, A.,, N. W. Isaacs, and, T. J. Mitchell. 2005. 1.2Å crystal structure of the S. pneumoniae PhtA histidine triad domain a novel zinc binding fold. FEBS Lett. 579:5353–5360.

95. Rosenow, C.,, P. Ryan,, J. N. Weiser,, S. Johnson,, P. Fontan,, A. Ortqvist, and, H. R. Masure. 1997. Contribution of novel choline-binding proteins to adherence, colonization, and immunogenicity of Streptococcus pneumoniae. Mol. Microbiol. 25:819–829.

96. Rubins, J. B.,, D. Charboneau,, C. Fasching,, A. M. Berry,, J. C. Paton,, J. E. Alexander,, P. W. Andrew,, T. J. Mitchell, and, E. N. Janoff. 1996. Distinct roles for pneumolysin's cytotoxic and complement activities in the pathogenesis of pneumococcal pneumonia. Am. J. Respir. Crit. Care Med. 153:1339–1346.

97. Sampson, J. S.,, Z. Furlow,, A. M. Whitney,, D. Williams,, R. Facklam, and, G. M. Carlone. 1997. Limited diversity of Streptococcus pneumoniae psaA among pneumococcal vaccine serotypes. Infect. Immun. 65:1967–1971.

98. Saunders, F. K.,, T. J. Mitchell,, J. A. Walker,, P. W. Andrew, and, G. J. Boulnois. 1989. Pneumolysin, the thiol-activated toxin of Streptococcus pneumoniae, does not require a thiol group for in vitro activity. Infect. Immun. 57:2547–2552.

99. Schneewind, O.,, D. Mihaylova-Petkov, and, P. Model. 1993. Cell wall sorting signals in surface proteins of Gram-positive bacteria. EMBO J. 12:4803–4811.

100. Shaper, M.,, S. K. Hollingshead,, W. H. Benjamin, Jr., and, D. E. Briles. 2004. PspA protects Streptococcus pneumoniae from killing by apolactoferrin, and antibody to PspA enhances killing of pneumococci by apolactoferrin. Infect. Immun. 72:5031–5040.

101. Swiatlo, E.,, L. S. McDaniel, and, D. E. Briles. 2004. Choline-binding proteins, p. 49–60. In E. Tuomanen (ed.), The Pneumococcus. ASM Press, Washington, DC.

102. Tai, S. S.,, C. Yu, and, J. K. Lee. 2003. A solute binding protein of Streptococcus pneumoniae iron transport. FEMS Microbiol. Lett. 220:303–308.

103. Talkington, D. F.,, D. L. Crimmins,, D. C. Voellinger,, J. Yother, and, D. E. Briles. 1991. A 43-kilodalton pneumococcal surface protein, PspA: isolation, protective abilities, and structural analysis of the amino-terminal sequence. Infect. Immun. 59:1285–1289.

104. Talkington, D. F.,, B. G. Brown,, J. A. Tharpe,, A. Koenig, and, H. Russell. 1996. Protection of mice against fatal pneumococcal challenge by immunization with pneumococcal surface adhesion A (PsaA). Microb. Pathog. 21:17–22.

105. Tettelin, H.,, K. E. Nelson,, I. T. Paulsen,, J. A. Eisen,, T. D. Read,, S. Peterson,, J. Heidelberg,, R. T. DeBoy,, D. H. Haft,, R. J. Dodson,, A. S. Durkin,, M. Gwinn,, J. F. Kolonay,, W. C. Nelson,, J. D. Peterson,, L. A. Umayam,, O. White,, S. L. Salzberg,, M. R. Lewis,, D. Radune,, E. Holtzapple,, H. Khouri,, A. M. Wolf,, T. R. Utterback,, C. L. Hansen,, L. A. McDonald,, T. V. Feldblyum,, S. Angiuoli,, T. Dickinson,, E. K. Hickey,, I. E. Holt,, B. J. Loftus,, F. Yang,, H. O. Smith,, J. C. Venter,, B. A. Dougherty,, D. A. Morrison,, S. K. Hollingshead, and, C. M. Fraser. 2001. Complete genome sequence of a virulent isolate of Streptococcus pneumoniae. Science 293:498–506.

106. Tong, H. H.,, L. E. Blue,, M. A. James, and, T. F. De-Maria. 2000. Evaluation of the virulence of a Streptococcus pneumoniae neuraminidase-deficient mutant in nasopharyngeal colonization and development of otitis media in the chinchilla model. Infect. Immun. 68:921–924.

107. Tong, H. H.,, D. Li,, S. Chen,, J. P. Long, and, T. F. De-Maria. 2005. Immunization with recombinant Streptococcus pneumoniae neuraminidase NanA protects chinchillas against nasopharyngeal colonization. Infect. Immun. 73:7775–7778.

108. Tseng, H. J.,, A. G. McEwan,, J. C. Paton, and, M. P. Jennings. 2002. Virulence of Streptococcus pneumoniae: PsaA mutants are hypersensitive to oxidative stress. Infect. Immun. 70:1635–1639.

109. Tu, A.-H. T.,, R. L. Fulgham,, M. A. McCory,, D. E. Briles, and, A. J. Szalai. 1999. Pneumococcal surface protein A (PspA) inhibits complement activation by Streptococcus pneumoniae. Infect. Immun. 67:4720–4724.

110. Vela Coral, M. C.,, N. Fonseca,, E. Castaneda,, J. L. Di Fabio, and, S. K. Hollingshead. 2001. Families of pneumococcal surface protein A (PspA) of Streptococcus pneumoniae invasive isolates recovered from Colombian children. Emerg. Infect. Dis. 7:832–836.

111. Weiser, J. N.,, D. Bae,, C. Fasching,, R. W. Scamurra,, A. J. Ratner, and, E. N. Janoff. 2003. Antibody-enhanced pneumococcal adherence requires IgA1 protease. Proc. Natl. Acad. Sci. USA 100:4215–4220.

112. Wizemann, T. M.,, J. H. Heinrichs,, J. E. Adamou,, A. L. Erwin,, C. Kunsch,, G. H. Choi,, S. C. Barash,, C. A. Rosen,, H. R. Masure,, E. Tuomanen,, A. Gayle,, Y. A. Brewah,, W. Walsh,, P. Barren,, R. Lathigra,, M. Hanson,, S. Langermann,, S. Johnson, and, S. Koenig. 2001. Use of a whole genome approach to identify vaccine molecules affording protection against Streptococcus pneumoniae infection. Infect. Immun. 69:1593–1598.

113. Wu, H. Y.,, M. H. Nahm,, Y. Guo,, M. W. Russell, and, D. E. Briles. 1997. Intranasal immunization of mice with PspA (pneumococcal surface protein A) can prevent intranasal carriage and infection with Streptococcus pneumoniae. J. Infect. Dis. 175:839–846.

114. Yamamoto, M.,, L. S. McDaniel,, K. Kawabata,, D. E. Briles,, R. J. Jackson,, J. R. McGhee, and, H. Kiyono. 1997. Oral immunization with PspA elicits protective humoral immunity against Streptococcus pneumoniae infection. Infect. Immun. 65:640–644.

115. Yother, J., and, J. M. White. 1994. Novel surface attachment mechanism for the Streptococcus pneumoniae protein PspA. J. Bacteriol. 176:2976–2985.

116. Zhang, J. R.,, K. E. Mostov,, M. E. Lamm,, M. Nanno,, S. Shimida,, M. Ohwaki, and, E. Tuomanen. 2000. The polymeric immunoglobulin receptor translocates pneumococci across human nasopharyngeal epithelial cells. Cell 102:827–837.

117. Zhang, Y.,, A. W. Masi,, V. Barniak,, K. Mountzouros,, M. K. Hostetter, and, B. A. Green. 2001. Recombinant PhpA protein, a unique histidine motif-containing protein from Streptococcus pneumoniae, protects mice against intranasal pneumococcal challenge. Infect. Immun. 69:3827–3836.