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 AffiliationsFinancial 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.).
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
54
Gasson MJ.
Plasmid complements of Streptococcus lactis NCDO 712 and other lactic streptococci after protoplast-induced curing. J Bacteriol 1983; 154: 1-9.
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.
