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Group A -Mediated Host Cell Signaling

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  • Author: Vijay Pancholi1
  • Editors: Vincent A. Fischetti2, Richard P. Novick3, Joseph J. Ferretti4, Daniel A. Portnoy5, Miriam Braunstein6, Julian I. Rood7
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Department of Pathology, The Ohio State University College of Medicine, Columbus, OH 43210; 2: The Rockefeller University, New York, NY; 3: Skirball Institute for Molecular Medicine, NYU Medical Center, New York, NY; 4: Department of Microbiology & Immunology, University of Oklahoma Health Science Center, Oklahoma City, OK; 5: Department of Molecular and Cellular Microbiology, University of California, Berkeley, Berkeley, CA; 6: Department of Microbiology and Immunology, University of North Carolina-Chapel Hill, Chapel Hill, NC; 7: Infection and Immunity Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Australia
  • Source: microbiolspec February 2019 vol. 7 no. 1 doi:10.1128/microbiolspec.GPP3-0021-2018
  • Received 09 February 2018 Accepted 17 December 2018 Published 15 February 2019
  • Vijay Pancholi, [email protected]
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  • Abstract:

    In the past decade, the field of the cellular microbiology of group A () infection has made tremendous advances and touched upon several important aspects of pathogenesis, including receptor biology, invasive and evasive phenomena, inflammasome activation, strain-specific autophagic bacterial killing, and virulence factor-mediated programmed cell death. The noteworthy aspect of -mediated cell signaling is the recognition of the role of M protein in a variety of signaling events, starting with the targeting of specific receptors on the cell surface and on through the induction and evasion of NETosis, inflammasome, and autophagy/xenophagy to pyroptosis and apoptosis. Variations in reports on -mediated signaling events highlight the complex mechanism of pathogenesis and underscore the importance of the host cell and strain specificity, as well as / experimental parameters. The severity of infection is, therefore, dependent on the virulence gene expression repertoire in the host environment and on host-specific dynamic signaling events in response to infection. Commonly known as an extracellular pathogen, finds host macrophages as safe havens wherein it survives and even multiplies. The fact that endothelial cells are inherently deficient in autophagic machinery compared to epithelial cells and macrophages underscores the invasive nature of and its ability to cause severe systemic diseases. is still one of the top 10 causes of infectious mortality. Understanding the orchestration of dynamic host signaling networks will provide a better understanding of the increasingly complex mechanism of diseases and novel ways of therapeutically intervening to thwart severe and often fatal infections.

  • Citation: Pancholi V. 2019. Group A -Mediated Host Cell Signaling. Microbiol Spectrum 7(1):GPP3-0021-2018. doi:10.1128/microbiolspec.GPP3-0021-2018.

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/content/journal/microbiolspec/10.1128/microbiolspec.GPP3-0021-2018
2019-02-15
2019-05-25

Abstract:

In the past decade, the field of the cellular microbiology of group A () infection has made tremendous advances and touched upon several important aspects of pathogenesis, including receptor biology, invasive and evasive phenomena, inflammasome activation, strain-specific autophagic bacterial killing, and virulence factor-mediated programmed cell death. The noteworthy aspect of -mediated cell signaling is the recognition of the role of M protein in a variety of signaling events, starting with the targeting of specific receptors on the cell surface and on through the induction and evasion of NETosis, inflammasome, and autophagy/xenophagy to pyroptosis and apoptosis. Variations in reports on -mediated signaling events highlight the complex mechanism of pathogenesis and underscore the importance of the host cell and strain specificity, as well as / experimental parameters. The severity of infection is, therefore, dependent on the virulence gene expression repertoire in the host environment and on host-specific dynamic signaling events in response to infection. Commonly known as an extracellular pathogen, finds host macrophages as safe havens wherein it survives and even multiplies. The fact that endothelial cells are inherently deficient in autophagic machinery compared to epithelial cells and macrophages underscores the invasive nature of and its ability to cause severe systemic diseases. is still one of the top 10 causes of infectious mortality. Understanding the orchestration of dynamic host signaling networks will provide a better understanding of the increasingly complex mechanism of diseases and novel ways of therapeutically intervening to thwart severe and often fatal infections.

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FIGURE 1

Group A -mediated signaling events responsible for inflammation. A group of cytosolic protein complexes called inflammasomes contributes to -mediated inflammation. activates NLRP3 inflammasomes. The activation of NLRP3 inflammasomes occurs in two steps. The first step involves transcriptional priming of inflammation. There are at least four well-studied receptors (uPAR, enolase, CD44, CD46) that directly interact with the surface proteins of . Fibronectin, fibrinogen, and other lectin-like proteins play a crucial bridging role in the binding of surface proteins to integrins of eukaryotic cells. These initial interaction-mediated signaling events help invade the host cells. lipoteichoic acid and peptidoglycan fragments, which serve as PAMPs/DAMPs, initiate inflammation by binding to the Toll-like receptors TLR-2/4, which serve as an external pattern-recognition receptor (PRR). DNA and RNA can initiate inflammation via binding to intracellular PRRs (TLR3, TLR8, TLR9). These PRR/PAMP interactions occur in a MyD88-dependent or independent manner via Toll/interleukin-1 receptor-domain-containing adapter-inducing interferon-β (TRIF). MyD88-dependent signaling activates NF-κB and the NF-κB-mediated induction of IL-1β, NLRP3, and other cytokines. TRIF activates type 1 IFN and the IFN-induced chemokines. The second step (activation), not known of until recently in -mediated inflammasome activation, is initiated by the SpeB-removed or secreted M-protein, which enters the cell via clathrin-coated pit-mediated endocytosis followed by activation of NLRP3 inflammasomes. Other factors, such as SLO and NADase may cooperatively make holes in eukaryotic cells and inject bacterial product in them to exploit intracellular signaling events and activate inflammasomes. Streptococcal ADP-ribosyl transferase (SpyA) seems also to activate NLRP3 inflammasomes. The assembly of the NLRP3 inflammasome complex is formed by NLRP3 (NACHT, LRR, and PYD domain-containing protein 3), the adaptor ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain), and caspase-1. The activated NLRP3 inflammasome cleaves and converts inactive pro-IL-1β to active and proinflammatory IL-1β. This signaling is called canonical IL-1β-dependent inflammasome activation. The mediators of noncanonical IL-1β-activation (red arrows) include SpeB, which may enter the cell after SLO/NADase-mediated pore formation and cleave Pro-IL-1β to active IL-1β in an NLRP3-independent manner. SP-STP may have a role in activation of the human homolog of caspase-11, the caspase-4/5 which triggers both caspase-1-dependent and -independent production of the inflammatory cytokine IL-1β. The inflammasome activation is associated with K+ efflux. The activation of inflammasome resulting in proinflammatory responses ultimately leads to pyroptosis, a phenomenon characterized by membrane blebbing, swelling and lysis of the cell, and release of cytosolic content. Although not shown in infection, pyroptosis is caused by the cleavage of gasdermin D (GSDSMD) to its N-terminal P30 fragment, which migrates to the membranes, binds to phospholipid, oligomerizes, and forms pores. The activated IL-1β is secreted out, and salts and water enter the cell through these pores, leading to swelling and rupture of the cell. The released contents then start another cycle of proinflammatory responses in adjacent cells.

Source: microbiolspec February 2019 vol. 7 no. 1 doi:10.1128/microbiolspec.GPP3-0021-2018
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Image of FIGURE 2
FIGURE 2

Intracellular signaling associated with autophagy/xenophagy of . invades host epithelial cells by one of two mechanisms, invagination at the point of bacterial contact with host cells or massive induction of microvilli, which form membrane ruffling for engulfment of bacteria (filopodia). Cytoskeletal rearrangements involve induction of the PI-3 kinase pathway or RAS/CDC42(Rat Sarcoma oncogene receptor family small GTPases/cell division control protein 42)/tyrosine kinase activation. Autophagy (self-eating) or xenophagy (eating of a nonself particle, e.g., bacteria) is controlled by Ser/Thr kinases and by the lipid kinase activity of PI-3 kinase and ATG14-like protein (ATG14L). Initial entry of happens through endocytosis, which is tightly regulated by several Rab GTPases. Typical donors of endosome membranes are endoplasmic reticulum, Golgi apparatus, mitochondrion, and plasma membrane. For physiological autophagy Rab1, 5, 7, 24, and 33B act in a regulated fashion to form autophagolysosome, which is the stepwise culmination of the fusion of a double-membrane phagophore with endosome with (phagosome) to form autophagosome followed by fusion of a double-membrane autophagosome with a lysosome. Upon endocytosis of , the infection-specific Rab GTPases Rab23, Rab7, Rab9a, and Rab17 act in a sequential manner for the initiation, elongation/closure, maturation, and maintenance of autophagic/xenophagic vacuole to degrade intracellular . is killed only when autophagosome is fused with a lysosome. During the initial phase of autophagy, the lipid kinases VPS34, Beclin1, GOPC (Golgi-associated PDZ and coiled-coil motif-containing protein), and ATG14L are involved in forming phagophore. Subsequently, ATG14L is replaced with UVRAG (UV resistance-associated gene protein) in the VPS34-Beclin1 complex to form autophagosome. During the final maturation of autophagosome containing to autophagolysosome, the SNARE protein STX6, VTI1B, and VAMP3 are involved. NLRP4 and Bcl-XL serve as a negative regulator of the autophagy of . Additional factors that are involved in the autophagy of are a sequestosome-1-like protein complex constituted by nuclear dot protein (NDP52), neighbor of BRCA1 gene 1 protein, and 1/P62 proteins that decorate the inner membrane of phagophore via binding to the LC3 protein. One of these SLR proteins, NDP52, directly interacts with E3 ligase, which ubiquitinates bacteria. Galectin 8 also plays an important role in the attachment of SLR with which ubiquitinated is associated. Phosphorylated SLR protein then multimerizes within phagophore and matures into autophagosome and retains within the autophagosomes. In keratinocytes infected with , autophagosomes do not mature to autophagolysosome, possibly because of the secretion of SLO/NADase, while in some cells, such as HeLa and HEP-2 cells, complete autophagolysosome occurs and is killed. Incomplete formation of autophagolysosome remains defective in acidic pH, which does not allow to be killed. A failure to maintain low pH may differentially regulate virulence gene expression, which in turn may affect bacterial survival. In response to entry, host cell systems also generate second messenger cyclic GMP and nitric oxide as well as ROS. Oxygen radical and nitric oxide together may form reactive peroxynitrite, which may then target cysteine residues of the surface protein to S-guanylate . As indicated, only S-guanylated is ubiquitinated and subsequently subjected to xenophagic killing. Endothelial cells are defective in the S-guanylation process. Endothelial cells also express relatively less specific galectin-8 than galectin-3, which results in abrogation of xenophagic killing and intracellular multiplication of . Xenophagic killing and survival of are strain specific (with variable SpeB expression and related protease activity, which degrades ubiquitin and SLR protein complex) and cell type specific (normal versus established cancer cell line, epithelial, macrophage versus endothelial).

Source: microbiolspec February 2019 vol. 7 no. 1 doi:10.1128/microbiolspec.GPP3-0021-2018
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FIGURE 3

Cell-signaling events that regulate -mediated programmed cell death. infection-mediated cell death of the host cells depends on the cell type and is triggered extracellularly and intracellularly as shown. Epithelial cells infected with undergo apoptotic cell death characterized by DNA fragmentation, cytochrome release, BAX (BCL2-Associated X apoptosis regulator protein) translocation to mitochondria, and inhibition of BcL2, Bcl-XL (B-cell lymphoma-extra large). -induced apoptosis is also characterized by increased expression of IL-1β; caspase-1, -9, -3, -4, -5, -6, and -14; cytochrome C oxidase; and protein involved in Ca-signaling. At least five purified proteins have been shown to contribute to -mediated apoptosis of host cells. SpeB causes apoptosis of Hep2-cells by activating matrix metalloproteinase (MMP) and induction of first apoptosis signal molecule (FAS) and TNF-α. SLO facilitates -mediated apoptosis by allowing NADase into the cell and cleaving NAD to ADP-ribose (ADPR) and possibly cyclic ADPR, which in turn activates calcium signaling, and mitochondrial membrane depolarization, releases reactive oxygen radical, IL-1β, and activates caspases in human and mouse macrophages. SDH and SP-STP induce apoptosis of human respiratory epithelial cells (Detroit 562 and A549) in part by inducing nuclear condensation via histone H3 phosphorylation and/or H1 dephosphorylation and by upregulating mRNA expression of several proapoptotic genes and downregulating prosurvival genes. SP-STP induces caspase-4 and caspase-5, crosses two membrane barriers, and transmigrates to the nucleus, where it dephosphorylates CDK1 phosphorylated histone H1 protein. SP-STP induces apoptosis both extracellularly and intracellularly. SP-STP expression increases several-fold in intracellular and is secreted in the cytoplasm and causes apoptosis possibly by modulating several intracellular signaling events within the cytoplasm and in the nucleus. Apoptosis and pyroptosis are both modulated by GSDMD. Caspase-3 activation inhibits pyroptosis, while caspase-1-mediated cleavage of GSDMD results in P30 GSDMD that multimerizes in the form of pore in the membrane that causes pyroptosis (see Fig. 1 ). GSDMD P45 resulting from the cleavage activity of caspase-3 is inactive and prevents pyroptosis but allows apoptosis. GSDMD is ultimately responsible for pyroptosis. Caspase-8 inhibition can lead to receptor-interacting serine/threonine-protein kinase 1 (RIPK1)-dependent activation of RIPK3, which upon phosphorylation of mixed-lineage kinase domain-like pseudokinase (MLKL), leads to necroptosis, the phenomenon which is observed in pneumococcus-infected or purified pneumolysin-treated eukaryotic respiratory cells and human cardiomyocytes.

Source: microbiolspec February 2019 vol. 7 no. 1 doi:10.1128/microbiolspec.GPP3-0021-2018
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