No metrics data to plot.
The attempt to load metrics for this article has failed.
The attempt to plot a graph for these metrics has failed.

Group A -Mediated Host Cell Signaling

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.
  • Author: Vijay Pancholi1
  • Editors: Vincent A. Fischetti2, Richard P. Novick3, Joseph J. Ferretti4, Daniel A. Portnoy5, Miriam Braunstein6, Julian I. Rood7
    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]
image of Group A <span class="jp-italic">Streptococcus</span>-Mediated Host Cell Signaling
    Preview this microbiology spectrum article:
    Zoom in

    Group A -Mediated Host Cell Signaling, Page 1 of 2

    | /docserver/preview/fulltext/microbiolspec/7/1/GPP3-0021-2018-1.gif /docserver/preview/fulltext/microbiolspec/7/1/GPP3-0021-2018-2.gif
  • 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.


1. Cunningham MW. 2000. Pathogenesis of group A streptococcal infections. Clin Microbiol Rev 13:470–511 http://dx.doi.org/10.1128/CMR.13.3.470. [PubMed]
2. Banks DJ, Beres SB, Musser JM. 2002. The fundamental contribution of phages to GAS evolution, genome diversification and strain emergence. Trends Microbiol 10:515–521 http://dx.doi.org/10.1016/S0966-842X(02)02461-7.
3. Walker MJ, Barnett TC, McArthur JD, Cole JN, Gillen CM, Henningham A, Sriprakash KS, Sanderson-Smith ML, Nizet V. 2014. Disease manifestations and pathogenic mechanisms of group A Streptococcus. Clin Microbiol Rev 27:264–301 http://dx.doi.org/10.1128/CMR.00101-13. [PubMed]
4. Carapetis JR, Steer AC, Mulholland EK, Weber M. 2005. The global burden of group A streptococcal diseases. Lancet Infect Dis 5:685–694 http://dx.doi.org/10.1016/S1473-3099(05)70267-X.
5. Ralph AP, Carapetis JR. 2013. Group a streptococcal diseases and their global burden. Curr Top Microbiol Immunol 368:1–27. [PubMed]
6. Kehoe MA. 1994. Cell-wall-associated proteins in Gram-positive bacteria, p 217–261. In Ghuysen J-M, Hakenbeck R (ed), Bacterial Cell Wall. Elsevier Science, Amsterdam, The Netherlands. http://dx.doi.org/10.1016/S0167-7306(08)60414-7
7. Navarre WW, Schneewind O. 1999. Surface proteins of Gram-positive bacteria and mechanisms of their targeting to the cell wall envelope. Microbiol Mol Biol Rev 63:174–229. [PubMed] [PubMed]
8. Fischetti VA. 2006. Surface proteins on Gram-positive bacteria, p 12–25. In Fischetti VA, Novick RP, Ferretti JJ, Portnoy DA, Rood JI (ed), Gram-Positive Pathogens, 2nd ed. ASM Press. Washington, DC.
9. Kreikemeyer B, McIver KS, Podbielski A. 2003. Virulence factor regulation and regulatory networks in Streptococcus pyogenes and their impact on pathogen-host interactions. Trends Microbiol 11:224–232 http://dx.doi.org/10.1016/S0966-842X(03)00098-2.
10. McIver KS, Heath AS, Scott JR. 1995. Regulation of virulence by environmental signals in group A streptococci: influence of osmolarity, temperature, gas exchange, and iron limitation on emm transcription. Infect Immun 63:4540–4542. [PubMed]
11. Caparon MG, Geist RT, Perez-Casal J, Scott JR. 1992. Environmental regulation of virulence in group A streptococci: transcription of the gene encoding M protein is stimulated by carbon dioxide. J Bacteriol 174:5693–5701 http://dx.doi.org/10.1128/jb.174.17.5693-5701.1992. [PubMed]
12. Shelburne SA, Musser JM. 2004. Virulence gene expression in vivo. Curr Opin Microbiol 7:283–289 http://dx.doi.org/10.1016/j.mib.2004.04.013. [PubMed]
13. Agarwal S, Agarwal S, Jin H, Pancholi P, Pancholi V. 2012. Serine/threonine phosphatase (SP-STP), secreted from Streptococcus pyogenes, is a pro-apoptotic protein. J Biol Chem 287:9147–9167 http://dx.doi.org/10.1074/jbc.M111.316554. [PubMed]
14. Hertzén E, Johansson L, Kansal R, Hecht A, Dahesh S, Janos M, Nizet V, Kotb M, Norrby-Teglund A. 2012. Intracellular Streptococcus pyogenes in human macrophages display an altered gene expression profile. PLoS One 7:e35218 http://dx.doi.org/10.1371/journal.pone.0035218. [PubMed]
15. Voyich JM, Braughton KR, Sturdevant DE, Vuong C, Kobayashi SD, Porcella SF, Otto M, Musser JM, DeLeo FR. 2004. Engagement of the pathogen survival response used by group A Streptococcus to avert destruction by innate host defense. J Immunol 173:1194–1201 http://dx.doi.org/10.4049/jimmunol.173.2.1194. [PubMed]
16. Voyich JM, Sturdevant DE, Braughton KR, Kobayashi SD, Lei B, Virtaneva K, Dorward DW, Musser JM, DeLeo FR. 2003. Genome-wide protective response used by group A Streptococcus to evade destruction by human polymorphonuclear leukocytes. Proc Natl Acad Sci U S A 100:1996–2001 http://dx.doi.org/10.1073/pnas.0337370100. [PubMed]
17. Kazmierczak BI, Mostov K, Engel JN. 2001. Interaction of bacterial pathogens with polarized epithelium. Annu Rev Microbiol 55:407–435 http://dx.doi.org/10.1146/annurev.micro.55.1.407. [PubMed]
18. Rodriguez-Boulan E, Nelson WJ. 1989. Morphogenesis of the polarized epithelial cell phenotype. Science 245:718–725 http://dx.doi.org/10.1126/science.2672330. [PubMed]
19. Simons K, Wandinger-Ness A. 1990. Polarized sorting in epithelia. Cell 62:207–210 http://dx.doi.org/10.1016/0092-8674(90)90357-K.
20. Finlay BB, Cossart P. 1997. Exploitation of mammalian host cell functions by bacterial pathogens. Science 276:718–725 http://dx.doi.org/10.1126/science.276.5313.718. [PubMed]
21. Bliska JB, Galán JE, Falkow S. 1993. Signal transduction in the mammalian cell during bacterial attachment and entry. Cell 73:903–920 http://dx.doi.org/10.1016/0092-8674(93)90270-Z.
22. Wick MJ, Madara JL, Fields BN, Normark SJ. 1991. Molecular cross talk between epithelial cells and pathogenic microorganisms. Cell 67:651–659 http://dx.doi.org/10.1016/0092-8674(91)90061-3.
23. Isberg RR. 1991. Discrimination between intracellular uptake and surface adhesion of bacterial pathogens. Science 252:934–938 http://dx.doi.org/10.1126/science.1674624. [PubMed]
24. Okumura CY, Nizet V. 2014. Subterfuge and sabotage: evasion of host innate defenses by invasive Gram-positive bacterial pathogens. Annu Rev Microbiol 68:439–458 http://dx.doi.org/10.1146/annurev-micro-092412-155711. [PubMed]
25. Cole JN, Barnett TC, Nizet V, Walker MJ. 2011. Molecular insight into invasive group A streptococcal disease. Nat Rev Microbiol 9:724–736 http://dx.doi.org/10.1038/nrmicro2648. [PubMed]
26. Nizet V. 2007. Understanding how leading bacterial pathogens subvert innate immunity to reveal novel therapeutic targets. J Allergy Clin Immunol 120:13–22 http://dx.doi.org/10.1016/j.jaci.2007.06.005. [PubMed]
27. Valderrama JA, Nizet V. 2018. Group A Streptococcus encounters with host macrophages. Future Microbiol 13:119–134 http://dx.doi.org/10.2217/fmb-2017-0142. [PubMed]
28. Döhrmann S, Cole JN, Nizet V. 2016. Conquering neutrophils. PLoS Pathog 12:e1005682 http://dx.doi.org/10.1371/journal.ppat.1005682. [PubMed]
29. Henningham A, Döhrmann S, Nizet V, Cole JN. 2015. Mechanisms of group A Streptococcus resistance to reactive oxygen species. FEMS Microbiol Rev 39:488–508 http://dx.doi.org/10.1093/femsre/fuu009. [PubMed]
30. Barnett TC, Cole JN, Rivera-Hernandez T, Henningham A, Paton JC, Nizet V, Walker MJ. 2015. Streptococcal toxins: role in pathogenesis and disease. Cell Microbiol 17:1721–1741 http://dx.doi.org/10.1111/cmi.12531. [PubMed]
31. Cole JN, Nizet V. 2016. Bacterial evasion of host antimicrobial peptide defenses. Microbiol Spectr 4:VMBF-0006-2015.
32. Pinheiro da Silva F, Nizet V. 2009. Cell death during sepsis: integration of disintegration in the inflammatory response to overwhelming infection. Apoptosis 14:509–521 http://dx.doi.org/10.1007/s10495-009-0320-3. [PubMed]
33. Vieira da Silva Pellegrina D, Severino P, Vieira Barbeiro H, Maziero Andreghetto F, Tadeu Velasco I, Possolo de Souza H, Machado MC, Reis EM, Pinheiro da Silva F. 2015. Septic shock in advanced age: transcriptome analysis reveals altered molecular signatures in neutrophil granulocytes. PLoS One 10:e0128341 http://dx.doi.org/10.1371/journal.pone.0128341. [PubMed]
34. LaRock CN, Nizet V. 2015. Inflammasome/IL-1b responses to streptococcal pathogens. Front Immunol 6:518 http://dx.doi.org/10.3389/fimmu.2015.00518.
35. Strous GJ, Dekker J. 1992. Mucin-type glycoproteins. Crit Rev Biochem Mol Biol 27:57–92 http://dx.doi.org/10.3109/10409239209082559. [PubMed]
36. Tabak LA. 1995. In defense of the oral cavity: structure, biosynthesis, and function of salivary mucins. Annu Rev Physiol 57:547–564 http://dx.doi.org/10.1146/annurev.ph.57.030195.002555. [PubMed]
37. Gendler SJ, Spicer AP. 1995. Epithelial mucin genes. Annu Rev Physiol 57:607–634 http://dx.doi.org/10.1146/annurev.ph.57.030195.003135. [PubMed]
38. Klinger JD, Tandler B, Liedtke CM, Boat TF. 1984. Proteinases of Pseudomonas aeruginosa evoke mucin release by tracheal epithelium. J Clin Invest 74:1669–1678 http://dx.doi.org/10.1172/JCI111583. [PubMed]
39. Döring G, Obernesser HJ, Botzenhart K, Flehmig B, Høiby N, Hofmann A. 1983. Proteases of Pseudomonas aeruginosa in patients with cystic fibrosis. J Infect Dis 147:744–750 http://dx.doi.org/10.1093/infdis/147.4.744. [PubMed]
40. Sajjan SU, Forstner JF. 1992. Identification of the mucin-binding adhesin of Pseudomonas cepacia isolated from patients with cystic fibrosis. Infect Immun 60:1434–1440. [PubMed]
41. Demuth DR, Golub EE, Malamud D. 1990. Streptococcal-host interactions. Structural and functional analysis of a Streptococcus sanguis receptor for a human salivary glycoprotein. J Biol Chem 265:7120–7126. [PubMed]
42. Shuter J, Hatcher VB, Lowy FD. 1996. Staphylococcus aureus binding to human nasal mucin. Infect Immun 64:310–318. [PubMed]
43. Courtney HS, Hasty DL. 1991. Aggregation of group A streptococci by human saliva and effect of saliva on streptococcal adherence to host cells. Infect Immun 59:1661–1666. [PubMed]
44. Mosquera JA, Katiyar VN, Coello J, Rodríguez-Iturbe B. 1985. Neuraminidase production by streptococci from patients with glomerulonephritis. J Infect Dis 151:259–263 http://dx.doi.org/10.1093/infdis/151.2.259. [PubMed]
45. Davis L, Baig MM, Ayoub EM. 1979. Properties of extracellular neuraminidase produced by group A streptococcus. Infect Immun 24:780–786. [PubMed]
46. Hytönen J, Haataja S, Isomäki P, Finne J. 2000. Identification of a novel glycoprotein-binding activity in Streptococcus pyogenes regulated by the mga gene. Microbiology 146:31–39 http://dx.doi.org/10.1099/00221287-146-1-31. [PubMed]
47. Ryan PA, Pancholi V, Fischetti VA. 2001. Group A streptococci bind to mucin and human pharyngeal cells through sialic acid-containing receptors. Infect Immun 69:7402–7412 http://dx.doi.org/10.1128/IAI.69.12.7402-7412.2001. [PubMed]
48. Hytönen J, Haataja S, Finne J. 2003. Streptococcus pyogenes glycoprotein-binding strepadhesin activity is mediated by a surface-associated carbohydrate-degrading enzyme, pullulanase. Infect Immun 71:784–793 http://dx.doi.org/10.1128/IAI.71.2.784-793.2003. [PubMed]
49. Murakami J, Terao Y, Morisaki I, Hamada S, Kawabata S. 2012. Group A streptococcus adheres to pharyngeal epithelial cells with salivary proline-rich proteins via GrpE chaperone protein. J Biol Chem 287:22266–22275 http://dx.doi.org/10.1074/jbc.M112.350082. [PubMed]
50. Chen CC, Cleary PP. 1989. Cloning and expression of the streptococcal C5a peptidase gene in Escherichia coli: linkage to the type 12 M protein gene. Infect Immun 57:1740–1745. [PubMed]
51. Lukomski S, Burns EH Jr, Wyde PR, Podbielski A, Rurangirwa J, Moore-Poveda DK, Musser JM. 1998. Genetic inactivation of an extracellular cysteine protease (SpeB) expressed by Streptococcus pyogenes decreases resistance to phagocytosis and dissemination to organs. Infect Immun 66:771–776. [PubMed]
52. Nelson DC, Garbe J, Collin M. 2011. Cysteine proteinase SpeB from Streptococcus pyogenes: a potent modifier of immunologically important host and bacterial proteins. Biol Chem 392:1077–1088 http://dx.doi.org/10.1515/BC.2011.208. [PubMed]
53. Dohrman A, Miyata S, Gallup M, Li J-D, Chapelin C, Coste A, Escudier E, Nadel J, Basbaum C. 1998. Mucin gene (MUC 2 and MUC 5AC) upregulation by Gram-positive and Gram-negative bacteria. Biochim Biophys Acta 1406:251–259 http://dx.doi.org/10.1016/S0925-4439(98)00010-6.
54. Hilkens J, Ligtenberg MJ, Vos HL, Litvinov SV. 1992. Cell membrane-associated mucins and their adhesion-modulating property. Trends Biochem Sci 17:359–363 http://dx.doi.org/10.1016/0968-0004(92)90315-Z.
55. Taylor-Papadimitriou J, Finn OJ. 1997. Biology, biochemistry and immunology of carcinoma-associated mucins. Immunol Today 18:105–107 http://dx.doi.org/10.1016/S0167-5699(97)01028-1.
56. Litvinov SV, Hilkens J. 1993. The epithelial sialomucin, episialin, is sialylated during recycling. J Biol Chem 268:21364–21371. [PubMed]
57. Forstner G. 1995. Signal transduction, packaging and secretion of mucins. Annu Rev Physiol 57:585–605 http://dx.doi.org/10.1146/annurev.ph.57.030195.003101. [PubMed]
58. Kaplan EL, Gastanaduy AS, Huwe BB. 1981. The role of the carrier in treatment failures after antibiotic for group A streptococci in the upper respiratory tract. J Lab Clin Med 98:326–335. [PubMed]
59. Bolscher JG, Groenink J, van der Kwaak JS, van den Keijbus PA, van ’t Hof W, Veerman EC, Nieuw Amerongen AV. 1999. Detection and quantification of MUC7 in submandibular, sublingual, palatine, and labial saliva by anti-peptide antiserum. J Dent Res 78:1362–1369 http://dx.doi.org/10.1177/00220345990780071101. [PubMed]
60. Wickström C, Davies JR, Eriksen GV, Veerman EC, Carlstedt I. 1998. MUC5B is a major gel-forming, oligomeric mucin from human salivary gland, respiratory tract and endocervix: identification of glycoforms and C-terminal cleavage. Biochem J 334:685–693 http://dx.doi.org/10.1042/bj3340685. [PubMed]
61. Rose MC, Voynow JA. 2006. Respiratory tract mucin genes and mucin glycoproteins in health and disease. Physiol Rev 86:245–278 http://dx.doi.org/10.1152/physrev.00010.2005. [PubMed]
62. Ruhl S, Rayment SA, Schmalz G, Hiller KA, Troxler RF. 2005. Proteins in whole saliva during the first year of infancy. J Dent Res 84:29–34 http://dx.doi.org/10.1177/154405910508400104. [PubMed]
63. Loomis RE, Prakobphol A, Levine MJ, Reddy MS, Jones PC. 1987. Biochemical and biophysical comparison of two mucins from human submandibular-sublingual saliva. Arch Biochem Biophys 258:452–464 http://dx.doi.org/10.1016/0003-9861(87)90366-3.
64. Denny PC, Denny PA, Klauser DK, Hong SH, Navazesh M, Tabak LA. 1991. Age-related changes in mucins from human whole saliva. J Dent Res 70:1320–1327 http://dx.doi.org/10.1177/00220345910700100201. [PubMed]
65. Ha UH, Lim JH, Kim HJ, Wu W, Jin S, Xu H, Li JD. 2008. MKP1 regulates the induction of MUC5AC mucin by Streptococcus pneumoniae pneumolysin by inhibiting the PAK4-JNK signaling pathway. J Biol Chem 283:30624–30631 http://dx.doi.org/10.1074/jbc.M802519200. [PubMed]
66. Alouf JE, Müller-Alouf H. 2003. Staphylococcal and streptococcal superantigens: molecular, biological and clinical aspects. Int J Med Microbiol 292:429–440 http://dx.doi.org/10.1078/1438-4221-00232. [PubMed]
67. Kotb M, Norrby-Teglund A, McGeer A, El-Sherbini H, Dorak MT, Khurshid A, Green K, Peeples J, Wade J, Thomson G, Schwartz B, Low DE. 2002. An immunogenetic and molecular basis for differences in outcomes of invasive group A streptococcal infections. Nat Med 8:1398–1404 http://dx.doi.org/10.1038/nm1202-800. [PubMed]
68. Norrby-Teglund A, Chatellier S, Low DE, McGeer A, Green K, Kotb M. 2000. Host variation in cytokine responses to superantigens determine the severity of invasive group A streptococcal infection. Eur J Immunol 30:3247–3255 http://dx.doi.org/10.1002/1521-4141(200011)30:11<3247::AID-IMMU3247>3.0.CO;2-D.
69. Parsonnet J. 1989. Mediators in the pathogenesis of toxic shock syndrome: overview. Rev Infect Dis 11(Suppl 1) :S263–S269 http://dx.doi.org/10.1093/clinids/11.Supplement_1.S263. [PubMed]
70. Soderholm AT, Barnett TC, Sweet MJ, Walker MJ. 2018. Group A streptococcal pharyngitis: immune responses involved in bacterial clearance and GAS-associated immunopathologies. J Leukoc Biol 103:193–213. [PubMed]
71. Kasper KJ, Zeppa JJ, Wakabayashi AT, Xu SX, Mazzuca DM, Welch I, Baroja ML, Kotb M, Cairns E, Cleary PP, Haeryfar SM, McCormick JK. 2014. Bacterial superantigens promote acute nasopharyngeal infection by Streptococcus pyogenes in a human MHC class II-dependent manner. PLoS Pathog 10:e1004155 http://dx.doi.org/10.1371/journal.ppat.1004155. [PubMed]
72. Zeppa JJ, Kasper KJ, Mohorovic I, Mazzuca DM, Haeryfar SMM, McCormick JK. 2017. Nasopharyngeal infection by Streptococcus pyogenes requires superantigen-responsive Vβ-specific T cells. Proc Natl Acad Sci U S A 114:10226–10231 http://dx.doi.org/10.1073/pnas.1700858114. [PubMed]
73. Shaler CR, Choi J, Rudak PT, Memarnejadian A, Szabo PA, Tun-Abraham ME, Rossjohn J, Corbett AJ, McCluskey J, McCormick JK, Lantz O, Hernandez-Alejandro R, Haeryfar SMM. 2017. MAIT cells launch a rapid, robust and distinct hyperinflammatory response to bacterial superantigens and quickly acquire an anergic phenotype that impedes their cognate antimicrobial function: defining a novel mechanism of superantigen-induced immunopathology and immunosuppression. PLoS Biol 15:e2001930 http://dx.doi.org/10.1371/journal.pbio.2001930. [PubMed]
74. Herwald H, Cramer H, Mörgelin M, Russell W, Sollenberg U, Norrby-Teglund A, Flodgaard H, Lindbom L, Björck L. 2004. M protein, a classical bacterial virulence determinant, forms complexes with fibrinogen that induce vascular leakage. Cell 116:367–379 http://dx.doi.org/10.1016/S0092-8674(04)00057-1.
75. Kantor FS. 1965. Fibrinogen precipitating by streptococcal M protein. I. Identity of the reactants and stoichiometry of the reaction. J Exp Med 121:849–859 http://dx.doi.org/10.1084/jem.121.5.849. [PubMed]
76. Akesson P, Schmidt K-H, Cooney J, Björck L. 1994. M1 protein and protein H: IgGFc- and albumin-binding streptococcal surface proteins encoded by adjacent genes. Biochem J 300:877–886 http://dx.doi.org/10.1042/bj3000877. [PubMed]
77. Cauwels A, Wan E, Leismann M, Tuomanen E. 1997. Coexistence of CD14-dependent and independent pathways for stimulation of human monocytes by Gram-positive bacteria. Infect Immun 65:3255–3260. [PubMed]
78. Wang B, Ruiz N, Pentland A, Caparon M. 1997. Keratinocyte proinflammatory responses to adherent and nonadherent group A streptococci. Infect Immun 65:2119–2126. [PubMed]
79. Okada N, Liszewski MK, Atkinson JP, Caparon M. 1995. Membrane cofactor protein (CD46) is a keratinocyte receptor for the M protein of the group A streptococcus. Proc Natl Acad Sci U S A 92:2489–2493 http://dx.doi.org/10.1073/pnas.92.7.2489. [PubMed]
80. Russell S. 2004. CD46: a complement regulator and pathogen receptor that mediates links between innate and acquired immune function. Tissue Antigens 64:111–118 http://dx.doi.org/10.1111/j.1399-0039.2004.00277.x. [PubMed]
81. Giannakis E, Jokiranta TS, Ormsby RJ, Duthy TG, Male DA, Christiansen D, Fischetti VA, Bagley C, Loveland BE, Gordon DL. 2002. Identification of the streptococcal M protein binding site on membrane cofactor protein (CD46). J Immunol 168:4585–4592 http://dx.doi.org/10.4049/jimmunol.168.9.4585. [PubMed]
82. Schrager HM, Albertí S, Cywes C, Dougherty GJ, Wessels MR. 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 101:1708–1716 http://dx.doi.org/10.1172/JCI2121. [PubMed]
83. Cywes C, Stamenkovic I, Wessels MR. 2000. CD44 as a receptor for colonization of the pharynx by group A Streptococcus. J Clin Invest 106:995–1002 http://dx.doi.org/10.1172/JCI10195. [PubMed]
84. Cywes C, Wessels MR. 2001. Group A Streptococcus tissue invasion by CD44-mediated cell signalling. Nature 414:648–652 http://dx.doi.org/10.1038/414648a. [PubMed]
85. Pancholi V, Fischetti VA. 1992. A major surface protein on group A streptococci is a glyceraldehyde-3-phosphate-dehydrogenase with multiple binding activity. J Exp Med 176:415–426 http://dx.doi.org/10.1084/jem.176.2.415. [PubMed]
86. Pancholi V, Fischetti VA. 1993. Glyceraldehyde-3-phosphate dehydrogenase on the surface of group A streptococci is also an ADP-ribosylating enzyme. Proc Natl Acad Sci U S A 90:8154–8158 http://dx.doi.org/10.1073/pnas.90.17.8154. [PubMed]
87. Winram SB, Lottenberg R. 1996. The plasmin-binding protein Plr of group A streptococci is identified as glyceraldehyde-3-phosphate dehydrogenase. Microbiology 142:2311–2320 http://dx.doi.org/10.1099/13500872-142-8-2311. [PubMed]
88. Moss J, Vaughan M. 1988. ADP-ribosylation of guanyl nucleotide-binding regulatory proteins by bacterial toxins. Adv Enzymol Relat Areas Mol Biol 61:303–379. [PubMed]
89. Pancholi V, Fischetti VA. 1997. Regulation of the phosphorylation of human pharyngeal cell proteins by group A streptococcal surface dehydrogenase: signal transduction between streptococci and pharyngeal cells. J Exp Med 186:1633–1643 http://dx.doi.org/10.1084/jem.186.10.1633. [PubMed]
90. Pancholi V. 2017. Streptococcus pyogenes GAPDH: a cell surface major virulence determinant, p 169–194. In Henderson B (ed), Moonlighting Proteins. Wiley Blackwell, Hoboken, NJ.
91. Pancholi V, Chhatwal GS. 2003. Housekeeping enzymes as virulence factors for pathogens. Int J Med Microbiol 293:391–401 http://dx.doi.org/10.1078/1438-4221-00283. [PubMed]
92. Pancholi V, Fischetti VA. 1998. alpha-Enolase, a novel strong plasmin(ogen) binding protein on the surface of pathogenic streptococci. J Biol Chem 273:14503–14515 http://dx.doi.org/10.1074/jbc.273.23.14503. [PubMed]
93. Bergmann S, Rohde M, Chhatwal GS, Hammerschmidt S. 2001. alpha-Enolase of Streptococcus pneumoniae is a plasmin(ogen)-binding protein displayed on the bacterial cell surface. Mol Microbiol 40:1273–1287 http://dx.doi.org/10.1046/j.1365-2958.2001.02448.x. [PubMed]
94. Redlitz A, Fowler BJ, Plow EF, Miles LA. 1995. The role of an enolase-related molecule in plasminogen binding to cells. Eur J Biochem 227:407–415 http://dx.doi.org/10.1111/j.1432-1033.1995.tb20403.x. [PubMed]
95. Miles LA, Dahlberg CM, Plescia J, Felez J, Kato K, Plow EF. 1991. Role of cell-surface lysines in plasminogen binding to cells: identification of alpha-enolase as a candidate plasminogen receptor. Biochemistry 30:1682–1691 http://dx.doi.org/10.1021/bi00220a034. [PubMed]
96. Dudani AK, Cummings C, Hashemi S, Ganz PR. 1993. Isolation of a novel 45 kDa plasminogen receptor from human endothelial cells. Thromb Res 69:185–196 http://dx.doi.org/10.1016/0049-3848(93)90044-O.
97. Pancholi V, Fontan P, Jin H. 2003. Plasminogen-mediated group A streptococcal adherence to and pericellular invasion of human pharyngeal cells. Microb Pathog 35:293–303 http://dx.doi.org/10.1016/j.micpath.2003.08.004. [PubMed]
98. Jin H, Song YP, Boel G, Kochar J, Pancholi V. 2005. Group A streptococcal surface GAPDH, SDH, recognizes uPAR/CD87 as its receptor on the human pharyngeal cell and mediates bacterial adherence to host cells. J Mol Biol 350:27–41 http://dx.doi.org/10.1016/j.jmb.2005.04.063. [PubMed]
99. D’Costa SS, Romer TG, Boyle MDP. 2000. Analysis of expression of a cytosolic enzyme on the surface of Streptococcus pyogenes. Biochem Biophys Res Commun 278:826–832 http://dx.doi.org/10.1006/bbrc.2000.3884. [PubMed]
100. Cortese K, Sahores M, Madsen CD, Tacchetti C, Blasi F. 2008. Clathrin and LRP-1-independent constitutive endocytosis and recycling of uPAR. PLoS One 3:e3730 http://dx.doi.org/10.1371/journal.pone.0003730. [PubMed]
101. Sturge J, Wienke D, East L, Jones GE, Isacke CM. 2003. GPI-anchored uPAR requires Endo180 for rapid directional sensing during chemotaxis. J Cell Biol 162:789–794 http://dx.doi.org/10.1083/jcb.200302124.
102. Nykjaer A, Conese M, Christensen EI, Olson D, Cremona O, Gliemann J, Blasi F. 1997. Recycling of the urokinase receptor upon internalization of the uPA:serpin complexes. EMBO J 16:2610–2620 http://dx.doi.org/10.1093/emboj/16.10.2610.
103. Koshelnick Y, Ehart M, Hufnagl P, Heinrich PC, Binder BR. 1997. Urokinase receptor is associated with the components of the JAK1/STAT1 signaling pathway and leads to activation of this pathway upon receptor clustering in the human kidney epithelial tumor cell line TCL-598. J Biol Chem 272:28563–28567 http://dx.doi.org/10.1074/jbc.272.45.28563.
104. Tarui T, Andronicos N, Czekay R-P, Mazar AP, Bdeir K, Parry GC, Kuo A, Loskutoff DJ, Cines DB, Takada Y. 2003. Critical role of integrin alpha 5 beta 1 in urokinase (uPA)/urokinase receptor (uPAR, CD87) signaling. J Biol Chem 278:29863–29872 http://dx.doi.org/10.1074/jbc.M304694200.
105. Tarui T, Mazar AP, Cines DB, Takada Y. 2001. Urokinase-type plasminogen activator receptor (CD87) is a ligand for integrins and mediates cell-cell interaction. J Biol Chem 276:3983–3990 http://dx.doi.org/10.1074/jbc.M008220200.
106. Sanderson-Smith ML, Zhang Y, Ly D, Donahue D, Hollands A, Nizet V, Ranson M, Ploplis VA, Walker MJ, Castellino FJ. 2013. A key role for the urokinase plasminogen activator (uPA) in invasive group A streptococcal infection. PLoS Pathog 9:e1003469 http://dx.doi.org/10.1371/journal.ppat.1003469.
107. Fu H, Subramanian RR, Masters SC. 2000. 14-3-3 Proteins: structure, function, and regulation. Annu Rev Pharmacol Toxicol 40:617–647 http://dx.doi.org/10.1146/annurev.pharmtox.40.1.617.
108. Nomura M, Shimizu S, Sugiyama T, Narita M, Ito T, Matsuda H, Tsujimoto Y. 2003. 14-3-3 Interacts directly with and negatively regulates pro-apoptotic Bax. J Biol Chem 278:2058–2065 http://dx.doi.org/10.1074/jbc.M207880200.
109. Rosenquist M. 2003. 14-3-3 Proteins in apoptosis. Braz J Med Biol Res 36:403–408 http://dx.doi.org/10.1590/S0100-879X2003000400001.
110. Yaffe MB. 2002. How do 14-3-3 proteins work? Gatekeeper phosphorylation and the molecular anvil hypothesis. FEBS Lett 513:53–57 http://dx.doi.org/10.1016/S0014-5793(01)03288-4.
111. Siles-Lucas MM, Gottstein B. 2003. The 14-3-3 protein: a key molecule in parasites as in other organisms. Trends Parasitol 19:575–581 http://dx.doi.org/10.1016/j.pt.2003.10.003.
112. Scidmore MA, Hackstadt T. 2001. Mammalian 14-3-3beta associates with the Chlamydia trachomatis inclusion membrane via its interaction with IncG. Mol Microbiol 39:1638–1650 http://dx.doi.org/10.1046/j.1365-2958.2001.02355.x.
113. Futosi K, Fodor S, Mócsai A. 2013. Neutrophil cell surface receptors and their intracellular signal transduction pathways. Int Immunopharmacol 17:638–650 http://dx.doi.org/10.1016/j.intimp.2013.06.034.
114. Neisch AL, Fehon RG. 2011. Ezrin, radixin and moesin: key regulators of membrane-cortex interactions and signaling. Curr Opin Cell Biol 23:377–382 http://dx.doi.org/10.1016/j.ceb.2011.04.011. [PubMed]
115. Fiévet B, Louvard D, Arpin M. 2007. ERM proteins in epithelial cell organization and functions. Biochim Biophys Acta 1773:653–660 http://dx.doi.org/10.1016/j.bbamcr.2006.06.013. [PubMed]
116. García-Ponce A, Citalán-Madrid AF, Velázquez-Avila M, Vargas-Robles H, Schnoor M. 2015. The role of actin-binding proteins in the control of endothelial barrier integrity. Thromb Haemost 113:20–36 http://dx.doi.org/10.1160/TH14-04-0298.
117. Ivetic A, Ridley AJ. 2004. Ezrin/radixin/moesin proteins and Rho GTPase signalling in leucocytes. Immunology 112:165–176 http://dx.doi.org/10.1111/j.1365-2567.2004.01882.x.
118. Hoe NP, Ireland RM, DeLeo FR, Gowen BB, Dorward DW, Voyich JM, Liu M, Burns EH Jr, Culnan DM, Bretscher A, Musser JM. 2002. Insight into the molecular basis of pathogen abundance: group A Streptococcus inhibitor of complement inhibits bacterial adherence and internalization into human cells. Proc Natl Acad Sci U S A 99:7646–7651 http://dx.doi.org/10.1073/pnas.112039899.
119. Wexler DE, Chenoweth DE, Cleary PP. 1985. Mechanism of action of the group A streptococcal C5a inactivator. Proc Natl Acad Sci U S A 82:8144–8148 http://dx.doi.org/10.1073/pnas.82.23.8144.
120. Cleary PP, Prahbu U, Dale JB, Wexler DE, Handley J. 1992. Streptococcal C5a peptidase is a highly specific endopeptidase. Infect Immun 60:5219–5223.
121. Terao Y, Yamaguchi M, Hamada S, Kawabata S. 2006. Multifunctional glyceraldehyde-3-phosphate dehydrogenase of Streptococcus pyogenes is essential for evasion from neutrophils. J Biol Chem 281:14215–14223 http://dx.doi.org/10.1074/jbc.M513408200.
122. Terrasse R, Tacnet-Delorme P, Moriscot C, Pérard J, Schoehn G, Vernet T, Thielens NM, Di Guilmi AM, Frachet P. 2012. Human and pneumococcal cell surface glyceraldehyde-3-phosphate dehydrogenase (GAPDH) proteins are both ligands of human C1q protein. J Biol Chem 287:42620–42633 http://dx.doi.org/10.1074/jbc.M112.423731.
123. Kant S, Agarwal S, Pancholi P, Pancholi V. 2015. The Streptococcus pyogenes orphan protein tyrosine phosphatase, SP-PTP, possesses dual specificity and essential virulence regulatory functions. Mol Microbiol 97:515–540 http://dx.doi.org/10.1111/mmi.13047.
124. Hynes RO. 1992. Integrins: versatility, modulation, and signaling in cell adhesion. Cell 69:11–25 http://dx.doi.org/10.1016/0092-8674(92)90115-S.
125. Hanski E, Caparon M. 1992. Protein F, a fibronectin-binding protein, is an adhesin of the group A streptococcus Streptococcus pyogenes. Proc Natl Acad Sci U S A 89:6172–6176 http://dx.doi.org/10.1073/pnas.89.13.6172.
126. Molinari G, Talay SR, Valentin-Weigand P, Rohde M, Chhatwal GS. 1997. The fibronectin-binding protein of Streptococcus pyogenes, SfbI, is involved in the internalization of group A streptococci by epithelial cells. Infect Immun 65:1357–1363.
127. Jaffe J, Natanson-Yaron S, Caparon MG, Hanski E. 1996. Protein F2, a novel fibronectin-binding protein from Streptococcus pyogenes, possesses two binding domains. Mol Microbiol 21:373–384 http://dx.doi.org/10.1046/j.1365-2958.1996.6331356.x.
128. Rakonjac JV, Robbins JC, Fischetti VA. 1995. DNA sequence of the serum opacity factor of group A streptococci: identification of a fibronectin-binding repeat domain. Infect Immun 63:622–631.
129. Frick I-M, Crossin KL, Edelman GM, Björck L. 1995. Protein H: a bacterial surface protein with affinity for both immunoglobulin and fibronectin type III domains. EMBO J 14:1674–1679 http://dx.doi.org/10.1002/j.1460-2075.1995.tb07156.x.
130. Courtney HS, Li Y, Dale JB, Hasty DL. 1994. Cloning, sequencing, and expression of a fibronectin/fibrinogen-binding protein from group A streptococci. Infect Immun 62:3937–3946.
131. Cue D, Dombek PE, Lam H, Cleary PP. 1998. Streptococcus pyogenes serotype M1 encodes multiple pathways for entry into human epithelial cells. Infect Immun 66:4593–4601.
132. Ozeri V, Rosenshine I, Mosher DF, Fässler R, Hanski E. 1998. Roles of integrins and fibronectin in the entry of Streptococcus pyogenes into cells via protein F1. Mol Microbiol 30:625–637 http://dx.doi.org/10.1046/j.1365-2958.1998.01097.x.
133. Isberg RR, Tran Van Nhieu G. 1994. Binding and internalization of microorganisms by integrin receptors. Trends Microbiol 2:10–14 http://dx.doi.org/10.1016/0966-842X(94)90338-7.
134. Timpl R, Brown JC. 1994. The laminins. Matrix Biol 14:275–281 http://dx.doi.org/10.1016/0945-053X(94)90192-9.
135. Molinari G, Rohde M, Guzmán CA, Chhatwal GS. 2000. Two distinct pathways for the invasion of Streptococcus pyogenes in non-phagocytic cells. Cell Microbiol 2:145–154 http://dx.doi.org/10.1046/j.1462-5822.2000.00040.x. [PubMed]
136. van Wijk XM, Döhrmann S, Hallström BM, Li S, Voldborg BG, Meng BX, McKee KK, van Kuppevelt TH, Yurchenco PD, Palsson BO, Lewis NE, Nizet V, Esko JD. 2017. Whole-genome sequencing of invasion-resistant cells identifies laminin α2 as a host factor for bacterial invasion. MBio 8:e02128-16 http://dx.doi.org/10.1128/mBio.02128-16. [PubMed]
137. Cossart P. 1997. Host/pathogen interactions. Subversion of the mammalian cell cytoskeleton by invasive bacteria. J Clin Invest 99:2307–2311 http://dx.doi.org/10.1172/JCI119409. [PubMed]
138. Dombek PE, Cue D, Sedgewick J, Lam H, Ruschkowski S, Finlay BB, Cleary PP. 1999. High-frequency intracellular invasion of epithelial cells by serotype M1 group A streptococci: M1 protein-mediated invasion and cytoskeletal rearrangements. Mol Microbiol 31:859–870 http://dx.doi.org/10.1046/j.1365-2958.1999.01223.x. [PubMed]
139. Purushothaman SS, Wang B, Cleary PP. 2003. M1 protein triggers a phosphoinositide cascade for group A Streptococcus invasion of epithelial cells. Infect Immun 71:5823–5830 http://dx.doi.org/10.1128/IAI.71.10.5823-5830.2003. [PubMed]
140. Ozeri V, Rosenshine I, Ben-Ze’Ev A, Bokoch GM, Jou T-S, Hanski E. 2001. De novo formation of focal complex-like structures in host cells by invading Streptococci. Mol Microbiol 41:561–573 http://dx.doi.org/10.1046/j.1365-2958.2001.02535.x. [PubMed]
141. Rohde M, Müller E, Chhatwal GS, Talay SR. 2003. Host cell caveolae act as an entry-port for group A streptococci. Cell Microbiol 5:323–342 http://dx.doi.org/10.1046/j.1462-5822.2003.00279.x.
142. Nerlich A, Rohde M, Talay SR, Genth H, Just I, Chhatwal GS. 2009. Invasion of endothelial cells by tissue-invasive M3 type group A streptococci requires Src kinase and activation of Rac1 by a phosphatidylinositol 3-kinase-independent mechanism. J Biol Chem 284:20319–20328 http://dx.doi.org/10.1074/jbc.M109.016501.
143. Jadoun J, Burstein E, Hanski E, Sela S. 1997. Proteins M6 and F1 are required for efficient invasion of group A streptococci into cultured epithelial cells. Adv Exp Med Biol 418:511–515 http://dx.doi.org/10.1007/978-1-4899-1825-3_121.
144. Okada N, Watarai M, Ozeri V, Hanski E, Caparon M, Sasakawa C. 1997. A matrix form of fibronectin mediates enhanced binding of Streptococcus pyogenes to host tissue. J Biol Chem 272:26978–26984 http://dx.doi.org/10.1074/jbc.272.43.26978.
145. Nyberg P, Sakai T, Cho KH, Caparon MG, Fässler R, Björck L. 2004. Interactions with fibronectin attenuate the virulence of Streptococcus pyogenes. EMBO J 23:2166–2174 http://dx.doi.org/10.1038/sj.emboj.7600214.
146. Gallo KA, Johnson GL. 2002. Mixed-lineage kinase control of JNK and p38 MAPK pathways. Nat Rev Mol Cell Biol 3:663–672 http://dx.doi.org/10.1038/nrm906.
147. Seger R, Krebs EG. 1995. The MAPK signaling cascade. FASEB J 9:726–735 http://dx.doi.org/10.1096/fasebj.9.9.7601337.
148. Siebenlist U, Franzoso G, Brown K. 1994. Structure, regulation and function of NF-kappa B. Annu Rev Cell Biol 10:405–455 http://dx.doi.org/10.1146/annurev.cb.10.110194.002201.
149. Baldwin AS Jr. 1996. The NF-kappa B and I kappa B proteins: new discoveries and insights. Annu Rev Immunol 14:649–683 http://dx.doi.org/10.1146/annurev.immunol.14.1.649.
150. Ghosh S, May MJ, Kopp EB. 1998. NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol 16:225–260 http://dx.doi.org/10.1146/annurev.immunol.16.1.225.
151. Darnell JE Jr. 1997. STATs and gene regulation. Science 277:1630–1635 http://dx.doi.org/10.1126/science.277.5332.1630. [PubMed]
152. Pellegrini S, Dusanter-Fourt I. 1997. The structure, regulation and function of the Janus kinases (JAKs) and the signal transducers and activators of transcription (STATs). Eur J Biochem 248:615–633 http://dx.doi.org/10.1111/j.1432-1033.1997.00615.x. [PubMed]
153. Mancuso G, Midiri A, Beninati C, Piraino G, Valenti A, Nicocia G, Teti D, Cook J, Teti G. 2002. Mitogen-activated protein kinases and NF-kappa B are involved in TNF-alpha responses to group B streptococci. J Immunol 169:1401–1409 http://dx.doi.org/10.4049/jimmunol.169.3.1401. [PubMed]
154. Neff L, Zeisel M, Sibilia J, Schöller-Guinard M, Klein JP, Wachsmann D. 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 3:703–712 http://dx.doi.org/10.1046/j.1462-5822.2001.00148.x. [PubMed]
155. Medvedev AE, Flo T, Ingalls RR, Golenbock DT, Teti G, Vogel SN, Espevik T. 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 160:4535–4542. [PubMed]
156. Medina E, Anders D, Chhatwal GS. 2002. Induction of NF-kappaB nuclear translocation in human respiratory epithelial cells by group A streptococci. Microb Pathog 33:307–313 http://dx.doi.org/10.1006/mpat.2002.0532. [PubMed]
157. Miettinen M, Lehtonen A, Julkunen I, Matikainen S. 2000. Lactobacilli and Streptococci activate NF-kappa B and STAT signaling pathways in human macrophages. J Immunol 164:3733–3740 http://dx.doi.org/10.4049/jimmunol.164.7.3733. [PubMed]
158. Tsai PJ, Chen YH, Hsueh CH, Hsieh HC, Liu YH, Wu JJ, Tsou CC. 2006. Streptococcus pyogenes induces epithelial inflammatory responses through NF-kappaB/MAPK signaling pathways. Microbes Infect 8:1440–1449 http://dx.doi.org/10.1016/j.micinf.2006.01.002. [PubMed]
159. Klenk M, Koczan D, Guthke R, Nakata M, Thiesen H-J, Podbielski A, Kreikemeyer B. 2005. Global epithelial cell transcriptional responses reveal Streptococcus pyogenes Fas regulator activity association with bacterial aggressiveness. Cell Microbiol 7:1237–1250 http://dx.doi.org/10.1111/j.1462-5822.2005.00548.x. [PubMed]
160. Wang B, Dileepan T, Briscoe S, Hyland KA, Kang J, Khoruts A, Cleary PP. 2010. Induction of TGF-beta1 and TGF-beta1-dependent predominant Th17 differentiation by group A streptococcal infection. Proc Natl Acad Sci U S A 107:5937–5942 http://dx.doi.org/10.1073/pnas.0904831107. [PubMed]
161. Gaffen SL, Jain R, Garg AV, Cua DJ. 2014. The IL-23-IL-17 immune axis: from mechanisms to therapeutic testing. Nat Rev Immunol 14:585–600 http://dx.doi.org/10.1038/nri3707. [PubMed]
162. Crockett-Torabi E. 1998. Selectins and mechanisms of signal transduction. J Leukoc Biol 63:1–14 http://dx.doi.org/10.1002/jlb.63.1.1. [PubMed]
163. Mayadas TN, Johnson RC, Rayburn H, Hynes RO, Wagner DD. 1993. Leukocyte rolling and extravasation are severely compromised in P selectin-deficient mice. Cell 74:541–554 http://dx.doi.org/10.1016/0092-8674(93)80055-J.
164. Bryant AE, Bayer CR, Chen RY, Guth PH, Wallace RJ, Stevens DL. 2005. Vascular dysfunction and ischemic destruction of tissue in Streptococcus pyogenes infection: the role of streptolysin O-induced platelet/neutrophil complexes. J Infect Dis 192:1014–1022 http://dx.doi.org/10.1086/432729. [PubMed]
165. Mayadas TN, Tsokos GC, Tsuboi N. 2009. Mechanisms of immune complex-mediated neutrophil recruitment and tissue injury. Circulation 120:2012–2024 http://dx.doi.org/10.1161/CIRCULATIONAHA.108.771170. [PubMed]
166. Shannon O, Hertzén E, Norrby-Teglund A, Mörgelin M, Sjöbring U, Björck L. 2007. Severe streptococcal infection is associated with M protein-induced platelet activation and thrombus formation. Mol Microbiol 65:1147–1157 http://dx.doi.org/10.1111/j.1365-2958.2007.05841.x. [PubMed]
167. Mayadas TN, Cullere X, Lowell CA. 2014. The multifaceted functions of neutrophils. Annu Rev Pathol 9:181–218 http://dx.doi.org/10.1146/annurev-pathol-020712-164023. [PubMed]
168. Pinheiro da Silva F, Machado MC. 2012. Antimicrobial peptides: clinical relevance and therapeutic implications. Peptides 36:308–314 http://dx.doi.org/10.1016/j.peptides.2012.05.014. [PubMed]
169. Winterbourn CC, Metodiewa D. 1999. Reactivity of biologically important thiol compounds with superoxide and hydrogen peroxide. Free Radic Biol Med 27:322–328 http://dx.doi.org/10.1016/S0891-5849(99)00051-9.
170. Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, Weinrauch Y, Zychlinsky A. 2004. Neutrophil extracellular traps kill bacteria. Science 303:1532–1535 http://dx.doi.org/10.1126/science.1092385. [PubMed]
171. Steinberg BE, Grinstein S. 2007. Unconventional roles of the NADPH oxidase: signaling, ion homeostasis, and cell death. Sci STKE 2007:pe11 http://dx.doi.org/10.1126/stke.3792007pe11. [PubMed]
172. von Köckritz-Blickwede M, Goldmann O, Thulin P, Heinemann K, Norrby-Teglund A, Rohde M, Medina E. 2008. Phagocytosis-independent antimicrobial activity of mast cells by means of extracellular trap formation. Blood 111:3070–3080 http://dx.doi.org/10.1182/blood-2007-07-104018. [PubMed]
173. Doster RS, Rogers LM, Gaddy JA, Aronoff DM. 2018. Macrophage extracellular traps: a scoping review. J Innate Immun 10:3–13 http://dx.doi.org/10.1159/000480373. [PubMed]
174. Morshed M, Hlushchuk R, Simon D, Walls AF, Obata-Ninomiya K, Karasuyama H, Djonov V, Eggel A, Kaufmann T, Simon HU, Yousefi S. 2014. NADPH oxidase-independent formation of extracellular DNA traps by basophils. J Immunol 192:5314–5323 http://dx.doi.org/10.4049/jimmunol.1303418. [PubMed]
175. Ueki S, Melo RC, Ghiran I, Spencer LA, Dvorak AM, Weller PF. 2013. Eosinophil extracellular DNA trap cell death mediates lytic release of free secretion-competent eosinophil granules in humans. Blood 121:2074–2083 http://dx.doi.org/10.1182/blood-2012-05-432088. [PubMed]
176. Wartha F, Henriques-Normark B. 2008. ETosis: a novel cell death pathway. Sci Signal 1:pe25 http://dx.doi.org/10.1126/stke.121pe25. [PubMed]
177. Westman J, Papareddy P, Dahlgren MW, Chakrakodi B, Norrby-Teglund A, Smeds E, Linder A, Mörgelin M, Johansson-Lindbom B, Egesten A, Herwald H. 2015. Extracellular histones induce chemokine production in whole blood ex vivo and leukocyte recruitment in vivo. PLoS Pathog 11:e1005319 http://dx.doi.org/10.1371/journal.ppat.1005319. [PubMed]
178. Silk E, Zhao H, Weng H, Ma D. 2017. The role of extracellular histone in organ injury. Cell Death Dis 8:e2812 http://dx.doi.org/10.1038/cddis.2017.52. [PubMed]
179. Hirsch JG. 1958. Bactericidal action of histone. J Exp Med 108:925–944 http://dx.doi.org/10.1084/jem.108.6.925. [PubMed]
180. Khan MA, Palaniyar N. 2017. Transcriptional firing helps to drive NETosis. Sci Rep 7:41749 http://dx.doi.org/10.1038/srep41749. [PubMed]
181. Buchanan JT, Simpson AJ, Aziz RK, Liu GY, Kristian SA, Kotb M, Feramisco J, Nizet V. 2006. DNase expression allows the pathogen group A Streptococcus to escape killing in neutrophil extracellular traps. Curr Biol 16:396–400 http://dx.doi.org/10.1016/j.cub.2005.12.039. [PubMed]
182. Döhrmann S, Anik S, Olson J, Anderson EL, Etesami N, No H, Snipper J, Nizet V, Okumura CY. 2014. Role for streptococcal collagen-like protein 1 in M1T1 group A Streptococcus resistance to neutrophil extracellular traps. Infect Immun 82:4011–4020 http://dx.doi.org/10.1128/IAI.01921-14. [PubMed]
183. Schommer NN, Muto J, Nizet V, Gallo RL. 2014. Hyaluronan breakdown contributes to immune defense against group A Streptococcus. J Biol Chem 289:26914–26921 http://dx.doi.org/10.1074/jbc.M114.575621. [PubMed]
184. Schwarz F, Landig CS, Siddiqui S, Secundino I, Olson J, Varki N, Nizet V, Varki A. 2017. Paired Siglec receptors generate opposite inflammatory responses to a human-specific pathogen. EMBO J 36:751–760 http://dx.doi.org/10.15252/embj.201695581. [PubMed]
185. Secundino I, Lizcano A, Roupé KM, Wang X, Cole JN, Olson J, Ali SR, Dahesh S, Amayreh LK, Henningham A, Varki A, Nizet V. 2016. Host and pathogen hyaluronan signal through human siglec-9 to suppress neutrophil activation. J Mol Med (Berl) 94:219–233 http://dx.doi.org/10.1007/s00109-015-1341-8. [PubMed]
186. Döhrmann S, LaRock CN, Anderson EL, Cole JN, Ryali B, Stewart C, Nonejuie P, Pogliano J, Corriden R, Ghosh P, Nizet V. 2017. Group A streptococcal M1 protein provides resistance against the antimicrobial activity of histones. Sci Rep 7:43039 http://dx.doi.org/10.1038/srep43039. [PubMed]
187. LaRock CN, Döhrmann S, Todd J, Corriden R, Olson J, Johannssen T, Lepenies B, Gallo RL, Ghosh P, Nizet V. 2015. Group A streptococcal M1 protein sequesters cathelicidin to evade innate immune killing. Cell Host Microbe 18:471–477 http://dx.doi.org/10.1016/j.chom.2015.09.004. [PubMed]
188. Stevens DL, Tanner MH, Winship J, Swarts R, Ries KM, Schlievert PM, Kaplan E. 1989. Severe group A streptococcal infections associated with a toxic shock-like syndrome and scarlet fever toxin A. N Engl J Med 321:1–7 http://dx.doi.org/10.1056/NEJM198907063210101. [PubMed]
189. Stevens DL, Bryant AE. 2017. Necrotizing soft-tissue infections. N Engl J Med 377:2253–2265 http://dx.doi.org/10.1056/NEJMra1600673. [PubMed]
190. Royet J, Dziarski R. 2007. Peptidoglycan recognition proteins: pleiotropic sensors and effectors of antimicrobial defences. Nat Rev Microbiol 5:264–277 http://dx.doi.org/10.1038/nrmicro1620. [PubMed]
191. von Moltke J, Ayres JS, Kofoed EM, Chavarría-Smith J, Vance RE. 2013. Recognition of bacteria by inflammasomes. Annu Rev Immunol 31:73–106 http://dx.doi.org/10.1146/annurev-immunol-032712-095944. [PubMed]
192. Franchi L, Muñoz-Planillo R, Núñez G. 2012. Sensing and reacting to microbes through the inflammasomes. Nat Immunol 13:325–332 http://dx.doi.org/10.1038/ni.2231. [PubMed]
193. Netea MG, Simon A, van de Veerdonk F, Kullberg BJ, Van der Meer JW, Joosten LA. 2010. IL-1beta processing in host defense: beyond the inflammasomes. PLoS Pathog 6:e1000661 http://dx.doi.org/10.1371/journal.ppat.1000661. [PubMed]
194. Lin AE, Beasley FC, Keller N, Hollands A, Urbano R, Troemel ER, Hoffman HM, Nizet V. 2015. A group A Streptococcus ADP-ribosyltransferase toxin stimulates a protective interleukin 1β-dependent macrophage immune response. MBio 6:e00133 http://dx.doi.org/10.1128/mBio.00133-15. [PubMed]
195. Miettinen M, Matikainen S, Vuopio-Varkila J, Pirhonen J, Varkila K, Kurimoto M, Julkunen I. 1998. Lactobacilli and streptococci induce interleukin-12 (IL-12), IL-18, and gamma interferon production in human peripheral blood mononuclear cells. Infect Immun 66:6058–6062. [PubMed]
196. Baccala R, Hoebe K, Kono DH, Beutler B, Theofilopoulos AN. 2007. TLR-dependent and TLR-independent pathways of type I interferon induction in systemic autoimmunity. Nat Med 13:543–551 http://dx.doi.org/10.1038/nm1590. [PubMed]
197. Man SM, Kanneganti TD. 2015. Regulation of inflammasome activation. Immunol Rev 265:6–21 http://dx.doi.org/10.1111/imr.12296. [PubMed]
198. Kanneganti TD, Lamkanfi M, Núñez G. 2007. Intracellular NOD-like receptors in host defense and disease. Immunity 27:549–559 http://dx.doi.org/10.1016/j.immuni.2007.10.002. [PubMed]
199. Netea MG, Nold-Petry CA, Nold MF, Joosten LA, Opitz B, van der Meer JH, van de Veerdonk FL, Ferwerda G, Heinhuis B, Devesa I, Funk CJ, Mason RJ, Kullberg BJ, Rubartelli A, van der Meer JW, Dinarello CA. 2009. Differential requirement for the activation of the inflammasome for processing and release of IL-1beta in monocytes and macrophages. Blood 113:2324–2335 http://dx.doi.org/10.1182/blood-2008-03-146720. [PubMed]
200. Gratz N, Siller M, Schaljo B, Pirzada ZA, Gattermeier I, Vojtek I, Kirschning CJ, Wagner H, Akira S, Charpentier E, Kovarik P. 2008. Group A Streptococcus activates type I interferon production and MyD88-dependent signaling without involvement of TLR2, TLR4, and TLR9. J Biol Chem 283:19879–19887 http://dx.doi.org/10.1074/jbc.M802848200.
201. Harder J, Franchi L, Muñoz-Planillo R, Park JH, Reimer T, Núñez G. 2009. Activation of the Nlrp3 inflammasome by Streptococcus pyogenes requires streptolysin O and NF-kappa B activation but proceeds independently of TLR signaling and P2X7 receptor. J Immunol 183:5823–5829 http://dx.doi.org/10.4049/jimmunol.0900444.
202. Latvala S, Mäkelä SM, Miettinen M, Charpentier E, Julkunen I. 2014. Dynamin inhibition interferes with inflammasome activation and cytokine gene expression in Streptococcus pyogenes-infected human macrophages. Clin Exp Immunol 178:320–333 http://dx.doi.org/10.1111/cei.12425. [PubMed]
203. Valderrama JA, Riestra AM, Gao NJ, LaRock CN, Gupta N, Ali SR, Hoffman HM, Ghosh P, Nizet V. 2017. Group A streptococcal M protein activates the NLRP3 inflammasome. Nat Microbiol 2:1425–1434 http://dx.doi.org/10.1038/s41564-017-0005-6. [PubMed]
204. Ferguson SM, De Camilli P. 2012. Dynamin, a membrane-remodelling GTPase. Nat Rev Mol Cell Biol 13:75–88 http://dx.doi.org/10.1038/nrm3266. [PubMed]
205. Uchiyama S, Andreoni F, Schuepbach RA, Nizet V, Zinkernagel AS. 2012. DNase Sda1 allows invasive M1T1 group A Streptococcus to prevent TLR9-dependent recognition. PLoS Pathog 8:e1002736 http://dx.doi.org/10.1371/journal.ppat.1002736. [PubMed]
206. Zinkernagel AS, Hruz P, Uchiyama S, von Köckritz-Blickwede M, Schuepbach RA, Hayashi T, Carson DA, Nizet V. 2012. Importance of Toll-like receptor 9 in host defense against M1T1 group A Streptococcus infections. J Innate Immun 4:213–218 http://dx.doi.org/10.1159/000329550. [PubMed]
207. Kovarik P, Castiglia V, Ivin M, Ebner F. 2016. Type I interferons in bacterial infections: a balancing act. Front Immunol 7:652 http://dx.doi.org/10.3389/fimmu.2016.00652. [PubMed]
208. Fieber C, Janos M, Koestler T, Gratz N, Li XD, Castiglia V, Aberle M, Sauert M, Wegner M, Alexopoulou L, Kirschning CJ, Chen ZJ, von Haeseler A, Kovarik P. 2015. Innate immune response to Streptococcus pyogenes depends on the combined activation of TLR13 and TLR2. PLoS One 10:e0119727 http://dx.doi.org/10.1371/journal.pone.0119727.
209. Eigenbrod T, Pelka K, Latz E, Kreikemeyer B, Dalpke AH. 2015. TLR8 senses bacterial RNA in human monocytes and plays a nonredundant role for recognition of Streptococcus pyogenes. J Immunol 195:1092–1099 http://dx.doi.org/10.4049/jimmunol.1403173.
210. Broz P, Ruby T, Belhocine K, Bouley DM, Kayagaki N, Dixit VM, Monack DM. 2012. Caspase-11 increases susceptibility to Salmonella infection in the absence of caspase-1. Nature 490:288–291 http://dx.doi.org/10.1038/nature11419.
211. Viganò E, Diamond CE, Spreafico R, Balachander A, Sobota RM, Mortellaro A. 2015. Human caspase-4 and caspase-5 regulate the one-step non-canonical inflammasome activation in monocytes. Nat Commun 6:8761 http://dx.doi.org/10.1038/ncomms9761.
212. Viganò E, Mortellaro A. 2013. Caspase-11: the driving factor for noncanonical inflammasomes. Eur J Immunol 43:2240–2245 http://dx.doi.org/10.1002/eji.201343800.
213. Mueller NJ, Wilkinson RA, Fishman JA. 2002. Listeria monocytogenes infection in caspase-11-deficient mice. Infect Immun 70:2657–2664 http://dx.doi.org/10.1128/IAI.70.5.2657-2664.2002.
214. Hara H, Seregin SS, Yang D, Fukase K, Chamaillard M, Alnemri ES, Inohara N, Chen GY, Núñez G. 2018. The NLRP6 inflammasome recognizes lipoteichoic acid and regulates Gram-positive pathogen infection. Cell 175:1651–1664.e14 http://dx.doi.org/10.1016/j.cell.2018.09.047.
215. González-Juarbe N, Bradley KM, Shenoy AT, Gilley RP, Reyes LF, Hinojosa CA, Restrepo MI, Dube PH, Bergman MA, Orihuela CJ. 2017. Pore-forming toxin-mediated ion dysregulation leads to death receptor-independent necroptosis of lung epithelial cells during bacterial pneumonia. Cell Death Differ 24:917–928 http://dx.doi.org/10.1038/cdd.2017.49.
216. Larock CN, Todd J, LaRock DL, Olson J, O’Donoghue AJ, Robertson AA, Cooper MA, Hoffman HM, Nizet V. 2016. IL-1b is an innate immune sensor of microbial proteolysis. Sci Immunol 1:eaah3539 http://dx.doi.org/10.1126/sciimmunol.aah3539.
217. Kansal RG, Datta V, Aziz RK, Abdeltawab NF, Rowe S, Kotb M. 2010. Dissection of the molecular basis for hypervirulence of an in vivo-selected phenotype of the widely disseminated M1T1 strain of group A Streptococcus bacteria. J Infect Dis 201:855–865 http://dx.doi.org/10.1086/651019.
218. Gaidt MM, Hornung V. 2016. Pore formation by GSDMD is the effector mechanism of pyroptosis. EMBO J 35:2167–2169 http://dx.doi.org/10.15252/embj.201695415.
219. Shi J, Zhao Y, Wang K, Shi X, Wang Y, Huang H, Zhuang Y, Cai T, Wang F, Shao F. 2015. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature 526:660–665 http://dx.doi.org/10.1038/nature15514.
220. Saeki N, Usui T, Aoyagi K, Kim DH, Sato M, Mabuchi T, Yanagihara K, Ogawa K, Sakamoto H, Yoshida T, Sasaki H. 2009. Distinctive expression and function of four GSDM family genes (GSDMA-D) in normal and malignant upper gastrointestinal epithelium. Genes Chromosomes Cancer 48:261–271 http://dx.doi.org/10.1002/gcc.20636.
221. Sborgi L, Rühl S, Mulvihill E, Pipercevic J, Heilig R, Stahlberg H, Farady CJ, Müller DJ, Broz P, Hiller S. 2016. GSDMD membrane pore formation constitutes the mechanism of pyroptotic cell death. EMBO J 35:1766–1778 http://dx.doi.org/10.15252/embj.201694696.
222. Rathkey JK, Benson BL, Chirieleison SM, Yang J, Xiao TS, Dubyak GR, Huang AY, Abbott DW. 2017. Live-cell visualization of gasdermin D-driven pyroptotic cell death. J Biol Chem 292:14649–14658 http://dx.doi.org/10.1074/jbc.M117.797217.
223. Evavold CL, Ruan J, Tan Y, Xia S, Wu H, Kagan JC. 2018. The pore-forming protein gasdermin D regulates interleukin-1 secretion from living macrophages. Immunity 48:35–44.e6 http://dx.doi.org/10.1016/j.immuni.2017.11.013.
224. Ding J, Wang K, Liu W, She Y, Sun Q, Shi J, Sun H, Wang DC, Shao F. 2016. Pore-forming activity and structural autoinhibition of the gasdermin family. Nature 535:111–116 http://dx.doi.org/10.1038/nature18590.
225. Hilbi H, Moss JE, Hersh D, Chen Y, Arondel J, Banerjee S, Flavell RA, Yuan J, Sansonetti PJ, Zychlinsky A. 1998. Shigella-induced apoptosis is dependent on caspase-1 which binds to IpaB. J Biol Chem 273:32895–32900 http://dx.doi.org/10.1074/jbc.273.49.32895.
226. Zychlinsky A, Thirumalai K, Arondel J, Cantey JR, Aliprantis AO, Sansonetti PJ. 1996. In vivo apoptosis in Shigella flexneri infections. Infect Immun 64:5357–5365.
227. Guzmán CA, Domann E, Rohde M, Bruder D, Darji A, Weiss S, Wehland J, Chakraborty T, Timmis KN. 1996. Apoptosis of mouse dendritic cells is triggered by listeriolysin, the major virulence determinant of Listeria monocytogenes. Mol Microbiol 20:119–126 http://dx.doi.org/10.1111/j.1365-2958.1996.tb02494.x.
228. Kemp K, Bruunsgaard H, Skinhøj P, Klarlund Pedersen B. 2002. Pneumococcal infections in humans are associated with increased apoptosis and trafficking of type 1 cytokine-producing T cells. Infect Immun 70:5019–5025 http://dx.doi.org/10.1128/IAI.70.9.5019-5025.2002.
229. Zysk G, Bejo L, Schneider-Wald BK, Nau R, Heinz H. 2000. Induction of necrosis and apoptosis of neutrophil granulocytes by Streptococcus pneumoniae. Clin Exp Immunol 122:61–66 http://dx.doi.org/10.1046/j.1365-2249.2000.01336.x.
230. O’Neill AM, Thurston TL, Holden DW. 2016. Cytosolic replication of group A Streptococcus in human macrophages. MBio 7:e00020-16.
231. Huang J, Brumell JH. 2014. Bacteria-autophagy interplay: a battle for survival. Nat Rev Microbiol 12:101–114 http://dx.doi.org/10.1038/nrmicro3160.
232. Nakagawa I, Amano A, Mizushima N, Yamamoto A, Yamaguchi H, Kamimoto T, Nara A, Funao J, Nakata M, Tsuda K, Hamada S, Yoshimori T. 2004. Autophagy defends cells against invading group A Streptococcus. Science 306:1037–1040 http://dx.doi.org/10.1126/science.1103966.
233. Nozawa T, Aikawa C, Goda A, Maruyama F, Hamada S, Nakagawa I. 2012. The small GTPases Rab9A and Rab23 function at distinct steps in autophagy during group A Streptococcus infection. Cell Microbiol 14:1149–1165 http://dx.doi.org/10.1111/j.1462-5822.2012.01792.x.
234. Haobam B, Nozawa T, Minowa-Nozawa A, Tanaka M, Oda S, Watanabe T, Aikawa C, Maruyama F, Nakagawa I. 2014. Rab17-mediated recycling endosomes contribute to autophagosome formation in response to group A Streptococcus invasion. Cell Microbiol 16:1806–1821 http://dx.doi.org/10.1111/cmi.12329.
235. Nozawa T, Minowa-Nozawa A, Aikawa C, Nakagawa I. 2017. The STX6-VTI1B-VAMP3 complex facilitates xenophagy by regulating the fusion between recycling endosomes and autophagosomes. Autophagy 13:57–69 http://dx.doi.org/10.1080/15548627.2016.1241924.
236. Oberstein A, Jeffrey PD, Shi Y. 2007. Crystal structure of the Bcl-XL-Beclin 1 peptide complex: Beclin 1 is a novel BH3-only protein. J Biol Chem 282:13123–13132 http://dx.doi.org/10.1074/jbc.M700492200.
237. Joubert PE, Meiffren G, Grégoire IP, Pontini G, Richetta C, Flacher M, Azocar O, Vidalain PO, Vidal M, Lotteau V, Codogno P, Rabourdin-Combe C, Faure M. 2009. Autophagy induction by the pathogen receptor CD46. Cell Host Microbe 6:354–366 http://dx.doi.org/10.1016/j.chom.2009.09.006.
238. Cattaneo R. 2004. Four viruses, two bacteria, and one receptor: membrane cofactor protein (CD46) as pathogens’ magnet. J Virol 78:4385–4388 http://dx.doi.org/10.1128/JVI.78.9.4385-4388.2004.
239. Zhong Y, Wang QJ, Li X, Yan Y, Backer JM, Chait BT, Heintz N, Yue Z. 2009. Distinct regulation of autophagic activity by Atg14L and Rubicon associated with Beclin 1-phosphatidylinositol-3-kinase complex. Nat Cell Biol 11:468–476 http://dx.doi.org/10.1038/ncb1854.
240. Liang C, Feng P, Ku B, Dotan I, Canaani D, Oh BH, Jung JU. 2006. Autophagic and tumour suppressor activity of a novel Beclin1-binding protein UVRAG. Nat Cell Biol 8:688–699 http://dx.doi.org/10.1038/ncb1426.
241. Liang C, Lee JS, Inn KS, Gack MU, Li Q, Roberts EA, Vergne I, Deretic V, Feng P, Akazawa C, Jung JU. 2008. Beclin1-binding UVRAG targets the class C Vps complex to coordinate autophagosome maturation and endocytic trafficking. Nat Cell Biol 10:776–787 http://dx.doi.org/10.1038/ncb1740.
242. Nakajima S, Aikawa C, Nozawa T, Minowa-Nozawa A, Toh H, Nakagawa I. 2017. Bcl-xL affects group A Streptococcus-induced autophagy directly, by inhibiting fusion between autophagosomes and lysosomes, and indirectly, by inhibiting bacterial internalization via interaction with Beclin 1-UVRAG. PLoS One 12:e0170138 http://dx.doi.org/10.1371/journal.pone.0170138.
243. Jounai N, Kobiyama K, Shiina M, Ogata K, Ishii KJ, Takeshita F. 2011. NLRP4 negatively regulates autophagic processes through an association with beclin1. J Immunol 186:1646–1655 http://dx.doi.org/10.4049/jimmunol.1001654.
244. Barnett TC, Liebl D, Seymour LM, Gillen CM, Lim JY, Larock CN, Davies MR, Schulz BL, Nizet V, Teasdale RD, Walker MJ. 2013. The globally disseminated M1T1 clone of group A Streptococcus evades autophagy for intracellular replication. Cell Host Microbe 14:675–682 http://dx.doi.org/10.1016/j.chom.2013.11.003.
245. Deretic V, Saitoh T, Akira S. 2013. Autophagy in infection, inflammation and immunity. Nat Rev Immunol 13:722–737 http://dx.doi.org/10.1038/nri3532.
246. O’Seaghdha M, Wessels MR. 2013. Streptolysin O and its co-toxin NAD-glycohydrolase protect group A Streptococcus from xenophagic killing. PLoS Pathog 9:e1003394 http://dx.doi.org/10.1371/journal.ppat.1003394.
247. Lu SL, Kuo CF, Chen HW, Yang YS, Liu CC, Anderson R, Wu JJ, Lin YS. 2015. Insufficient acidification of autophagosomes facilitates group A Streptococcus survival and growth in endothelial cells. MBio 6:e01435-15 http://dx.doi.org/10.1128/mBio.01435-15.
248. Lu SL, Kawabata T, Cheng YL, Omori H, Hamasaki M, Kusaba T, Iwamoto R, Arimoto H, Noda T, Lin YS, Yoshimori T. 2017. Endothelial cells are intrinsically defective in xenophagy of Streptococcus pyogenes. PLoS Pathog 13:e1006444 http://dx.doi.org/10.1371/journal.ppat.1006444.
249. Wood DN, Weinstein KE, Podbielski A, Kreikemeyer B, Gaughan JP, Valentine S, Buttaro BA. 2009. Generation of metabolically diverse strains of Streptococcus pyogenes during survival in stationary phase. J Bacteriol 191:6242–6252 http://dx.doi.org/10.1128/JB.00440-09.
250. Bastiat-Sempe B, Love JF, Lomayesva N, Wessels MR. 2014. Streptolysin O and NAD-glycohydrolase prevent phagolysosome acidification and promote group A Streptococcus survival in macrophages. MBio 5:e01690-14 http://dx.doi.org/10.1128/mBio.01690-14.
251. Cheng YL, Wu YW, Kuo CF, Lu SL, Liu FT, Anderson R, Lin CF, Liu YL, Wang WY, Chen YD, Zheng PX, Wu JJ, Lin YS. 2017. Galectin-3 inhibits galectin-8/parkin-mediated ubiquitination of group A Streptococcus. MBio 8:e00899-17 http://dx.doi.org/10.1128/mBio.00899-17.
252. Mackinnon FG, Borrow R, Gorringe AR, Fox AJ, Jones DM, Robinson A. 1993. Demonstration of lipooligosaccharide immunotype and capsule as virulence factors for Neisseria meningitidis using an infant mouse intranasal infection model. Microb Pathog 15:359–366 http://dx.doi.org/10.1006/mpat.1993.1085.
253. Quattroni P, Li Y, Lucchesi D, Lucas S, Hood DW, Herrmann M, Gabius HJ, Tang CM, Exley RM. 2012. Galectin-3 binds Neisseria meningitidis and increases interaction with phagocytic cells. Cell Microbiol 14:1657–1675 http://dx.doi.org/10.1111/j.1462-5822.2012.01838.x.
254. Remijsen Q, Vanden Berghe T, Wirawan E, Asselbergh B, Parthoens E, De Rycke R, Noppen S, Delforge M, Willems J, Vandenabeele P. 2011. Neutrophil extracellular trap cell death requires both autophagy and superoxide generation. Cell Res 21:290–304 http://dx.doi.org/10.1038/cr.2010.150. [PubMed]
255. Shahnazari S, Brumell JH. 2011. Mechanisms and consequences of bacterial targeting by the autophagy pathway. Curr Opin Microbiol 14:68–75 http://dx.doi.org/10.1016/j.mib.2010.11.001. [PubMed]
256. Huang J, Canadien V, Lam GY, Steinberg BE, Dinauer MC, Magalhaes MA, Glogauer M, Grinstein S, Brumell JH. 2009. Activation of antibacterial autophagy by NADPH oxidases. Proc Natl Acad Sci U S A 106:6226–6231 http://dx.doi.org/10.1073/pnas.0811045106. [PubMed]
257. Chung H-T, Pae H-O, Choi B-M, Billiar TR, Kim YM. 2001. Nitric oxide as a bioregulator of apoptosis. Biochem Biophys Res Commun 282:1075–1079 http://dx.doi.org/10.1006/bbrc.2001.4670.
258. Ito C, Saito Y, Nozawa T, Fujii S, Sawa T, Inoue H, Matsunaga T, Khan S, Akashi S, Hashimoto R, Aikawa C, Takahashi E, Sagara H, Komatsu M, Tanaka K, Akaike T, Nakagawa I, Arimoto H. 2013. Endogenous nitrated nucleotide is a key mediator of autophagy and innate defense against bacteria. Mol Cell 52:794–804 http://dx.doi.org/10.1016/j.molcel.2013.10.024. [PubMed]
259. Alameda JP, Fernández-Aceñero MJ, Quintana RM, Page A, Ramírez Á, Navarro M, Casanova ML. 2013. Functional inactivation of CYLD promotes the metastatic potential of tumor epidermal cells. J Invest Dermatol 133:1870–1878 http://dx.doi.org/10.1038/jid.2013.76. [PubMed]
260. Alameda JP, Moreno-Maldonado R, Navarro M, Bravo A, Ramírez A, Page A, Jorcano JL, Fernández-Aceñero MJ, Casanova ML. 2010. An inactivating CYLD mutation promotes skin tumor progression by conferring enhanced proliferative, survival and angiogenic properties to epidermal cancer cells. Oncogene 29:6522–6532 http://dx.doi.org/10.1038/onc.2010.378. [PubMed]
261. Bhattacharya S, Ghosh MK. 2014. Cell death and deubiquitinases: perspectives in cancer. BioMed Res Int 2014:435197 http://dx.doi.org/10.1155/2014/435197. [PubMed]
262. Koga T, Lim JH, Jono H, Ha UH, Xu H, Ishinaga H, Morino S, Xu X, Yan C, Kai H, Li JD. 2008. Tumor suppressor cylindromatosis acts as a negative regulator for Streptococcus pneumoniae-induced NFAT signaling. J Biol Chem 283:12546–12554 http://dx.doi.org/10.1074/jbc.M710518200. [PubMed]
263. Lim JH, Jono H, Koga T, Woo CH, Ishinaga H, Bourne P, Xu H, Ha UH, Xu H, Li JD. 2007. Tumor suppressor CYLD acts as a negative regulator for non-typeable Haemophilus influenza-induced inflammation in the middle ear and lung of mice. PLoS One 2:e1032 http://dx.doi.org/10.1371/journal.pone.0001032. [PubMed]
264. Nishanth G, Deckert M, Wex K, Massoumi R, Schweitzer K, Naumann M, Schlüter D. 2013. CYLD enhances severe listeriosis by impairing IL-6/STAT3-dependent fibrin production. PLoS Pathog 9:e1003455 http://dx.doi.org/10.1371/journal.ppat.1003455. [PubMed]
265. Tsai PJ, Lin YS, Kuo CF, Lei HY, Wu JJ. 1999. Group A Streptococcus induces apoptosis in human epithelial cells. Infect Immun 67:4334–4339. [PubMed]
266. Nakagawa I, Nakata M, Kawabata S, Hamada S. 2001. Cytochrome c-mediated caspase-9 activation triggers apoptosis in Streptococcus pyogenes-infected epithelial cells. Cell Microbiol 3:395–405 http://dx.doi.org/10.1046/j.1462-5822.2001.00122.x. [PubMed]
267. Steller H. 1995. Mechanisms and genes of cellular suicide. Science 267:1445–1449 http://dx.doi.org/10.1126/science.7878463. [PubMed]
268. Nagata S. 1997. Apoptosis by death factor. Cell 88:355–365 http://dx.doi.org/10.1016/S0092-8674(00)81874-7.
269. Zychlinsky A, Sansonetti PJ. 1997. Apoptosis as a proinflammatory event: what can we learn from bacteria-induced cell death? Trends Microbiol 5:201–204 http://dx.doi.org/10.1016/S0966-842X(97)01044-5.
270. Bricker AL, Cywes C, Ashbaugh CD, Wessels MR. 2002. NAD+-glycohydrolase acts as an intracellular toxin to enhance the extracellular survival of group A streptococci. Mol Microbiol 44:257–269 http://dx.doi.org/10.1046/j.1365-2958.2002.02876.x. [PubMed]
271. Madden JC, Ruiz N, Caparon M. 2001. Cytolysin-mediated translocation (CMT): a functional equivalent of type III secretion in Gram-positive bacteria. Cell 104:143–152 http://dx.doi.org/10.1016/S0092-8674(01)00198-2.
272. Mehta K, Shahid U, Malavasi F. 1996. Human CD38, a cell-surface protein with multiple functions. FASEB J 10:1408–1417 http://dx.doi.org/10.1096/fasebj.10.12.8903511. [PubMed]
273. Timmer AM, Timmer JC, Pence MA, Hsu LC, Ghochani M, Frey TG, Karin M, Salvesen GS, Nizet V. 2009. Streptolysin O promotes group A Streptococcus immune evasion by accelerated macrophage apoptosis. J Biol Chem 284:862–871 http://dx.doi.org/10.1074/jbc.M804632200. [PubMed]
274. Kobayashi SD, Braughton KR, Whitney AR, Voyich JM, Schwan TG, Musser JM, DeLeo FR. 2003. Bacterial pathogens modulate an apoptosis differentiation program in human neutrophils. Proc Natl Acad Sci U S A 100:10948–10953 http://dx.doi.org/10.1073/pnas.1833375100. [PubMed]
275. Ajiro K, Nishimoto T. 1985. Specific site of histone H3 phosphorylation related to the maintenance of premature chromosome condensation. Evidence for catalytically induced interchange of the subunits. J Biol Chem 260:15379–15381. [PubMed]
276. Wolffe AP, Wong J, Pruss D. 1997. Activators and repressors: making use of chromatin to regulate transcription. Genes Cells 2:291–302 http://dx.doi.org/10.1046/j.1365-2443.1997.1260323.x. [PubMed]
277. Ciccarelli A, Giustetto M. 2014. Role of ERK signaling in activity-dependent modifications of histone proteins. Neuropharmacology 80:34–44 http://dx.doi.org/10.1016/j.neuropharm.2014.01.039. [PubMed]
278. Sawicka A, Seiser C. 2014. Sensing core histone phosphorylation: a matter of perfect timing. Biochim Biophys Acta 1839:711–718 http://dx.doi.org/10.1016/j.bbagrm.2014.04.013. [PubMed]
279. Tikoo K, Lau SS, Monks TJ. 2001. Histone H3 phosphorylation is coupled to poly-(ADP-ribosylation) during reactive oxygen species-induced cell death in renal proximal tubular epithelial cells. Mol Pharmacol 60:394–402 http://dx.doi.org/10.1124/mol.60.2.394. [PubMed]
280. 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. 101st ASM General Meeting, Orlando, FL, 20–24 May, B-177, p 80 (abstr).
281. Ishitani R, Sunaga K, Tanaka M, Aishita H, Chuang D-M. 1997. Overexpression of glyceraldehyde-3-phosphate dehydrogenase is involved in low K+-induced apoptosis but not necrosis of cultured cerebellar granule cells. Mol Pharmacol 51:542–550 http://dx.doi.org/10.1124/mol.51.4.542. [PubMed]
282. Kusner LL, Sarthy VP, Mohr S. 2004. Nuclear translocation of glyceraldehyde-3-phosphate dehydrogenase: a role in high glucose-induced apoptosis in retinal Müller cells. Invest Ophthalmol Vis Sci 45:1553–1561. [PubMed]
283. Sirover MA. 2005. New nuclear functions of the glycolytic protein, glyceraldehyde-3-phosphate dehydrogenase, in mammalian cells. J Cell Biochem 95:45–52 http://dx.doi.org/10.1002/jcb.20399. [PubMed]
284. Oliveira L, Madureira P, Andrade EB, Bouaboud A, Morello E, Ferreira P, Poyart C, Trieu-Cuot P, Dramsi S. 2012. Group B Streptococcus GAPDH is released upon cell lysis, associates with bacterial surface, and induces apoptosis in murine macrophages. PLoS One 7:e29963 http://dx.doi.org/10.1371/journal.pone.0029963. [PubMed]
285. Kratzmeier M, Albig W, Hanecke K, Doenecke D. 2000. Rapid dephosphorylation of H1 histones after apoptosis induction. J Biol Chem 275:30478–30486 http://dx.doi.org/10.1074/jbc.M003956200. [PubMed]
286. von Mering M, Wellmer A, Michel U, Bunkowski S, Tłustochowska A, Brück W, Kuhnt U, Nau R. 2001. Transcriptional regulation of caspases in experimental pneumococcal meningitis. Brain Pathol 11:282–295 http://dx.doi.org/10.1111/j.1750-3639.2001.tb00399.x. [PubMed]
287. Braun JS, Novak R, Herzog KH, Bodner SM, Cleveland JL, Tuomanen EI. 1999. Neuroprotection by a caspase inhibitor in acute bacterial meningitis. Nat Med 5:298–302 http://dx.doi.org/10.1038/6514. [PubMed]
288. Braun JS, Novak R, Murray PJ, Eischen CM, Susin SA, Kroemer G, Halle A, Weber JR, Tuomanen EI, Cleveland JL. 2001. Apoptosis-inducing factor mediates microglial and neuronal apoptosis caused by pneumococcus. J Infect Dis 184:1300–1309 http://dx.doi.org/10.1086/324013. [PubMed]
289. Schmeck B, Gross R, N’Guessan PD, Hocke AC, Hammerschmidt S, Mitchell TJ, Rosseau S, Suttorp N, Hippenstiel S. 2004. Streptococcus pneumoniae-induced caspase 6-dependent apoptosis in lung epithelium. Infect Immun 72:4940–4947 http://dx.doi.org/10.1128/IAI.72.9.4940-4947.2004. [PubMed]
290. Brown AO, Mann B, Gao G, Hankins JS, Humann J, Giardina J, Faverio P, Restrepo MI, Halade GV, Mortensen EM, Lindsey ML, Hanes M, Happel KI, Nelson S, Bagby GJ, Lorent JA, Cardinal P, Granados R, Esteban A, LeSaux CJ, Tuomanen EI, Orihuela CJ. 2014. Streptococcus pneumoniae translocates into the myocardium and forms unique microlesions that disrupt cardiac function. PLoS Pathog 10:e1004383 http://dx.doi.org/10.1371/journal.ppat.1004383. [PubMed]
291. Reyes LF, Restrepo MI, Hinojosa CA, Soni NJ, Anzueto A, Babu BL, Gonzalez-Juarbe N, Rodriguez AH, Jimenez A, Chalmers JD, Aliberti S, Sibila O, Winter VT, Coalson JJ, Giavedoni LD, Dela Cruz CS, Waterer GW, Witzenrath M, Suttorp N, Dube PH, Orihuela CJ. 2017. Severe pneumococcal pneumonia causes acute cardiac toxicity and subsequent cardiac remodeling. Am J Respir Crit Care Med 196:609–620 http://dx.doi.org/10.1164/rccm.201701-0104OC. [PubMed]
292. Rodriguez DA, Weinlich R, Brown S, Guy C, Fitzgerald P, Dillon CP, Oberst A, Quarato G, Low J, Cripps JG, Chen T, Green DR. 2016. Characterization of RIPK3-mediated phosphorylation of the activation loop of MLKL during necroptosis. Cell Death Differ 23:76–88 http://dx.doi.org/10.1038/cdd.2015.70. [PubMed]
293. Remijsen Q, Goossens V, Grootjans S, Van den Haute C, Vanlangenakker N, Dondelinger Y, Roelandt R, Bruggeman I, Goncalves A, Bertrand MJ, Baekelandt V, Takahashi N, Berghe TV, Vandenabeele P. 2014. Depletion of RIPK3 or MLKL blocks TNF-driven necroptosis and switches towards a delayed RIPK1 kinase-dependent apoptosis. Cell Death Dis 5:e1004 http://dx.doi.org/10.1038/cddis.2013.531. [PubMed]
294. Hakansson AP, Bergenfelz C. 2017. Low NF-kappaB activation and necroptosis in alveolar macrophages: a new virulence property of Streptococcus pneumoniae. J Infect Dis 216:402–404 http://dx.doi.org/10.1093/infdis/jix161. [PubMed]
295. Coleman FT, Blahna MT, Kamata H, Yamamoto K, Zabinski MC, Kramnik I, Wilson AA, Kotton DN, Quinton LJ, Jones MR, Pelton SI, Mizgerd JP. 2017. Capacity of pneumococci to activate macrophage nuclear factor kappaB: influence on necroptosis and pneumonia severity. J Infect Dis 216:425–435 http://dx.doi.org/10.1093/infdis/jix159. [PubMed]
296. Taabazuing CY, Okondo MC, Bachovchin DA. 2017. Pyroptosis and apoptosis pathways engage in bidirectional crosstalk in monocytes and macrophages. Cell Chem Biol 24:507–514.e4 http://dx.doi.org/10.1016/j.chembiol.2017.03.009. [PubMed]
297. Okondo MC, Johnson DC, Sridharan R, Go EB, Chui AJ, Wang MS, Poplawski SE, Wu W, Liu Y, Lai JH, Sanford DG, Arciprete MO, Golub TR, Bachovchin WW, Bachovchin DA. 2017. DPP8 and DPP9 inhibition induces pro-caspase-1-dependent monocyte and macrophage pyroptosis. Nat Chem Biol 13:46–53 http://dx.doi.org/10.1038/nchembio.2229. [PubMed]
298. Schneider KS, Groß CJ, Dreier RF, Saller BS, Mishra R, Gorka O, Heilig R, Meunier E, Dick MS, Ćiković T, Sodenkamp J, Médard G, Naumann R, Ruland J, Kuster B, Broz P, Groß O. 2017. The inflammasome drives GSDMD-independent secondary pyroptosis and IL-1 release in the absence of caspase-1 protease activity. Cell Reports 21:3846–3859 http://dx.doi.org/10.1016/j.celrep.2017.12.018. [PubMed]
299. Jorgensen I, Rayamajhi M, Miao EA. 2017. Programmed cell death as a defence against infection. Nat Rev Immunol 17:151–164 http://dx.doi.org/10.1038/nri.2016.147. [PubMed]
300. Gamradt P, Xu Y, Gratz N, Duncan K, Kobzik L, Högler S, Kovarik P, Decker T, Jamieson AM. 2016. The influence of programmed cell death in myeloid cells on host resilience to infection with Legionella pneumophila or Streptococcus pyogenes. PLoS Pathog 12:e1006032 http://dx.doi.org/10.1371/journal.ppat.1006032. [PubMed]
301. Natanson C, Hoffman WD, Suffredini AF, Eichacker PQ, Danner RL. 1994. Selected treatment strategies for septic shock based on proposed mechanisms of pathogenesis. Ann Intern Med 120:771–783 http://dx.doi.org/10.7326/0003-4819-120-9-199405010-00009. [PubMed]
302. Levitzki A, Gazit A. 1995. Tyrosine kinase inhibition: an approach to drug development. Science 267:1782–1788 http://dx.doi.org/10.1126/science.7892601. [PubMed]
303. Sun J, Lei L, Tsai CM, Wang Y, Shi Y, Ouyang M, Lu S, Seong J, Kim TJ, Wang P, Huang M, Xu X, Nizet V, Chien S, Wang Y. 2017. Engineered proteins with sensing and activating modules for automated reprogramming of cellular functions. Nat Commun 8:477 http://dx.doi.org/10.1038/s41467-017-00569-6. [PubMed]
304. Rubinsztein DC, Bento CF, Deretic V. 2015. Therapeutic targeting of autophagy in neurodegenerative and infectious diseases. J Exp Med 212:979–990 http://dx.doi.org/10.1084/jem.20150956. [PubMed]
305. Thamphiwatana S, Angsantikul P, Escajadillo T, Zhang Q, Olson J, Luk BT, Zhang S, Fang RH, Gao W, Nizet V, Zhang L. 2017. Macrophage-like nanoparticles concurrently absorbing endotoxins and proinflammatory cytokines for sepsis management. Proc Natl Acad Sci U S A 114:11488–11493 http://dx.doi.org/10.1073/pnas.1714267114. [PubMed]
306. Galluzzi L, Bravo-San Pedro JM, Levine B, Green DR, Kroemer G. 2017. Pharmacological modulation of autophagy: therapeutic potential and persisting obstacles. Nat Rev Drug Discov 16:487–511 http://dx.doi.org/10.1038/nrd.2017.22. [PubMed]

Article metrics loading...



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.

Highlighted Text: Show | Hide
Loading full text...

Full text loading...


Image of 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
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of 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
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of 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
Permissions and Reprints Request Permissions
Download as Powerpoint

Supplemental Material

No supplementary material available for this content.

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error