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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