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Thromb Haemost 2015; 113(01): 125-142
DOI: 10.1160/TH14-06-0561
Blood Cells, Inflammation and Infection
Schattauer GmbH

Binding of vitronectin and Factor H to Hic contributes to immune evasion of Streptococcus pneumoniae serotype 3

Sylvia Kohler
1   Department Genetics of Microorganisms, Interfaculty Institute for Genetics and Functional Genomics, University of Greifswald, Greifswald, Germany
,
Teresia Hallström
2   Department of Infection Biology, Hans Knoell Institute, Leibniz Institute for Natural Product Research and Infection Biology, Jena
,
Birendra Singh
3   Medical Microbiology, Department of Laboratory Medicine Malmö, Lund University, Malmö, Sweden
,
Kristian Riesbeck
3   Medical Microbiology, Department of Laboratory Medicine Malmö, Lund University, Malmö, Sweden
,
Giuseppina Spartà
4   University Children´s Hospital, Zurich, Switzerland
,
Peter F. Zipfel
2   Department of Infection Biology, Hans Knoell Institute, Leibniz Institute for Natural Product Research and Infection Biology, Jena
5   Friedrich Schiller University, Jena, Germany
,
Sven Hammerschmidt
1   Department Genetics of Microorganisms, Interfaculty Institute for Genetics and Functional Genomics, University of Greifswald, Greifswald, Germany
› Author Affiliations Financial support: This work was supported by Grants from the Deutsche Forschungsgemeinschaft DFG HA 3125/4-2 and the DFG-GRK840 (to S. H.) as well as the Anna and Edwin Berger foundation and the Swedish Medical Research Council (grant number 521-2010-4221) (to K. R.).
Further Information

Publication History

Received: 28 June 2014

Accepted after minor revision: 24 July 2014

Publication Date:
27 November 2017 (online)

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Summary

Streptococcus pneumoniae serotype 3 strains are highly resistant to opsonophagocytosis due to recruitment of the complement inhibitor Factor H via Hic, a member of the pneumococcal surface protein C (PspC) family. In this study, we demonstrated that Hic also interacts with vitronectin, a fluid-phase regulator involved in haemostasis, angiogenesis, and the terminal complement cascade as well as a component of the extracellular matrix. Blocking of Hic by specific antiserum or genetic deletion significantly reduced pneumococcal binding to soluble and immobilised vitronectin and to Factor H, respectively. In parallel, ectopic expression of Hic on the surface of Lactococcus lactis conferred binding to soluble and immobilised vitronectin as well as Factor H. Molecular analyses with truncated Hic fragments narrowed down the vitronectin-binding site to the central core of Hic (aa 151–201). This vitronectin-binding region is separate from that of Factor H, which binds to the N-terminus of Hic (aa 38–92). Binding of pneumococcal Hic was localised to the C-terminal heparin-binding domain (HBD3) of vitronectin. However, an N-terminal region to HBD3 was further involved in Hic-binding to immobilised vitronectin. Finally, vitronectin bound to Hic was functionally active and inhibited formation of the terminal complement complex. In conclusion, Hic interacts with vitronectin and simultaneously with Factor H, and both human proteins may contribute to colonisation and invasive disease caused by serotype 3 pneumococci.

Keywords

Complement - Hic - pathogenesis - PspC11 - serotype 3 - Streptococcus pneumoniae - vitronectin
 

  • References

  • 1 Cartwright K. Pneumococcal disease in western Europe: burden of disease, antibiotic resistance and management. Eur J Pediatr 2002; 161: 188-195.
    CrossrefPubMedGoogle Scholar
  • 2 Marriott HM, Mitchell TJ, Dockrell DH. Pneumolysin: a double-edged sword during the host-pathogen interaction. Curr Mol Med 2008; 08: 497-509.
    CrossrefPubMedGoogle Scholar
  • 3 Mook-Kanamori BB, Geldhoff M, van der Poll T. et al. Pathogenesis and pathophysiology of pneumococcal meningitis. Clin Microbiol Rev 2011; 24: 557-591.
    CrossrefPubMedGoogle Scholar
  • 4 Bentley SD, Aanensen DM, Mavroidi A. et al. Genetic analysis of the capsular biosynthetic locus from all 90 pneumococcal serotypes. PLoS Genet 2006; 02: e31.
    CrossrefPubMedGoogle Scholar
  • 5 Gamez G, Hammerschmidt S. Combat pneumococcal infections: adhesins as candidates for protein-based vaccine development. Curr Drug Targets 2012; 13: 323-337.
    CrossrefPubMedGoogle Scholar
  • 6 Voss S, Gamez G, Hammerschmidt S. Impact of pneumococcal microbial surface components recognizing adhesive matrix molecules on colonisation. Mol Oral Microbiol 2012; 27: 246-256.
    CrossrefPubMedGoogle Scholar
  • 7 Bogaert D, De Groot R, Hermans PW. Streptococcus pneumoniae colonisation: the key to pneumococcal disease. Lancet Infect Dis 2004; 04: 144-154.
    CrossrefPubMedGoogle Scholar
  • 8 Alonso M, Marimon JM, Ercibengoa M. et al. Dynamics of Streptococcus pneu-moniae serotypes causing acute otitis media isolated from children with spontaneous middle-ear drainage over a 12-year period (1999-2010) in a region of northern Spain. PLoS One 2013; 08: e54333.
    CrossrefPubMedGoogle Scholar
  • 9 Selva L, Ciruela P, Esteva C. et al. Serotype 3 is a common serotype causing invasive pneumococcal disease in children less than 5 years old, as identified by real-time PCR. Eur J Clin Microbiol Infect Dis 2012; 31: 1487-1495.
    CrossrefPubMedGoogle Scholar
  • 10 Weinberger DM, Harboe ZB, Sanders EA. et al. Association of serotype with risk of death due to pneumococcal pneumonia: a meta-analysis. Clin Infect Dis 2010; 51: 692-699.
    CrossrefPubMedGoogle Scholar
  • 11 Jarva H, Janulczyk R, Hellwage J. et al. 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 2002; 168: 1886-1894.
    CrossrefPubMedGoogle Scholar
  • 12 Zipfel PF, Hallstrom T, Riesbeck K. Human complement control and complement evasion by pathogenic microbes—tipping the balance. Mol Immunol 2013; 56: 152-160.
    CrossrefPubMedGoogle Scholar
  • 13 Zipfel PF, Hallstrom T, Hammerschmidt S. et al. The complement fitness factor H: role in human diseases and for immune escape of pathogens, like pneumococci. Vaccine 2008; 26 (Suppl. 08) I67-74.
    CrossrefPubMedGoogle Scholar
  • 14 Agarwal V, Asmat TM, Luo S. et al. Complement regulator Factor H mediates a two-step uptake of Streptococcus pneumoniae by human cells. J Biol Chem 2010; 285: 23486-23495.
    CrossrefPubMedGoogle Scholar
  • 15 Hammerschmidt S, Agarwal V, Kunert A. et al. The host immune regulator factor H interacts via two contact sites with the PspC protein of Streptococcus pneu-moniae and mediates adhesion to host epithelial cells. J Immunol 2007; 178: 5848-5858.
    CrossrefPubMedGoogle Scholar
  • 16 Hyams C, Trzcinski K, Camberlein E. et al. Streptococcus pneumoniae capsular serotype invasiveness correlates with the degree of factor H binding and opsoni-sation with C3b/iC3b. Infect Immun 2013; 81: 354-363.
    CrossrefPubMedGoogle Scholar
  • 17 Iannelli F, Oggioni MR, and Pozzi G. Allelic variation in the highly polymorphic locus pspC of Streptococcus pneumoniae. . Gene 2002; 284: 63-71..
    CrossrefPubMedGoogle Scholar
  • 18 Janulczyk R, Iannelli F, Sjoholm AG. et al. Hic, a novel surface protein of Streptococcus pneumoniae that interferes with complement function. J Biol Chem 2000; 275: 37257-37263.
    CrossrefPubMedGoogle Scholar
  • 19 Jarva H, Hellwage J, Jokiranta TS. et al. The group B streptococcal beta and pneumococcal Hic proteins are structurally related immune evasion molecules that bind the complement inhibitor factor H in an analogous fashion. J Immunol 2004; 172: 3111-3118.
    CrossrefPubMedGoogle Scholar
  • 20 Preissner KT, Reuning U. Vitronectin in vascular context: facets of a multita-lented matricellular protein. Semin Thromb Hemost 2011; 37: 408-424.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 21 Chillakuri CR, Jones C, Mardon HJ. Heparin binding domain in vitronectin is required for oligomerisation and thus enhances integrin mediated cell adhesion and spreading. FEBS Lett 2010; 584: 3287-3291.
    CrossrefPubMedGoogle Scholar
  • 22 Bergmann S, Lang A, Rohde M. et al. Integrin-linked kinase is required for vit-ronectin-mediated internalisation of Streptococcus pneumoniae by host cells. J Cell Sci 2009; 122: 256-267.
    CrossrefPubMedGoogle Scholar
  • 23 Voss S, Hallström T, Saleh M. et al. The choline-binding protein PspC of Streptococcus pneumoniae interacts with the C-terminal heparin-binding domain of vitronectin. J Biol Chem 2013; 288: 15614-15627.
    CrossrefPubMedGoogle Scholar
  • 24 Hammerschmidt S, Wolff S, Hocke A. et al. Illustration of pneumococcal poly-saccharide capsule during adherence and invasion of epithelial cells. Infect Immun 2005; 73: 4653-4667.
    CrossrefPubMedGoogle Scholar
  • 25 Singh B, Jalalvand F, Morgelin M. et al. Haemophilus influenzae protein E recognizes the C-terminal domain of vitronectin and modulates the membrane attack complex. Mol Microbiol 2011; 81: 80-98.
    CrossrefPubMedGoogle Scholar
  • 26 Hammerschmidt S, Talay SR, Brandtzaeg P. et al. SpsA, a novel pneumococcal surface protein with specific binding to secretory immunoglobulin A and secretory component. Mol Microbiol 1997; 25: 1113-1124.
    CrossrefPubMedGoogle Scholar
  • 27 Asmat TM, Klingbeil K, Jensch I. et al. Heterologous expression of pneumococ-cal virulence factor PspC on the surface of Lactococcus lactis confers adhesive properties. Microbiology 2012; 158: 771-780.
    CrossrefPubMedGoogle Scholar
  • 28 Saleh M, Bartual SG, Abdullah MR. et al. Molecular architecture of Streptococcus pneumoniae surface thioredoxin-fold lipoproteins crucial for extracellular ox-idative stress resistance and maintenance of virulence. EMBO Mol Med 2013; 05: 1852-1870.
    CrossrefPubMedGoogle Scholar
  • 29 Rennemeier C, Hammerschmidt S, Niemann S. et al. Thrombospondin-1 promotes cellular adherence of gram-positive pathogens via recognition of peptidoglycan. Faseb J 2007; 21: 3118-3132.
    CrossrefPubMedGoogle Scholar
  • 30 Dieudonne-Vatran A, Krentz S, Blom AM. et al. Clinical isolates of Streptococcus pneumoniae bind the complement inhibitor C4b-binding protein in a PspC al-lele-dependent fashion. J Immunol 2009; 182: 7865-7877.
    CrossrefPubMedGoogle Scholar
  • 31 Hammerschmidt S, Tillig MP, Wolff S. et al. Species-specific binding of human secretory component to SpsA protein of Streptococcus pneumoniae via a hexapeptide motif. Mol Microbiol 2000; 36: 726-736.
    PubMedGoogle Scholar
  • 32 Orihuela CJ, Mahdavi J, Thornton J. et al. Laminin receptor initiates bacterial contact with the blood brain barrier in experimental meningitis models. J Clin Invest 2009; 119: 1638-1646.
    CrossrefPubMedGoogle Scholar
  • 33 Singh B, Su YC, Riesbeck K. Vitronectin in bacterial pathogenesis: a host protein used in complement escape and cellular invasion. Mol Microbiol 2010; 78: 545-560.
    CrossrefPubMedGoogle Scholar
  • 34 Hauck CR, Ohlsen K. Sticky connections: extracellular matrix protein recognition and integrin-mediated cellular invasion by Staphylococcus aureus. . Curr Opin Microbiol 2006; 09: 5-11..
    CrossrefPubMedGoogle Scholar
  • 35 Zipfel PF. Complement factor H: physiology and pathophysiology. Semin Thromb Hemost 2001; 27: 191-199.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 36 Daniels CC, Coan P, King J. et al. The proline-rich region of pneumococcal surface proteins A and C contains surface-accessible epitopes common to all pneu-mococci and elicits antibody-mediated protection against sepsis. Infect Immun 2010; 78: 2163-2172.
    CrossrefPubMedGoogle Scholar
  • 37 Holmes AR, McNab R, Millsap KW. et al. The pavA gene of Streptococcus pneu-moniae encodes a fibronectin-binding protein that is essential for virulence. Mol Microbiol 2001; 41: 1395-1408.
    CrossrefPubMedGoogle Scholar
  • 38 Jensch I, Gamez G, Rothe M. et al. PavB is a surface-exposed adhesin of Streptococcus pneumoniae contributing to nasopharyngeal colonisation and airways infections. Mol Microbiol 2010; 77: 22-43.
    CrossrefPubMedGoogle Scholar
  • 39 Hilleringmann M, Giusti F, Baudner BC. et al. Pneumococcal pili are composed of protofilaments exposing adhesive clusters of Rrg A. PLoS Pathog 2008; 04: e1000026.
    CrossrefPubMedGoogle Scholar
  • 40 Yamaguchi M, Terao Y, Mori Y. et al. PfbA, a novel plasmin- and fibronectin-binding protein of Streptococcus pneumoniae, contributes to fibronectin-de-pendent adhesion and antiphagocytosis. J Biol Chem 2008; 283: 36272-36279.
    CrossrefPubMedGoogle Scholar
  • 41 Mann B, Orihuela C, Antikainen J. et al. Multifunctional role of choline binding protein G in pneumococcal pathogenesis. Infect Immun 2006; 74: 821-829.
    CrossrefPubMedGoogle Scholar
  • 42 Hallstrom T, Blom AM, Zipfel PF. et al. Nontypeable Haemophilus influenzae protein E binds vitronectin and is important for serum resistance. J Immunol 2009; 183: 2593-2601.
    CrossrefPubMedGoogle Scholar
  • 43 Su YC, Jalalvand F, Morgelin M. et al. Haemophilus influenzae acquires vitronec-tin via the ubiquitous Protein F to subvert host innate immunity. Mol Microbiol 2013; 87: 1245-1266.
    CrossrefPubMedGoogle Scholar
  • 44 Griffiths NJ, Hill DJ, Borodina E. et al. Meningococcal surface fibril (Msf) binds to activated vitronectin and inhibits the terminal complement pathway to increase serum resistance. Mol Microbiol 2011; 82: 1129-1149.
    CrossrefPubMedGoogle Scholar
  • 45 Sa E Cunha C, Griffiths NJ, and Virji M. Neisseria meningitidis Opc invasin binds to the sulphated tyrosines of activated vitronectin to attach to and invade human brain endothelial cells. PLoS Pathog 2010; 06: e1000911.
    CrossrefPubMedGoogle Scholar
  • 46 Singh B, Blom AM, Unal C. et al. Vitronectin binds to the head region of Mora-xella catarrhalis ubiquitous surface protein A2 and confers complement-inhibitory activity. Mol Microbiol 2010; 75: 1426-1444.
    CrossrefPubMedGoogle Scholar
  • 47 Styriak I, Laukova A, Fallgren C. et al. Binding of extracellular matrix proteins by animal strains of staphylococcal species. Vet Microbiol 1999; 67: 99-112.
    CrossrefPubMedGoogle Scholar
  • 48 Preissner KT. Structure and biological role of vitronectin. Annu Rev Cell Biol 1991; 07: 275-310.
    CrossrefPubMedGoogle Scholar
  • 49 Berends ET, Dekkers JF, Nijland R. et al. Distinct localisation of the complement C5b-9 complex on Gram-positive bacteria. Cell Microbiol 2013; 15: 1955-1968.
    CrossrefPubMedGoogle Scholar
  • 50 Tramontini NL, Kuipers PJ, Huber CM. et al. Modulation of leukocyte recruitment and IL-8 expression by the membrane attack complex of complement (C5b-9) in a rabbit model of antigen-induced arthritis. Inflammation 2002; 26: 311-319.
    CrossrefPubMedGoogle Scholar
  • 51 Kilgore KS, Schmid E, Shanley TP. et al. Sublytic concentrations of the membrane attack complex of complement induce endothelial interleukin-8 and monocyte chemoattractant protein-1 through nuclear factor-kappa B activation. Am J Pathol 1997; 150: 2019-2031.
    PubMedGoogle Scholar
  • 52 Triantafilou K, Hughes TR, Triantafilou M. et al. The complement membrane attack complex triggers intracellular Ca2+ fluxes leading to NLRP3 inflam-masome activation. J Cell Sci 2013; 126: 2903-2913.
    CrossrefPubMedGoogle Scholar
  • 53 Sheehan M, Morris CA, Pussell BA. et al. Complement inhibition by human vit-ronectin involves non-heparin binding domains. Clin Exp Immunol 1995; 101: 136-141.
    PubMedGoogle Scholar
  • 54 Gasson MJ. Plasmid complements of Streptococcus lactis NCDO 712 and other lactic streptococci after protoplast-induced curing. J Bacteriol 1983; 154: 1-9.
    PubMedGoogle Scholar
  • 55 Bryan EM, Bae T, Kleerebezem M. et al. Improved vectors for nisin-controlled expression in gram-positive bacteria. Plasmid 2000; 44: 183-190.
    CrossrefPubMedGoogle Scholar
  • 56 Lanie JA, Ng WL, Kazmierczak KM. et al. Genome sequence of Avery’s virulent serotype 2 strain D39 of Streptococcus pneumoniae and comparison with that of unencapsulated laboratory strain R6. J Bacteriol 2007; 189: 38-51.
    CrossrefPubMedGoogle Scholar