Chapter 9 : Streptococcus-Mediated Host Cell Signaling

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This chapter provides information on host cell-signaling events induced by streptococci. With the availability of complete genome sequence analyses of five group A (GAS) strains, including M1, M3 (two strains), M18, and M6, it is easy to predict the number of surface proteins, which may serve as potential adhesins during initial interactions with host cells. Pathogenic gram-positive cocci through their surface proteins interact with specific receptors on the target cell and induce a series of biochemical signals. These signals, which are characterized by the induction of phosphokinase enzymes and phosphorylation of several intracellular proteins, ultimately target the nucleus and lead to either generalized or specific gene activation. Activation of some of these genes may result in the modulation of interleukin or cytokine expression, which may then initiate a proinflammatory response. These induced signals, and subsequent products, could have several effects on the invasion of bacteria. For example, these induced signals may modulate cytoskeletal structure and/or specific host cell receptor expression or may destroy adjoining cells and disrupt natural protective barriers in autocrine or paracrine modes. This, in turn, could facilitate bacterial entry.

Citation: Pancholi V. 2006. Streptococcus-Mediated Host Cell Signaling, p 100-112. In Fischetti V, Novick R, Ferretti J, Portnoy D, Rood J (ed), Gram-Positive Pathogens, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816513.ch9

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() Streptococcus-mediated signaling events and their implications. The cartoon illustrates reported signaling events. Some of the pathways are hypothesized on the basis of available specific reports on streptococci-mediated signaling events and established signal transduction pathways in eukaryotes. There are at least four receptors (uPAR, enolase, CD44, CD46) that directly interact with group A (GAS) surface proteins. Indirect binding to eukaryotic cells through fibronectin is likely mediated by α5β1 integrin. GAS invades host epithelial cells by two different mechanisms, either by invagination at the point of bacterial contact with host cells or by massive induction of microvilli, which form membrane ruffling for engulfment of bacteria (filopodia). Cytoskeletal rearrangements involve induction of the IP-3 kinase pathway or RAS/CDC42/tyrosine kinase activation. Some of the GAS secretory products such as SLO and NAD glycohydrolase may cooperatively make holes in eukaryotic cells and inject bacterial product in eukaryotic cells to exploit intracellular signaling events in a manner similar to the type III secretory system of gram-negative bacteria. Intracellular GAS may then direct host cells to undergo apoptosis via caspase-dependent and -independent pathways. In GAS-mediated apoptosis mitochondria seem to play a crucial role. NAD-glycohydrolase of GAS may convert NAD to ADP-ribose and/or cyclic ADP-ribose, which may then direct the host cell to undergo apoptosis through the Ca signaling pathway. Although not fully explored, transcriptional regulation of many inflammatory cytokines and apoptosis in the GAS-infected host cells may be mediated via NF-κB and JAK/STAT pathways. Histone-phosphorylation/dephosphorylation and histone acetylation/deacetylation also seem to play important roles in gene transcription in GAS-infected host cells. The induction of signaling pathways may vary depending on the cell lines, status of the cell (polarized versus nonpolarized), type of GAS strains, and growth phase. Abbreviations: ADPR-adenosine diphosphate-ribose; cADPR-cyclic ADPR; AIF-apoptosis inducing factor; Akt-AKT retroviral oncogene protein Ser/Thr kinase; APAF1-apoptosis protease activating factor-1 or CED-4; Arp2/3-actin-related protein 2 and 3; ASK1-apoptosis signal-regulating kinase 1 (also known as MEKK5); ATF2-activating transcription factor 2; BAD-Bcl-xL/Bcl-2 associated death promoter; Bid-BH-3 interacting domain death agonist that induces ICE-like proteases and apoptosis; Bcl2-B-cell lymphoma 2, which belongs to the Bcl-2 family of proteins and is known to inhibit apoptosis; BAK-Bcl-2 antagonist/killer. Bak is a pro-apoptotic protein; BAX-Bcl-2 associated x protein. Bax is as member of the Bcl-2 family and is pro-apoptotic; tBid-truncated Bid; CARD-caspase activation and recruitment domain; Caspase-cysteinyl aspartic acid-protease; CD44-human leukocyte differentiation receptor antigen for hyaluronate and proteoglycin serglycin; CD46-member of RCA gene family, receptor for measles virus and the M protein of GAS; Cdc42-cell division cycle 42 (GTP-binding protein); CytC-cytochrome C; c-Fos/c-Jun-transcription factor, also known as activator protein or AP-1; ELK1-Ets domain containing DNA-binding protein. Mammalian ELK-1, ELK-3 (also known as Net or SAP-2) and ELK-4 (also known as SRF accessory protein 1 [SAP-1]), which all form a ternary complex with the serum response factor (SRF); ERK-extracellular signal-related protein kinase; FADD-Fas-associated death domain; FAK-focal adhesion kinase; FAS-known as CD95 or APO-1. Fas is a member of the TNF receptor family and promotes apoptosis. FasL-Fas ligand. FasL is also known as APO-1 ligand or Apo-L; FLIP-FLICE (Fadd-like ICE [interleukin-1b converting enzyme also known as caspase-1]) inhibitory protein; G-G-protein α, β, and γ; HAT-histone acetyl transferase; HDAC-histone deacetylase; IKB-inhibitory IB (inhibitor of NF-κB) proteins; IKKs-IKK-1 and IKK-2 are two direct IB kinases; IL-interleukins; INF-interferon α or γ; INFR-interferon- γ receptor; IRAK-interleukin-1 receptor-associated kinases; JAK-Janus kinase; JNK-c-Jun N terminal kinase; MAPK-mitogen-activated protein kinase; MEK-MAPK activator; MEKKs-mitogen-activated protein/ERK kinase kinases; MLK1,2-CdC42-dependent kinases; MLK4,7-CdC42-dependent kinases; mTOR-mammalian target of Rapamycin (an immunosuppressant) protein; MyD88-myeloid differentiation factor 88; NAD-nicotinamide adenine dinucleotide; NFKB-nuclear factor of immunoglobulin κ locus in B cells. NF-κB activates transcription of genes in many tissues; NIK-Nck interacting kinase (interacting with MEKK) is different from NIK (NFκB-interacting kinase); PI-3K-Phosphatidyl inositol-3 kinase; RAC-small GTP-binding protein encoded by the gene; RAS-small GTP-binding protein protooncogene encoded by the gene; RIP-receptor interacting protein; ROS-reactive oxygen species; SEN, streptococcal surface enolase; SH2-Src homology region 2; SLO, streptolysin O; STAT-signal transducers and activators of transcription; TIRAP-Toll-interleukin 1 receptor domain-containing adaptor protein; TLR-Toll-like receptor; TNF-tumor necrosis factor; TNFR-tumor necrosis factor receptor; TOLL-human homologue of the Toll protein; TOLLIP-Toll-interacting protein; TRAD-TNF receptor I associated death domain; TRAF-tumor necrosis factor receptor-associated factors; SDH-streptococcal surface dehydrogenase; uPAR-urokinase plasminogen activator receptor.

Citation: Pancholi V. 2006. Streptococcus-Mediated Host Cell Signaling, p 100-112. In Fischetti V, Novick R, Ferretti J, Portnoy D, Rood J (ed), Gram-Positive Pathogens, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816513.ch9
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1. Ajiro, K.,, and T. Nishimoto. 1985. Specific site of histone H3 phosphorylation related to the maintenance of premature chromosome condensation. J. Biol. Chem. 260:1537915381.
2. Akesson, P.,, K.-H. Schmidt,, J. Cooney,, and L. Bjorck. 1994. M1 protein and protein H: IgGFc- and albumin-binding streptococcal surface proteins encoded by adjacent genes. Biochem. J. 300:877886.
3. Alouf, J. E.,, and H. Muller-Alouf. 2003. Staphylococcal and streptococcal superantigens: molecular, biological and clinical aspects. Int. J. Med. Microbiol. 292:429440.
4. Ambrosino, D. M.,, N. R. Delaney,, and R. C. Shamberger. 1990. Human polysaccharide-specific B cells are responsive to pokeweed mitogen and IL-6. J. Immunol. 144:12211226.
5. Baldwin, A. S., Jr. 1996. The NF-κB and IkB proteins: new discoveries and insights. Annu. Rev. Immunol. 14:649681.
6. Banks, D. J.,, S. F. Porcella,, K. D. Barbian,, S. B. Beres,, L. E. Philips,, J. M. Voyich,, F. R. DeLeo,, J. M. Martin,, G. A. Somerville,, and J. M. Musser. 2004. Progress toward characterization of the group A Streptococcus metagenome: complete genome sequence of a macrolide-resistant serotype M6 strain. J. Infect. Dis. 190:727738.
7. Barratt, M. J.,, C. A. Hazzalin,, E. Cano,, and L. C. Mahadevan. 1994. Mitogen-stimulated phosphorylation of histone H3 is targeted to a small hyperacetylation-sensitive fraction. Proc. Natl. Acad. Sci. USA 91:47814785.
8. Beres, S. B.,, G. L. Sylva,, K. D. Barbian,, B. Lei,, J. S. Hoff,, N. D. Mammarella,, M.-Y. Liu,, J. C. Smoot,, S. F. Porcella,, L. D. Parkins,, D. S. Campbell,, T. M. Smith,, J. K. McCormick,, D. Y. M. Leung,, P. Schlievert,, and J. M. Musser. 2002. Genome sequence of a serotype M3 strain of group A Streptococcus: phage-encoded toxins, the high-virulence phenotype, and clone emergence. Proc. Natl. Acad. Sci. USA 99:1007810083.
9. Bergmann, S.,, M. Rohde,, G. S. Chhatwal,, and S. Hammerschmidt. 2001. Alpha-enolase of Streptococcus pneumonia is a plasmin(ogen)-binding protein displayed on the bacterial cell surface. Mol. Microbiol. 40:12731287.
10. Bissell, M. J. 1993. Introduction: form and function in the epithelia. Sem. Cell. Bio. 4:157159.
11. Bliska, J. B.,, J. E. Galan,, and S. Falkow. 1993. Signal transduction in the mammalian cell during bacterial attachment and entry. Cell 73:903920.
12. Braun, J. S.,, R. Novak,, K. H. Herzog,, S. M. Bodner,, J. L. Cleveland,, and E. Tuomanen. 1999. Neuroprotection by a caspase inhibitor in acute bacterial meningitis. Nat. Med. 5:298302.
13. Braun, J. S.,, R. Novak,, P. J. Murray,, C.M. Eischen,, S. A. Susin,, G. Kroemer,, A. Halle,, J. R. Weber,, E. I. Tuomanen,, and J. L. Cleveland. 2001. Apoptosis-inducing factor mediates microglial and neuronal apoptosis caused by pneumococcus. J. Infect. Dis. 184:13001309.
14. Bricker, A. L.,, C. Cywes,, C. D. Ashbaugh,, and M. R. Wessels. 2002. NAD+-glycohydrolase acts as an intracellular toxin to enhance the extracellular survival of group A streptococci. Mol. Microbiol. 44:257269.
15. Buchanan, R. M.,, B. P. Arulanandam,, and D. W. Metzger. 1998. IL-12 enhances antibody responses to T-independent polysaccharide vaccines in the absence of T and NK cells. J. Immunol. 161:55255533.
16. Caparon, M. G.,, R. T. Geist,, J. Perez-Casal,, and J. R. Scott. 1992. Environmental regulation of virulence in group A streptococci: transcription of the gene encoding M protein is stimulated by carbon dioxide. J. Bacteriol. 174:56935701.
17. Cauwels, A.,, E. Wan,, M. Leismann,, and E. Tuomanen. 1997. Coexistence of CD14-dependent and independent pathways for stimulation of human monocytes by gram-positive bacteria. Infect. Immun. 65:32553260.
18. Chen, C. C.,, and P. P. Cleary. 1989. Cloning and expression of the streptococcal C5a peptidase gene in Escherichia coli: linkage to the type 12 M protein gene. Infect. Immun. 57:17401745.
19. Cleary, P. P.,, E. L. Kaplan,, J. P. Handley,, A. Wlazlo,, M. H. Kim,, A. R. Hauser,, and P. M. Schlievert. 1992. Clonal basis for resurgence of serious Streptococcus pyogenes disease in the 1980s. Lancet 339:518521.
20. Cossart, P. 1997. Subversion of the mammalian cell cytoskeleton by invasive bacteria. J. Clin. Invest. 99:23072311.
21. Cossart, P.,, P. Boquet,, S. Normark,, and R. Rappuoli. 1996. Cellular microbiology emerging. Science 271:315316.
22. Cotter, P. A.,, and J. F. Miller. 1996. Triggering bacterial virulence. Science 273:11831184.
23. Courtney, H. S.,, and D. L. Hasty. 1991. Aggregation of group A streptococci by human saliva and effect of saliva on streptococcal adherence to host cells. Infect. Immun. 59:16611666.
24. Courtney, H. S.,, Y. Li,, J. B. Dale,, and D. L. Hasty. 1994. Cloning, sequencing, and expression of a fibronectin/fibrinogen-binding protein from group A streptococci. Infect. Immun. 62:39373946.
25. Cue, D.,, P. E. Dombek,, H. Lam,, and P. P. Cleary. 1998. Streptococcus pyogenes serotype M1 encodes multiple pathways for entry into human epithelial cells. Infect. Immun. 66:45934601.
26. Cundell, D. R.,, N. P. Gerard,, C. Gerard,, I. Indanpaan-Heikkila,, and E. I. Tuomanen. 1995. Streptococcus pneumonia anchor to activated human cells by the receptor for platelet-activating factor. Nature 377:435438.
27. Cundell, D. R.,, C. Gerard,, I. Idanpaan-Keikkila,, E. I. Tuomanen,, and N. P. Gerard. 1996. PAf receptor anchors Streptococcus pneumoniae to activated human endothelial cells. Adv. Exp. Med. Biol. 416:8994.
28. Cunningham, M. W. 2000. Pathogenesis of a group A streptococcal infections. Clin. Microbiol. Rev. 13:470511.
29. Cywes, C.,, and M. R. Wessels. 2001. Group A Streptococcus tissue invasion by CD44-mediated cell signalling. Nature 414:648652.
30. Cywes, C.,, I. Stamenkovic,, and M. R. Wessels. 2000. CD44 as a receptor for colonization of the pharynx by group A Streptococcus. J. Clin. Invest. 106:9951002.
31. Darnell, J. E. 1998. STATs and gene regulation. Science 277:16301635.
32. Davies, H. D.,, A. McGeer,, B. Schwartz,, K. Green,, D. Cann,, A. E. Simor,, and D. E. Low. 1996. Invasive group A streptococcal infections in Ontario, Canada. N. Engl. J. Med. 335:547554.
33. Davis, L.,, M. M. Baig,, and E. M. Ayoub. 1979. Properties of extracellular neuraminidase produced by group A Streptococcus. Infect. Immun. 24:780786.
34. D’Costa, S. S.,, T. G. Romer,, and M. D. P. Boyle. 2000. Analysis of expression of a cytosolic enzyme on the surface of Streptococcus pyogenes. Biochem. Biophys. Res. Commun. 278:826832.
35. Demuth, D. R.,, E. E. Golub,, and D. Malamud. 1990. Streptococcal-host interactions. J. Biol. Chem. 265:71207126.
36. Dohrman, A.,, S. Miyata,, M. Gallup,, J.-D. Li,, C. Chapelin,, A. Coste,, E. Escudier,, J. Nadel,, and A. Bashir. 1998. Mucin gene (MUC 2 and MUC 5AC) up-regulation by gram-positive and gram-negative bacteria. Biochim. Biophys. Acta 1406:251259.
37. Dombek, P. E.,, D. Cue,, J. Sedgewick,, H. Lam,, S. Ruschkowski,, B. B. Finlay,, and P. P. Cleary. 1999. High-frequency intracellular invasion of epithelial cells by serotype M1 group A streptococci: M1 protein-mediated invasion and cytoskeletal rearrangements. Mol. Microbiol. 31:859870.
38. Doring, G.,, H. Obernessen,, K. Botzenhart,, B. Flehmig,, N. Hoiby,, and A. Hofmann. 1983. Proteases of Pseudomonas aeruginosa in patients with cystic fibrosis. J. Infect. Dis. 147:744750.
39. Drubin, D. G.,, and W. J. Nelson. 1996. Origins of polarity. Cell 84:335344.
40. Dudani, A. K.,, C. Cummings,, S. Hashemi,, and P. R. Ganz. 1993. Isolation of a novel 45 kDa plasminogen receptor from human endothelial cells. Thromb. Res. 69:185196.
41. Ferretti, J. J.,, W. M. McShan,, D. Ajdic,, D. J. Savic,, G. Savic,, K. Lyon,, C. Primeaux,, S. Sezate,, A. N. Suvorov,, S. Kenton,, H. S. Lai,, S. P. Lin,, Y. Qian,, H. G. Jia,, F. Z. Najar,, Q. Ren,, H. Zhu,, L. Song,, J. White,, X. Yuan,, S.W. Clifton,, B. A. Roe,, and R. McLaughlin. 2001. Complete genome sequence of an M1 strain of Streptococcus pyogenes. Proc. Natl. Acad. Sci. USA 98:46584663.
42. Finlay, B. B.,, and P. Cossart. 1997. Exploitation of mammalian host cell functions by bacterial pathogens. Science 276:718725.
43. Forstner, G. 1995. Signal transduction, packaging and secretion of mucins. Annu. Rev. Physiol. 57:585605.
44. Freyer, D.,, M. Weih,, J. R. Weber,, W. Burger,, P. Scholz,, R. Manz,, A. Zeigenhorn,, C. Angstwurm,, and U. Dirnagl. 1996. Pneumococcal cell wall components induce nitric oxide synthase and TNF-alpha in astroglial-enriched cultures. Glia 16:16.
45. Frick, I.-M.,, K. L. Crossin,, G. M. Edelman,, and L. Bjorck. 1995. Protein H—a bacterial surface protein with affinity for both immunoglobulin and fibronectin type III domains. EMBO J. 14:16741679.
46. Gallo, K. A.,, and G. L. Johnson. 2002. Mixed-lineage kinase control of JNK and p38 MAPK pathways. Nat. Rev. Mol. Cell Biol. 3:663671.
47. Garcia, R. C.,, D. R. Cundell,, E. I. Tuomanen,, L. F. Kolakowski,, C. Gerard,, and N. P. Gerard. 1995. The role of N-glycosylation for functional expression of the human platelet-activating factor receptor. Glycosylation is required for efficient membrane trafficking. J. Biol. Chem. 270:2517825184.
48. Geelen, S.,, C. Bhattacharyya,, and E. Tuomanen. 1992. Induction of procoagulant activity on human endothelial cells by Streptococcus pneumoniae. Infect. Immun. 60:41794183.
49. Gendler, S. J.,, and A. P. Spicer. 1995. Epithelial mucin genes. Annu. Rev. Physiol. 57:607634.
50. Ghosh, S.,, M. J. May,, and E. B. Kopp. 1998. NF-kappaB and Rel proteins: evolutionary conserved mediators of immune responses. Annu. Rev. Immunol. 16:225260.
51. Giannakis, E.,, T. S. Jokiranta,, R. J. Ormsby,, T.G. Duthy,, D. A. Male,, D. Christiansen,, V. A. Fischetti,, C. Bagley,, B. E. Loveland,, and D. L. Gordon. 2002. Identification of the streptococcal M protein-binding site on membrane cofactor protein (CD46). J. Immunol. 168:45854592.
52. Graham, M. G.,, L. M. Smoot,, C. A. Lux Migliaccio,, K. Virtaneva,, D. E. Sturdevant,, S. F. Porcella,, M. J. Federle,, G. J. Adams,, J. R. Scott,, and J. M. Musser. 2002. Virulence control in group A Streptococcus by a two-component gene regulatory system: global expression profiling and in vivo infection modeling. Proc. Natl. Acad. Sci. USA 99:1385513860.
53. Guzman, C. A.,, E. Domann,, M. Rohde,, D. Bruder,, A. Darji,, S. Weiss,, J. Wehland,, T. Chakraborty,, and K. N. Timmis. 1997. Apoptosis of mouse dendritic cells is triggered by listerolysin, the major virulence determinant of Listeria monocytogenes. Mol. Microbiol. 20:119126.
54. Hanski, E.,, and M. Caparon. 1992. Protein F, a fibronectin-binding protein, is an adhesin of the group A Streptococcus, Streptococcus pyogenes. Proc. Natl. Acad. Sci. USA 89:61726176.
55. Henneke, P.,, O. Takeuchi,, J. A. van Strijp,, H. K. Guttormsen,, J. A. Smith,, A. B. Schromm,, T. A. Espevik,, S. Akira,, V. Nizet,, D. L. Kasper,, and D. T. Golenbock. 2001. Novel engagement of CD14 and multiple toll-like receptors by group B streptococci. J. Immunol. 167:70697076.
56. Hermann, C.,, I. Spreitzer,, N. Schroeder,, S. Morath,, M. Lehner,, W. Fischer,, C. Schutt,, R. Schumann,, and T. Hartung. 2002. Cytokine induction by purified lipoteichoic acids from various bacterial species-role of LBP, sCD14, CD14 and failure to induce TL-12 and subsequent IFN release. Eur. J. Immunol. 32:551.
57. Herwald, H.,, H. Cramer,, M. Morgelin,, W. Russell,, U. Sollenberg,, A. Norrby-Teglund,, H. Flodgaard,, L. Lindbom,, and L. Bjorck. 2004. M protein, a classical bacterial virulence determinant, forms complexes with fibrinogen that induce vascular leakage. Cell 116:367379.
58. Hilbi, H.,, J. E. Moss,, D. Hersh,, Y. Chen,, J. Arondel,, S. Banerjee,, R. A. Flavell,, J. Yuan,, P. J. Sansonetti,, and A. Zychlinsky. 1998. Shigella-induced apoptosis is dependent on caspase-1 which binds to IpaB. J. Biol. Chem. 273:3289532900.
59. Hilkens, J.,, M. J. L. Ligtengerg,, H. L. Vos,, and S. V. Litvinov. 1992. Cell membrane-associated mucins and their adhesion-modulating property. Trends Biol. Sci. 17:359363.
60. Hopkin, K. 1997. Spools, switches, or scaffolds: how might histones regulate transcription? J. NIH Res. 9:3437.
61. Hultgren, S. J.,, S. Abraham,, M. Caparon,, P. Falk,, J. W. St. Geme III, and S. Normack. 1993. Pilus and nonpilus bacterial adhesions: assembly and function in cell regulation. Cell 73:887901.
62. Hynes, R. O. 1992. Integrins: versatility, modulation, and signaling in cell adhesion. Cell 69:1125.
63. Hytonen, J.,, S. Haataja,, P. Isomaki,, and J. Finne. 2000. Identification of a novel glycoprotein-binding activity in Streptococcus pyogenes regulated by the mga gene. Microbiology 146:3139.
64. Hytonen, J.,, S. Haataja,, and J. Finne. 2003. Streptococcus pyogenes glycoprotein-binding strepadhesin activity is mediated by a surface-associated carbohydrate-degrading enzyme, pullulanase. Infect. Immun. 71:784793.
65. Iseberg, R. R. 1991. Discrimination between intracellular uptake and surface adhesion of bacterial pathogens. Science 252:934938.
66. Iseberg, R. R.,, and G. T. V. Nhieu. 1994. Binding and internalization of microorganisms by integrin receptors. Trends Microbiol. 2:1014.
67. Jadoun, J.,, V. Ozeri,, E. Burstein,, E. Skutelsky,, E. Hanski,, and S. Sela. 1998. Protein F1 is required for efficient entry of Streptococcus pyogenes into epithelia cells. J. Infect. Dis. 178:147158.
68. Jaffe, J.,, S. Natanson-Yaron,, M. G. Caparon,, and E. Hanski. 1996. Protein F2, a novel fibronectin-binding protein from Streptococcus pyogenes, possesses two binding domains. Mol. Microbiol. 21:373384.
69. Jin, H.,, Y. P. Song,, and V. Pancholi. 2004. Urokinase plasminogen activator receptor (uPAr/CD87) is a receptor for group A streptococcal surface dehydrogenase (SDH) on the surface of human pharyngeal cells: identification of ligand-receptor binding regions, abstr. B-378, p. 99. Abstr. 104th Annu. Meet. Am. Soc. Microbiol. 2004. American Society for Microbiology, Washington, D.C.
70. Kantor, F. S. 1965. Fibrinogen precipitating by streptococcal M protein. I. Identity of the reactants and stoichiometry of the reaction. J. Exp. Med. 121:849859.
71. Kehoe, M. A., 1994. Cell-wall-associated proteins in gram-positive bacteria, p. 217261. In J.-M. Ghuysen, and R. Hakenbeck (ed.), Bacterial Cell Wall. Elsevier Science, New York, N.Y.
72. Kemp, K.,, H. Bruunsgaard,, P. Skinhoj,, and P. B. Klarlund. 2002. Pneumococcal infections in humans are associated with increased apoptosis and trafficking of type 1 cytokine-producing T cells. Infect. Immun. 70:50195025.
73. Kerr, A. R.,, X. Q. Wei,, P. W. Andrew,, and T. J. Mitchell. 2004. Nitric oxide exerts distinct effects in local and systemic infections with Streptococcus pneumoniae. Microb. Pathog. 36:303310.
74. Klinger, J.,, B. Tandler,, C. Kiedtke,, and T. Boat. 1984. Proteinases of Pseudomonas aeruginosa evoke mucins release by tracheal epithelium. J. Clin. Invest. 74:16691678.
75. Kobayashi, S. D.,, K. R. Braughton,, A. R. Whitney,, J. M. Voyich,, T. G. Schwan,, J. M. Musser,, and F. R. DeLeo. 2003. Bacterial pathogens modulate an apoptosis differentiation program in human neutrophils. Proc. Natl. Acad. Sci. USA 100:1094810953.
76. Koedel, U.,, B. Angele,, T. Rupprecht,, H. Wagner,, A. Roggenkamp,, H. W. Pfister,, and C. J. Kirschning. 2003. Toll-like receptor 2 participates in mediation of immune response in experimental pneumococcal meningitis. J. Immunol. 170:438444.
77. Kotb, M.,, A. Norrby-Teglund,, A. McGeer,, H. El Sherbini,, M. T. Dorak,, A. Khurshid,, K. Green,, J. Peeples,, J. Wade,, G. Thomson,, B. Schwartz,, and D. E. Low. 2002. An immunogenetic and molecular basis for differences in outcomes of invasive group A streptococcal infections. Nat. Med. 8:13981404.
78. Kreikemeyer, B.,, K. S. McIver,, and A. Podbielski. 2003. Virulence factors regulation and regulatory networks in Streptococcus pyogenes and their impact on pathogen-host interactions. Trends Microbiol. 11:224232.
79. Levitzki, A.,, and A. Gazit. 1995. Tyrosine kinase inhibition: an approach to drug development. Science 267:17821788.
80. Lieberman, D.,, S. Livnat,, F. Schlaeffer,, A. Porath,, S. Horowitz,, and R. Levy. 1997. IL-1beta and IL-6 in community- acquired pneumonia: bacteremic pneumococcal pneumonia versus Mycoplasma pneumoniae pneumonia. Infection 25:9094.
81. Livinov, S. V.,, and J. Hilkens. 1993. The epithelial sialomucin, episialin, is sialylated during recycling. J. Biol. Chem. 268:2136421371.
82. Luger, K.,, A. W. Mader,, R. K. Richmond,, D. F. Sargent,, and T. J. Richmond. 1997. Crystal structure of the nucleosome core particle at 2.8A resolution. Nature 389:251260.
83. Lukomski, S.,, E. H. Burns Jr,, P. R. Wyde,, A. Podbielski,, J. Rurangirwa,, D. K. Moore-Poveda,, and J. M. Musser. 1998. Genetic inactivation of an extracellular cysteine protease (SpeB) expressed by Streptococcus pyogenes decreases resistance to phagocytosis and dissemination to organs. Infect. Immun. 66:771776.
84. Madden, J. C.,, N. Ruiz,, and M. Caparon. 2001. Cytolysin-mediated translocation (CMT): a functional equivalent of type III secretion in Gram-positive bacteria. Cell 104:143152.
85. Mahadevan, L. C.,, A. C. Willis,, and M. J. Barratt. 1991. Rapid histone H3 phosphorylation in response to growth factors, phorbol esters, okadaic acid, and protein synthesis inhibitors. Cell 65:775783.
86. 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. T. Golenbock. 2003. Recognition of pneumolysin by Toll-like receptor 4 confers resistance to pneumococcal infection. Proc. Natl. Acad. Sci. USA 100:19661971.
87. Mancuso, G.,, A. Midiri,, C. Beninati,, G. Piraino,, A. Valenti,, G. Nicocia,, D. Teti,, J. Cook,, and G. Teti. 2002. Mitogen-activated protein kinases and NF-kappa B are involved in TNF-alpha responses to group B streptococci. J. Immunol. 169:14011409.
88. McIver, K. S.,, and J. R. Scott. 1997. Role of mga in growth phase regulation of virulence genes of the group A streptococcus. J. Bacteriol. 179:51785187.
89. McIver, K. S.,, A. S. Heath,, and J. R. Scott. 1995. Regulation of virulence by environmental signals in group A streptococci: influence of osmolarity, temperature, gas exchange, and iron limitation of emm transcription. Infect. Immun. 63:45404542.
90. Medina, E.,, D. Anders,, and G. S. Chhatwal. 2002. Induction of NF-kappaB nuclear translocation in human respiratory epithelial cells by group A streptococci. Microb. Pathog. 33:307313.
91. Medvedev, A. E.,, T. Flo,, R. R. Ingalls,, D. T. Golenbock,, G. Teti,, S. N. Vogel,, and T. Espevik. 1998. Involvement of CD14 and complement receptors CR3 and CR4 in nuclear factor-kappaB activation and TNF production induced by lipopolysaccharide and group B streptococcal cell walls. J. Immunol. 160:45354542.
92. Mehta, K.,, U. Sahid,, and F. Malavasi. 1996. Human CD38, a cell-surface protein with multiple function. FASEB J. 10:14081417.
93. Miettinen, M.,, A. Lehtonen,, I. Julkunen,, and S. Matikainen. 2000. Lactobacilli and streptococci activate NF-kappa B and STAT signaling pathways in human macrophages. J. Immunol. 164:37333740.
94. Miles, L. A.,, C. M. Dahlberg,, J. Plescia,, J. Felez,, K. Kato,, and E. F. Plow. 1991. Role of cell-surface lysines in plasminogen binding to cells: identification of alpha-enolase as a candidate plasminogen receptor. Biochemistry 30:16821691.
95. Molinari, G.,, S. R. Talay,, P. Valentin-Weigand,, M. Rohde,, and G. S. Chhatwal. 1998. The fibronectin-binding protein of Streptococcus pyogenes, SfbI, is involved in the internalization of group A streptococci by epithelial cells. Infect. Immun. 65:13571363.
96. Molinari, G.,, M. Rohde,, C. A. Guzman,, and G. S. Chhatwal. 2000. Two distinct pathways for the invasion of Streptococcus pyogenes in non-phagocytic cells. Cell. Microbiol. 2:145154.
97. Mosquera, J.,, A., V. N. Katiyar, J.Coello, and B. Rodriguez-Iturbe. 1985. Neuraminidase production by streptococci from patients with glomerulonephritis. J. Infect. Dis. 151:259263.
98. Moss, J.,, and M. Vaughan. 1988. ADP-ribosylation of guanyl nucleotide-binding regulatory proteins by bacterial toxins. Adv. Enzymol. 61:303379.
99. Muller-Alouf, H.,, J. E. Alouf,, D. Gerlach,, J.-H. Ozegowski,, C. Fitting,, and J.-M. Cavaillon. 1994. Comparative study of cytokine release by human peripheral blood mononuclear cells stimulated with Streptococcus pyogenes superantigenic erythrogenic toxins, heat-killed streptococci and lipopolysaccaride. Infect. Immun. 62:49154921.
100. Nagata, S. 1997. Apoptosis by death factor. Cell 88:355365.
101. Nakagawa, I.,, M. Nakata,, S. Kawabata,, and S. Hamada. 2002. Cytochrome C-mediated caspase-9 activation triggers apoptosis in Streptococcus pyogenes-infected epithelial cells. Cell. Microbiol. 3:395405.
102. Nakagawa, I.,, K. Kurokawa,, A. Yamashita,, M. Nakata,, Y. Tomiyasu,, N. Okahashi,, S. Kawabata,, K. Yamazaki,, T. Shiba,, T. Yasunaga,, H. Hayashi,, M. Hattori,, and S. Hamada. 2003. Genome sequence of an M3 strain of Streptococcus pyogenes reveals a large-scale genomic rearrangement in invasive strains and new insights into phage evolution. Genome Res. 13:10421055.
103. Natanson, C.,, W. D. Hoffman,, A. F. Suffredini,, P. Q. Eichacker,, and R. L. Danner. 1994. Selected treatment strategies for septic shock based on proposed mechanisms of pathogenesis. Ann. Intern. Med. 120:771783.
104. Navarre, W. W.,, and O. Schneewind. 1999. Surface proteins of gram-positive bacteria and mechanisms of their targeting to the cell wall envelope. Microbiol. Molec. Biol. Rev. 63:174229.
105. Neff, L.,, M. Zeisel,, J. Sibilia,, M. Scholler-Guinard,, J. P. Klein,, and D. Wachsmann. 2001. NF-kappaB and the MAP kinases/AP-1 pathways are both involved in interleukin-6 and interleukin-8 expression in fibroblast-like synoviocytes stimulated by protein I/II, a modulin from oral streptococci. Cell. Microbiol. 3:703712.
106. Norgren, M.,, A. Norrby,, and S. E. Holm. 1992. Genetic diversity in T1M1 group A streptococci in relation to clinical outcome of infection. J. Infect. Dis. 166:10141020.
107. Norrby-Teglund, A.,, S. Chatellier,, D. E. Low,, A. McGeer,, K. Green,, and M. Kotb. 2000. Host variation in cytokine responses to superantigens determine the severity of invasive group A streptococcal infection. Eur. J. Immunol. 30:32473255.
108. Nyberg, P.,, T. Sakai,, K. H. Cho,, M. G. Caparon,, R. Fassler,, and L. Bjorck. 2004. Interactions with fibronectin attenuate the virulence of Streptococcus pyogenes. EMBO J. 23:21662174.
109. Okada, N.,, M. K. Liszewski,, J. P. Atkinson,, and M. Caparon. 1995. Membrane cofactor protein (CD46) is a keratinocyte receptor for the M protein of group A streptococcus. Proc. Natl. Acad. Sci. USA 92:24892493.
110. Okada, N.,, M. Watarai,, V. Ozeri,, E. Hanski,, M. Caparon,, and C. Sasakawa. 1998. A matrix form of fibronectin mediates enhanced binding of Streptococcus pyogenes to host tissue. J. Biol. Chem. 272:2697826984.
111. Ozeri, V.,, I. Rosenshine,, D. F. Mosher,, R. Fassler,, and E. Hanski. 1998. Roles of integrins and fibronectin in the entry of Streptococcus pyogenes into cells via protein F1. Mol. Microbiol. 30:625637.
112. Ozeri, V.,, I. Rosenshine,, A. Ben-Ze’ev,, G. M. Bokoch,, T.-S. Jou,, and E. Hanski. 2001. De novo formation of focal complex-like structures in host cells by invading streptococci. Mol. Microbiol. 41:561573.
113. Pancholi, V. 2001. The regulatory role of streptococcal surface deHydrogenase (SDH) in the expression of cytokines and apoptosis related genes in group A streptococci infected human pharyngeal cells, abstr. B-177, p. 80. Abstr. 101st Annu. Meet. Am. Soc. Microbiol. 2001. American Society for Microbiology, Washington, D.C.
114. Pancholi, V.,, and G. S. Chhatwal. 2003. Housekeeping enzymes as virulence factors for pathogens. Int. J. Med. Microbiol. 293:111.
115. Pancholi, V.,, and V. A. Fischetti. 1992. A major surface protein on group A streptococci is a glyceraldehyde-3-phosphate dehydrogenase with multiple binding activity. J. Exp. Med. 176:415426.
116. Pancholi, V.,, and V. A. Fischetti. 1993. Glyceraldehyde-3-phosphate dehydrogenase on the surface of group A streptococci is also an ADP-ribosylating enzyme. Proc. Natl. Acad. Sci. USA 90:81548158.
117. Pancholi, V.,, and V. A. Fischetti. 1997. Identification of a glycolytic enzyme complex on the surface of group A streptococci. abstr. B-42, p. 35. Abstr. 98th Annu. Meet. Am. Soc. Microbiol. 1997. American Society for Microbiology, Washington, D.C.
118. Pancholi, V.,, and V. A. Fischetti. 1997. Regulation of the phosphorylation of human pharyngeal cell proteins by group A streptococcal surface dehydrogenase (SDH): signal transduction between streptococci and pharyngeal cells. J. Exp. Med. 186:16331643.
119. Pancholi, V.,, and V. A. Fischetti. 1998. a-Enolase, a novel strong plasmin(ogen) binding protein on the surface of pathogenic streptococci. J. Biol. Chem. 273:1450314515.
120. Pancholi, V.,, P. A. Fontan,, and H. Jin. 2003. Plasminogen-mediated group A streptococcal adherence to and pericellular invasion of human pharyngeal cells. Microb. Pathog. 35:293303.
121. Parsonnet, J. 1989. Mediators in the pathogenesis of toxic shock syndrome: overview. J. Infect. Dis. 11:52635269.
122. Pellegrini, S.,, and I. Dusanter-Fourt. 1997. The structure, regulation and function of the Janus kinases (JAKs) and the signal transducers and activators of transcription (STATs). Eur. J. Biochem. 248:615633.
123. Pennisi, E. 1997. Opening the way to gene activity. Science 275:155157.
124. Perez-Casal, J.,, M. G. Caparon,, and J. R. Scott. 1991. Mry, a trans-acting positive regulator of the M protein gene of Streptococcus pyogenes with similarity to the receptor proteins of two-component regulatory systems. J. Bacteriol. 173:26172624.
125. Purushothaman, S. S.,, B. Wang,, and P. P. Cleary. 2003. M1 protein triggers a phosphoinositide cascade for group A Streptococcus invasion of epithelial cells. Infect. Immun. 71:58235830.
126. Rakonjac, J. V.,, J. C. Robbins,, and V. A. Fischetti. 1995. DNA sequence of the serum opacity factor of group A streptococci: identification of a fibronectin-binding repeat domain. Infect. Immun. 63:622631.
127. Redlitz, A.,, B. J. Fowler,, E. F. Plow,, and L. A. Miles. 1995. The role of an enolase-related molecule in plasminogen binding to cells. Eur. J. Biochem. 227:407415.
128. Rijneveld, A. W.,, S. Florquin,, J. Branger,, P. Speelman,, S. J. van Deventer,, and P. T. Van Der. 2001. TNF-alpha compensates for the impaired host defense of IL-1 type I receptor-deficient mice during pneumococcal pneumonia. J. Immunol. 167:52405246.
129. Rodriguez-Boulan, E.,, and W. J. Nelson. 1989. Morphogenesis of the polarized epithelial cell phenotype. Science 245:718725.
130. Rohde, M.,, E. Muller,, G. S. Chhatwal,, and S. R. Talay. 2003. Host cell caveolae act as an entry-port for group A streptococci. Cell. Microbiol. 5:323342.
131. Roth, S. Y.,, and C. D. Allis. 1996. Histone acetylation. Cell 87:58.
132. Russell, S. 2004. CD46: a complement regulator and pathogen receptor that mediates links between innate and acquired immune function. Tissue Antigens 64:111118.
133. Ryan, P. A.,, V. Pancholi,, and V. A. Fischetti. 1998. Binding of group A streptococci to mucin and its implications in the colonization process, abstr. B-4, p. 56. Abstr. 98th Annu. Meet. Am. Soc. Microbiol. 1998. American Society for Microbiology, Washington, D.C.
134. Ryan, P. A.,, V. Pancholi,, and V. A. Fischetti. 2002. Group A streptococci bind to mucin and human pharyngeal cells through sialic acid-containing receptors. Infect. Immun. 69:74027412.
135. Sajjan, S. U.,, and J. F. Forstner. 1998. Identification of the mucin-binding adhesin of Pseudomonas cepacia isolated from patients with cystic fibrosis. Infect. Immun. 60:14341440.
136. Schmeck, B.,, R. Gross,, P. D. N’Guessan,, A. C. Hocke,, S. Hammerschmidt,, T. J. Mitchell,, S. Rosseau,, N. Suttorp,, and S. Hippenstiel. 2004. Streptococcus pneumoniae-induced caspase 6-dependent apoptosis in lung epithelium. Infect. Immun. 72:49404947.
137. Schrager, H. M.,, S. Alberti,, C. Cywes,, G. Dougherty,, and M. R. Wessels. 1998. Hyaluronic acid capsule modulates M protein-mediated adherence and acts as a ligand for attachment of group A Streptococcus to CD44 on human keratinocytes. J. Clin. Invest. 101:17081716.
138. Schroder, N. W.,, S. Morath,, C. Alexander,, L. Hamann,, T. Hartung,, U. Zahringer,, U. B. Goebel,, J. R. Weber,, and R. R. Schumann. 2003. Lipoteichoic acid (LTA) of Streptococcus pneumoniae and Staphylococcus aureus activates immune cells via Toll-like receptor (TLR)-2, lipopolysaccharide-binding protein (LBP), and CD14, whereas TLR-4 and MD-2 are not involved. J. Biol. Chem. 278:1558715594.
139. Schumann, R. R.,, D. Pfeil,, D. Freyer,, W. Buerger,, N. Lamping,, C. J. Kirschning,, U. B. Goebel,, and J. R. Weber. 1998. Lipopolysaccharide and pneumococcal cell wall components activate the mitogen activated protein kinases (MAPK) erk-1, erk-2, and p38 in astrocytes. Glia 22:295305.
140. Seger, R.,, and E. G. Krebs. 1995. The MAPK signaling cascade. FASEB J. 9:726735.
141. Shelburne, S. A.,, and J. M. Musser. 2004. Virulence gene expression in vivo. Curr. Opin. Microbiol. 7:283289.
142. Shuter, J.,, V. B. Hatcher,, and F. D. Lowy. 1998. Staphylococcus aureus binding to human nasal mucin. Infect. Immun. 64:310318.
143.. Siebenlist, U.,, G. Franzoso,, and K. Brown. 1994. Structure, regulation, and function of NF-κB. Annu. Rev. Cell Biol. 10:405455.
144. Smoot, J. C.,, K. D. Barbian,, J. J. Van Gompel,, L. M. Smoot,, M. S. Chaussee,, G. L. Sylva,, D. E. Sturdevant,, S. M. Ricklefs,, S. F. Porcella,, L. D. Parkins,, S. B. Beres,, D. S. Campbell,, T. M. Smith,, Q. Zhang,, V. Kapur,, J. A. Daly,, L. G. Veasey,, and J. M. Musser. 2002. Genome sequence and comparative microarray analysis of serotype M18 group A Streptococcus strains associated with acute rheumatic fever outbreaks. Proc. Natl. Acad. Sci. USA 99:46684673.
145. Steller, H. 1995. Mechanisms and genes of cellular suicide. Science 267:14451449.
146. Strous, G. J.,, and J. Dekker. 1992. Mucin-type glycoproteins. Crit. Rev. Biochem. Mol. Biol. 27:5792.
147. Sweet, M. T.,, G. Carlson,, R. G. Cook,, D. Nelson,, and C. D. Allis. 1997. Phosphorylation of linker histones by a protein kinase A-like activity in mitotic nuclei. J. Biol. Chem. 272:916923.
148. Tabak, L. A. 1995. In defense of the oral cavity: structure, biosynthesis, and function of salivary mucins. Annu. Rev. Physiol. 57:547564.
149. Taylor-Papadimitriou, J.,, and O. J. Finn. 1997. Biology, biochemistry and immunology of carcinoma-associated mucins. Immunol. Today 18:105107.
150. Timpl, R.,, and J. C. Brown. 1998. The laminins. Matrix Biol. 14:275281.
151. Tsai, P. J.,, Y. S. Lin,, C. F. Kuo,, H. Y. Lei,, and J. J. Wu. 1999. Group A Streptococcus induces apoptosis in human epithelial cells. Infect. Immun. 67:43344339.
152. Tuomanen, E.,, R. Austrian,, and H. R. Masure. 1995. Pathogenesis of pneumococcal infection. N. Engl. J. Med. 332:12801284.
153. von Mering, M.,, A. Wellmer,, U. Michel,, S. Bunkowski,, A. Tlustochowska,, W. Bruck,, U. Kuhnt,, and R. Nau. 2001. Transcriptional regulation of caspases in experimental pneumococcal meningitis. Brain Pathol. 11:282295.
154. Voyich, J. M.,, D. E. Sturdevant,, K. R. Braughton,, S. D. Kobayashi,, B. Lei,, K. Virtaneva,, D. W. Dorward,, J. M. Musser,, and F. R. DeLeo. 2003. Genome-wide protective response used by group A Streptococcus to evade destruction by human polymorphonuclear leukocytes. Proc. Natl. Acad. Sci. USA 100:19962001.
155. Voyich, J. M.,, K. R. Braughton,, D. E. Sturdevant,, C. Vuong,, S. D. Kobayashi,, S. F. Porcella,, M. Otto,, J. M. Musser,, and F. R. DeLeo. 2004. Engagement of the pathogen survival response used by group A Streptococcus to avert destruction by innate host defense. J. Immunol. 173:11941201.
156. Wang, B.,, N. Ruiz,, A. Pentland,, and M. Caparon. 1997. Keratinocyte proinflammatory responses to adherent and nonadherent group A streptococci. Infect. Immun. 65:21192126.
157. Wannamaker, L. W. 1970. Differences between streptococcal infections of the throat and of the skin. N. Engl. J. Med. 282:2331.
158. Wannamaker, L. W. 1970. Differences between streptococcal infections of the throat and of the skin (second of two parts). N. Engl. J. Med. 282:7885.
159. Wannamaker, L. W. 1973. The chains that link the throat to the heart. Circulation 48:918.
160. Wick, M. J.,, J. L. Madara,, B. N. Fields,, and S. J. Normark. 1991. Molecular cross talk between epithelial cells and pathogenic microorganisms. Cell 67:651659.
161. Wolffe, A.,, J. Wong,, and D. Pruss. 1997. Activators and repressors: making use of chromatin to regulate transcription. Genes Cells 2:291302.
162. Wright, S. D.,, R. A. Ramos,, P. S. Tobias,, R. J. Ulevitch,, and J. C. Mathison. 1990. CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein. Science 249:14311433.
163. Zychlinsky, A.,, and P. J. Sansonetti. 1997. Apoptosis as a proinflammatory event: what can we learn from bacteria-induced cell death? Trends Microbiol. 5:201204.
164. Zychlinsky, A.,, K. Thirumalai,, J. Arondel,, J. R. Cantey,, A. O. Aliprantis,, and P. Sansonetti. 1996. In vivo apoptosis in Shigella flexneri infection. Infect. Immun. 64:53575365.
165. Zysk, G.,, L. Bejo,, B. K. Schneider-Wald,, R. Nau,, and H. Heinz. 2000. Induction of necrosis and apoptosis of neutrophil granulocytes by Streptococcus pneumoniae. Clin. Exp. Immunol. 122:6166.

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