The development of a severe invasive bacterial infection in an otherwise healthy individual is one of the most striking and fascinating aspects of human medicine. A small cadre of gram-positive pathogens of the genera and stand out for their unique invasive disease potential and sophisticated ability to counteract the multifaceted components of human innate defense. This review illustrates how these leading human disease agents evade host complement deposition and activation, impede phagocyte recruitment and activation, resist the microbicidal activities of host antimicrobial peptides and reactive oxygen species, escape neutrophil extracellular traps, and promote and accelerate phagocyte cell death through the action of pore-forming cytolysins. Understanding the molecular basis of bacterial innate immune resistance can open new avenues for therapeutic intervention geared to disabling specific virulence factors and resensitizing the pathogen to host innate immune clearance.


Article metrics loading...

Loading full text...

Full text loading...


Literature Cited

  1. Agarwal V, Ahl J, Riesbeck K, Blom AM. 1.  2013. An alternative role of C1q in bacterial infections: facilitating Streptococcus pneumoniae adherence and invasion of host cells. J. Immunol. 191:4235–45 [Google Scholar]
  2. Agarwal V, Hammerschmidt S, Malm S, Bergmann S, Riesbeck K, Blom AM. 2.  2012. Enolase of Streptococcus pneumoniae binds human complement inhibitor C4b-binding protein and contributes to complement evasion. J. Immunol. 189:3575–84 [Google Scholar]
  3. Agarwal V, Kuchipudi A, Fulde M, Riesbeck K, Bergmann S, Blom AM. 3.  2013. Streptococcus pneumoniae endopeptidase O (PepO) is a multifunctional plasminogen- and fibronectin-binding protein, facilitating evasion of innate immunity and invasion of host cells. J. Biol. Chem. 288:6849–63 [Google Scholar]
  4. Alonzo F 3rd, Kozhaya L, Rawlings SA, Reyes-Robles T, DuMont AL. 4.  et al. 2013. CCR5 is a receptor for Staphylococcus aureus leukotoxin ED. Nature 493:51–55Discovery of CCR5 as the receptor for a staphylococcal pore-forming toxin. [Google Scholar]
  5. Amulic B, Cazalet C, Hayes GL, Metzler KD, Zychlinsky A. 5.  2012. Neutrophil function: from mechanisms to disease. Annu. Rev. Immunol. 30:459–89 [Google Scholar]
  6. Anderson R, Steel HC, Cockeran R, Smith AM, von Gottberg A. 6.  et al. 2007. Clarithromycin alone and in combination with ceftriaxone inhibits the production of pneumolysin by both macrolide-susceptible and macrolide-resistant strains of Streptococcus pneumoniae. J. Antimicrob. Chemother. 59:224–29 [Google Scholar]
  7. Askariana F, van Sorge NM, Sangvika M, Beasley FC, Henriksend JR. 7.  et al. 2014. A Staphylococcus aureus TIR-domain protein virulence factor blocks TLR2-mediated NF-κB signaling. J. Innate Immun. 6485–98 [Google Scholar]
  8. Atilano ML, Yates J, Glittenberg M, Filipe SR, Ligoxygakis P. 8.  2011. Wall teichoic acids of Staphylococcus aureus limit recognition by the Drosophila peptidoglycan recognition protein-SA to promote pathogenicity. PLoS Pathog. 7:e1002421 [Google Scholar]
  9. Balaban N, Cirioni O, Giacometti A, Ghiselli R, Braunstein JB. 9.  et al. 2007. Treatment of Staphylococcus aureus biofilm infection by the quorum-sensing inhibitor RIP. Antimicrob. Agents Chemother. 51:2226–29 [Google Scholar]
  10. Beiter K, Wartha F, Albiger B, Normark S, Zychlinsky A, Henriques-Normark B. 10.  2006. An endonuclease allows Streptococcus pneumoniae to escape from neutrophil extracellular traps. Curr. Biol. 16:401–7 [Google Scholar]
  11. Bera A, Biswas R, Herbert S, Kulauzovic E, Weidenmaier C. 11.  et al. 2006. Influence of wall teichoic acid on lysozyme resistance in Staphylococcus aureus. J. Bacteriol. 189:280–83 [Google Scholar]
  12. Berends ETM, Dekkers JF, Nijland R, Kuipers A, Soppe JA. 12.  et al. 2013. Distinct localization of the complement C5b-9 complex on gram-positive bacteria. Cell Microbiol. 5:1955–68 [Google Scholar]
  13. Berends ETM, Horswill AR, Haste NM, Monestier M, Nizet V, von Köckritz-Blickwede M. 13.  2010. Nuclease expression by Staphylococcus aureus facilitates escape from neutrophil extracellular traps. J. Innate Immun. 2:576–86 [Google Scholar]
  14. Brown S, Santa Maria J, John P, Walker S. 14.  2013. Wall teichoic acids of gram-positive bacteria. Annu. Rev. Microbiol. 67:313–36 [Google Scholar]
  15. Bryan JD, Shelver DW. 15.  2009. Streptococcus agalactiae CspA is a serine protease that inactivates chemokines. J. Bacteriol. 191:1847–54 [Google Scholar]
  16. Buchanan JT, Simpson AJ, Aziz RK, Liu GY, Kristian SA. 16.  et al. 2006. DNase expression allows the pathogen group A Streptococcus to escape killing in neutrophil extracellular traps. Curr. Biol. 16:396–400 [Google Scholar]
  17. Carapetis JR, Steer AC, Mulholland EK, Weber M. 17.  2005. The global burden of group A streptococcal diseases. Lancet Infect. Dis. 5:685–94 [Google Scholar]
  18. Carlin AF, Chang Y-C, Areschoug T, Lindahl G, Hurtado-Ziola N. 18.  et al. 2009. Group B Streptococcus suppression of phagocyte functions by protein-mediated engagement of human Siglec-5. J. Exp. Med. 206:1691–99 [Google Scholar]
  19. Carlin AF, Lewis AL, Varki A, Nizet V. 19.  2007. Group B streptococcal capsular sialic acids interact with siglecs (immunoglobulin-like lectins) on human leukocytes. J. Bacteriol. 189:1231–37 [Google Scholar]
  20. Carlin AF, Uchiyama S, Chang Y-C, Lewis AL, Nizet V, Varki A. 20.  2009. Molecular mimicry of host sialylated glycans allows a bacterial pathogen to engage neutrophil Siglec-9 and dampen the innate immune response. Blood 113:3333–36 [Google Scholar]
  21. Carlsson F, Sandin C, Lindahl G. 21.  2005. Human fibrinogen bound to Streptococcus pyogenes M protein inhibits complement deposition via the classical pathway. Mol. Microbiol. 56:28–39 [Google Scholar]
  22. Cegelski L, Marshall GR, Eldridge GR, Hultgren SJ. 22.  2008. The biology and future prospects of antivirulence therapies. Nat. Rev. Microbiol. 6:17–27 [Google Scholar]
  23. Chang YC, Olson J, Beasley FC, Tung C, Zhang J. 23.  et al. 2014. Group B Streptococcus engages an inhibitory Siglec through sialic acid mimicry to blunt innate immune and inflammatory responses in vivo. PLoS Pathog. 10:e1003846 [Google Scholar]
  24. Charrel-Dennis M, Latz E, Halmen KA, Trieu-Cuot P, Fitzgerald KA. 24.  et al. 2008. TLR-independent type I interferon induction in response to an extracellular bacterial pathogen via intracellular recognition of its DNA. Cell Host Microbe 4:543–54 [Google Scholar]
  25. Cho JH. 25.  2005. Human peptidoglycan recognition protein S is an effector of neutrophil-mediated innate immunity. Blood 106:2551–58 [Google Scholar]
  26. Chow OA, von Kockritz-Blickwede M, Bright AT, Hensler ME, Zinkernagel AS. 26.  et al. 2010. Statins enhance formation of phagocyte extracellular traps. Cell Host Microbe 8:445–54 [Google Scholar]
  27. Cirioni O, Giacometti A, Ghiselli R, Dell’Acqua G, Orlando F. 27.  et al. 2006. RNAIII-inhibiting peptide significantly reduces bacterial load and enhances the effect of antibiotics in the treatment of central venous catheter–associated Staphylococcus aureus infections. J. Infect. Dis. 193:180–86 [Google Scholar]
  28. Cockeran R, Durandt C, Feldman C, Mitchell TJ, Anderson R. 28.  2002. Pneumolysin activates the synthesis and release of interleukin-8 by human neutrophils in vitro. J. Infect. Dis. 186:562–65 [Google Scholar]
  29. Cole JN, Pence MA, von Kockritz-Blickwede M, Hollands A, Gallo RL. 29.  et al. 2010. M protein and hyaluronic acid capsule are essential for in vivo selection of covRS mutations characteristic of invasive serotype M1T1 group A Streptococcus. Mbio 1:e00191–10 [Google Scholar]
  30. Collin M, Svensson MD, Sjoholm AG, Jensenius JC, Sjobring U, Olsen A. 30.  2002. EndoS and SpeB from Streptococcus pyogenes inhibit immunoglobulin-mediated opsonophagocytosis. Infect. Immun. 70:6646–51 [Google Scholar]
  31. Costa A, Gupta R, Signorino G, Malara A, Cardile F. 31.  et al. 2012. Activation of the NLRP3 inflammasome by Group B streptococci. J. Immunol. 188:1953–60 [Google Scholar]
  32. Crisostomo MI, Vollmer W, Kharat AS, Inhulsen S, Gehre F. 32.  et al. 2006. Attenuation of penicillin resistance in a peptidoglycan O-acetyl transferase mutant of Streptococcus pneumoniae. Mol. Microbiol. 61:1497–509 [Google Scholar]
  33. Datta V, Myskowski SM, Kwinn LA, Chiem DN, Varki N. 33.  et al. 2005. Mutational analysis of the group A streptococcal operon encoding streptolysin S and its virulence role in invasive infection. Mol. Microbiol. 56:681–95 [Google Scholar]
  34. Dave S, Brooks-Walter A, Pangburn MK, McDaniel LS. 34.  2001. PspC, a pneumococcal surface protein, binds human factor H. Infect. Immun. 69:3435–37 [Google Scholar]
  35. Davis KM, Nakamura S, Weiser JN. 35.  2011. Nod2 sensing of lysozyme-digested peptidoglycan promotes macrophage recruitment and clearance of S. pneumoniae colonization in mice. J. Clin. Investig. 121:3666–76S. pneumoniae prevents lysozyme recognition, evading intracellular PRR detection and activation of the inflammatory response. [Google Scholar]
  36. Derré-Bobillot A, Cortes-Perez NG, Yamamoto Y, Kharrat P, Couvé E. 36.  et al. 2013. Nuclease A (Gbs0661), an extracellular nuclease of Streptococcus agalactiae, attacks the neutrophil extracellular traps and is needed for full virulence. Mol. Microbiol. 89:518–31 [Google Scholar]
  37. DuMont AL, Yoong P, Surewaard BGJ, Benson MA, Nijland R. 37.  et al. 2013. Staphylococcus aureus elaborates leukocidin AB to mediate escape from within human neutrophils. Infect. Immun. 81:1830–41 [Google Scholar]
  38. Ermert D, Weckel A, Agarwal V, Frick IM, Björck L, Blom AM. 38.  2013. Binding of complement inhibitor C4b-binding protein to a highly virulent Streptococcus pyogenes M1 strain is mediated by protein H and enhances adhesion to and invasion of endothelial cells. J. Biol. Chem. 288:32172–83 [Google Scholar]
  39. Escaich S. 39.  2008. Antivirulence as a new antibacterial approach for chemotherapy. Curr. Opin. Chem. Biol. 12:400–8 [Google Scholar]
  40. Farshchi Andisi V, Hinojosa CA, de Jong A, Kuipers OP, Orihuela CJ, Bijlsma JJE. 40.  2012. Pneumococcal gene complex involved in resistance to extracellular oxidative stress. Infect. Immun. 80:1037–49 [Google Scholar]
  41. Gallis HA, Miller SE, Wheat RW. 41.  1976. Degradation of 14C-labeled streptococcal cell walls by egg white lysozyme and lysosomal enzymes. Infect. Immun. 13:1459–66 [Google Scholar]
  42. Gratz N, Siller M, Schaljo B, Pirzada ZA, Gattermeier I. 42.  et al. 2008. Group A Streptococcus activates type I interferon production and MyD88-dependent signaling without involvement of TLR2, TLR4, and TLR9. J. Biol. Chem. 283:19879–87 [Google Scholar]
  43. Grosz M, Kolter J, Paprotka K, Winkler A-C, Schäfer D. 43.  et al. 2014. Cytoplasmic replication of Staphylococcus aureus upon phagosomal escape triggered by phenol-soluble modulin α. Cell Microbiol. 16451–65 [Google Scholar]
  44. Gusarov I, Shatalin K, Starodubtseva M, Nudler E. 44.  2009. Endogenous nitric oxide protects bacteria against a wide spectrum of antibiotics. Science 325:1380–84Discovery of unexpected contribution of S. aureus bNOS production to oxidant defense. [Google Scholar]
  45. Hair PS, Echague CG, Sholl AM, Watkins JA, Geoghegan JA. 45.  et al. 2010. Clumping factor A interaction with complement factor I increases C3b cleavage on the bacterial surface of Staphylococcus aureus and decreases complement-mediated phagocytosis. Infect. Immun. 78:1717–27 [Google Scholar]
  46. Hakansson A, Bentley CC, Shakhnovic EA, Wessels MR. 46.  2005. Cytolysin-dependent evasion of lysosomal killing. Proc. Natl. Acad. Sci. USA 102:5192–97 [Google Scholar]
  47. Henneke P, Takeuchi O, Malley R, Lien E, Ingalls RR. 47.  et al. 2002. Cellular activation, phagocytosis, and bactericidal activity against group B streptococcus involve parallel myeloid differentiation factor 88-dependent and independent signaling pathways. J. Immunol. 169:3970–77 [Google Scholar]
  48. Hirst RA, Yesilkaya H, Clitheroe E, Rutman A, Dufty N. 48.  et al. 2002. Sensitivities of human monocytes and epithelial cells to pneumolysin are different. Infect. Immun. 70:1017–22 [Google Scholar]
  49. Holden JK, Li H, Jing Q, Kang S, Richo J. 49.  et al. 2013. Structural and biological studies on bacterial nitric oxide synthase inhibitors. Proc. Natl. Acad. Sci. USA 110:18127–31 [Google Scholar]
  50. Hollands A, Gonzalez D, Leire E, Donald C, Gallo RL. 50.  et al. 2012. A bacterial pathogen co-opts host plasmin to resist killing by cathelicidin antimicrobial peptides. J. Biol. Chem. 287:40891–97 [Google Scholar]
  51. Honda-Ogawa M, Ogawa T, Terao Y, Sumitomo T, Nakata M. 51.  et al. 2013. Cysteine proteinase from Streptococcus pyogenes enables evasion of innate immunity via degradation of complement factors. J. Biol. Chem. 288:15854–64 [Google Scholar]
  52. Hongo I, Baba T, Oishi K, Morimoto Y, Ito T, Hiramatsu K. 52.  2009. Phenol-soluble modulin α3 enhances the human neutrophil lysis mediated by Panton-Valentine leukocidin. J. Infect. Dis. 200:715–23 [Google Scholar]
  53. Hu CM, Fang RH, Copp J, Luk BT, Zhang L. 53.  2013. A biomimetic nanosponge that absorbs pore-forming toxins. Nat. Nanotechnol. 8:336–40 [Google Scholar]
  54. Hyams C, Camberlein E, Cohen JM, Bax K, Brown JS. 54.  2010. The Streptococcus pneumoniae capsule inhibits complement activity and neutrophil phagocytosis by multiple mechanisms. Infect. Immun. 78:704–15 [Google Scholar]
  55. Inoshima I, Inoshima N, Wilke GA, Powers ME, Frank KM. 55.  et al. 2011. A Staphylococcus aureus pore-forming toxin subverts the activity of ADAM10 to cause lethal infection in mice. Nat. Med. 17:1310–14 [Google Scholar]
  56. Janowiak BE. 56.  2005. Glutathione synthesis in Streptococcus agalactiae: One protein accounts for γ-glutamylcysteine synthetase and glutathione synthetase activities. J. Biol. Chem. 280:11829–39 [Google Scholar]
  57. Jarva H, Hellwage J, Jokiranta TS, Lehtinen MJ, Zipfel PF, Meri S. 57.  2004. The group B streptococcal β and pneumococcal Hic proteins are structurally related immune evasion molecules that bind the complement inhibitor factor H in an analogous fashion. J. Immunol. 172:3111–18 [Google Scholar]
  58. Jin T, Bokarewa M, Foster T, Mitchell J, Higgins J, Tarkowski A. 58.  2004. Staphylococcus aureus resists human defensins by production of staphylokinase, a novel bacterial evasion mechanism. J. Immunol. 172:1169–76 [Google Scholar]
  59. Johansson L, Thulin P, Sendi P, Hertzén E, Linder A. 59.  et al. 2008. Cathelicidin LL-37 in severe Streptococcus pyogenes soft tissue infections in humans. Infect. Immun. 76:3399–404 [Google Scholar]
  60. Jones AL, Mertz RH, Carl DJ, Rubens CE. 60.  2007. A streptococcal penicillin-binding protein is critical for resisting innate airway defenses in the neonatal lung. J. Immunol. 179:3196–202 [Google Scholar]
  61. Jongerius I, Kohl J, Pandey MK, Ruyken M, van Kessel KPM. 61.  et al. 2007. Staphylococcal complement evasion by various convertase-blocking molecules. J. Exp. Med. 204:2461–71 [Google Scholar]
  62. Jusko M, Potempa J, Kantyka T, Bielecka E, Miller HK. 62.  et al. 2014. Staphylococcal proteases aid in evasion of the human complement system. J. Innate Immun. 6:31–46 [Google Scholar]
  63. Kagawa TF, O’Connell MR, Mouat P, Paoli M, O’Toole PW, Cooney JC. 63.  2009. Model for substrate interactions in C5a peptidase from Streptococcus pyogenes: A 1.9 Å crystal structure of the active form of ScpA. J. Mol. Biol. 386:754–72 [Google Scholar]
  64. Kang M, Ko YP, Liang X, Ross CL, Liu Q. 64.  et al. 2013. Collagen-binding microbial surface components recognizing adhesive matrix molecule (MSCRAMM) of gram-positive bacteria inhibit complement activation via the classical pathway. J. Biol. Chem. 288:20520–31 [Google Scholar]
  65. Kaplan A, Ma J, Kyme P, Wolf AJ, Becker CA. 65.  et al. 2012. Failure to induce IFN-β production during Staphylococcus aureus infection contributes to pathogenicity. J. Immunol. 189:4537–45 [Google Scholar]
  66. Karavolos MH. 66.  2003. Role and regulation of the superoxide dismutases of Staphylococcus aureus. Microbiology 149:2749–58 [Google Scholar]
  67. Khodaverdian V, Pesho M, Truitt B, Bollinger L, Patel P. 67.  et al. 2013. Discovery of antivirulence agents against methicillin-resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 57:3645–52 [Google Scholar]
  68. Kim HK, Thammavongsa V, Schneewind O, Missiakas D. 68.  2012. Recurrent infections and immune evasion strategies of Staphylococcus aureus. Curr. Opin. Microbiol. 15:92–99 [Google Scholar]
  69. Knapp S, Wieland CW, van ’t Veer C, Takeuchi O, Akira S. 69.  et al. 2004. Toll-like receptor 2 plays a role in the early inflammatory response to murine pneumococcal pneumonia but does not contribute to antibacterial defense. J. Immunol. 172:3132–38 [Google Scholar]
  70. Kobayashi SD, Braughton KR, Palazzolo-Ballance AM, Kennedy AD, Sampaio E. 70.  et al. 2010. Rapid neutrophil destruction following phagocytosis of Staphylococcus aureus. J. Innate Immun. 2:560–75 [Google Scholar]
  71. Kobayashi SD, Braughton KR, Whitney AR, Voyich JM, Schwan TG. 71.  et al. 2003. Bacterial pathogens modulate an apoptosis differentiation program in human neutrophils. Proc. Natl. Acad. Sci. USA 100:10948–53 [Google Scholar]
  72. Kretschmer D, Gleske AK, Rautenberg M, Wang R, Koberle M. 72.  et al. 2010. Human formyl peptide receptor 2 senses highly pathogenic Staphylococcus aureus. Cell Host Microbe 7:463–73 [Google Scholar]
  73. Kristian SA, Datta V, Weidenmaier C, Kansal R, Fedtke I. 73.  et al. 2005. D-alanylation of teichoic acids promotes group A streptococcus antimicrobial peptide resistance, neutrophil survival, and epithelial cell invasion. J. Bacteriol. 187:6719–25 [Google Scholar]
  74. Laarman AJ, Ruyken M, Malone CL, van Strijp JAG, Horswill AR, Rooijakkers SHM. 74.  2011. Staphylococcus aureus metalloprotease aureolysin cleaves complement C3 to mediate immune evasion. J. Immunol. 186:6445–53 [Google Scholar]
  75. Lauth X, von Köckritz-Blickwede M, McNamara CW, Myskowski S, Zinkernagel AS. 75.  et al. 2009. M1 protein allows group A streptococcal survival in phagocyte extracellular traps through cathelicidin inhibition. J. Innate Immun. 1:202–14 [Google Scholar]
  76. Lee J-H, Cho HS, Kim Y, Kim J-A, Banskota S. 76.  et al. 2013. Indole and 7-benzyloxyindole attenuate the virulence of Staphylococcus aureus. Appl. Microbiol. Biotechnol. 97:4543–52 [Google Scholar]
  77. Lei B, DeLeo FR, Hoe NP, Graham MR, Mackie SM. 77.  et al. 2001. Evasion of human innate and acquired immunity by a bacterial homolog of CD11b that inhibits opsonophagocytosis. Nat. Med. 7:1298–305 [Google Scholar]
  78. Limbago B, Penumalli V, Weinrick B, Scott JR. 78.  2000. Role of streptolysin O in a mouse model of invasive group A streptococcal disease. Infect. Immun. 68:6384–90 [Google Scholar]
  79. Lin FY, Zhang Y, Hensler M, Liu YL, Chow OA. 79.  et al. 2012. Dual dehydrosqualene/squalene synthase inhibitors: leads for innate immune system-based therapeutics. ChemMedChem 7:561–64 [Google Scholar]
  80. Liu CI, Liu GY, Song Y, Yin F, Hensler ME. 80.  et al. 2008. A cholesterol biosynthesis inhibitor blocks Staphylococcus aureus virulence. Science 319:1391–94Provides approach to repositioning a human cholesterol drug to block pigment production and virulence. [Google Scholar]
  81. Liu GY, Doran KS, Lawrence T, Turkson N, Puliti M. 81.  et al. 2004. Sword and shield: linked group B streptococcal β-hemolysin/cytolysin and carotenoid pigment function to subvert host phagocyte defense. Proc. Natl. Acad. Sci. USA 101:14491–96 [Google Scholar]
  82. Liu GY, Essex A, Buchanan JT, Datta V, Hoffman HM. 82.  et al. 2005. Staphylococcus aureus golden pigment impairs neutrophil killing and promotes virulence through its antioxidant activity. J. Exp. Med. 202:209–15 [Google Scholar]
  83. Ly D, Taylor JM, Tsatsaronis JA, Monteleone MM, Skora AS. 83.  et al. 2014. Plasmin(ogen) acquisition by group A Streptococcus protects against C3b-mediated neutrophil killing. J. Innate Immun. 6:340–50 [Google Scholar]
  84. Maisey HC, Quach D, Hensler ME, Liu GY, Gallo RL. 84.  et al. 2008. A group B streptococcal pilus protein promotes phagocyte resistance and systemic virulence. FASEB J. 22:1715–24 [Google Scholar]
  85. Marques MB, Kasper DL, Pangburn MK, Wessels MR. 85.  1992. Prevention of C3 deposition by capsular polysaccharide is a virulence mechanism of type III group B streptococci. Infect. Immun. 60:3986–93 [Google Scholar]
  86. McNeela EA, Burke Á, Neill DR, Baxter C, Fernandes VE. 86.  et al. 2010. Pneumolysin activates the NLRP3 inflammasome and promotes proinflammatory cytokines independently of TLR4. PLoS Pathog. 6:e1001191 [Google Scholar]
  87. Miyoshi-Akiyama T, Takamatsu D, Koyanagi M, Zhao J, Imanishi K, Uchiyama T. 87.  2005. Cytocidal effect of Streptococcus pyogenes on mouse neutrophils in vivo and the critical role of streptolysin S. J. Infect. Dis. 192:107–16 [Google Scholar]
  88. Moreland JG, Bailey G. 88.  2006. Neutrophil transendothelial migration in vitro to Streptococcus pneumoniae is pneumolysin dependent. Am. J. Physiol. Lung Cell. Mol. Physiol. 290:L833–40 [Google Scholar]
  89. Niemann S, Kehrel BE, Heilmann C, Rennemeier C, Peters G, Hammerschmidt S. 89.  2009. Pneumococcal association to platelets is mediated by soluble fibrin and supported by thrombospondin-1. Thromb. Haemost. 102:735–42 [Google Scholar]
  90. Nishi H, Komatsuzawa H, Fujiwara T, McCallum N, Sugai M. 90.  2004. Reduced content of lysyl-phosphatidylglycerol in the cytoplasmic membrane affects susceptibility to moenomycin, as well as vancomycin, gentamicin, and antimicrobial peptides, in Staphylococcus aureus. Antimicrob. Agents Chemother. 48:4800–7 [Google Scholar]
  91. Nordenfelt P, Grinstein S, Björck L, Tapper H. 91.  2012. V-ATPase-mediated phagosomal acidification is impaired by Streptococcus pyogenes through Mga-regulated surface proteins. Microb. Infect. 14:1319–29 [Google Scholar]
  92. Nordenfelt P, Waldemarson S, Linder A, Morgelin M, Karlsson C. 92.  et al. 2012. Antibody orientation at bacterial surfaces is related to invasive infection. J. Exp. Med. 209:2367–81 [Google Scholar]
  93. O’Brien KL, Wolfson LJ, Watt JP, Henkle E, Deloria-Knoll M. 93.  et al. 2009. Burden of disease caused by Streptococcus pneumoniae in children younger than 5 years: global estimates. Lancet 374:893–902 [Google Scholar]
  94. Okumura CYM, Anderson EL, Dohrmann S, Tran DN, Olson J. 94.  et al. 2013. IgG protease Mac/IdeS is not essential for phagocyte resistance or mouse virulence of M1T1 group A Streptococcus. Mbio 4:e00499–13-e99-13 [Google Scholar]
  95. O’Seaghdha M, Wessels MR. 95.  2013. Streptolysin O and its co-toxin NAD-glycohydrolase protect group A Streptococcus from xenophagic killing. PLoS Pathog. 9:e1003394 [Google Scholar]
  96. Pandiripally V, Gregory E, Cue D. 96.  2002. Acquisition of regulators of complement activation by Streptococcus pyogenes serotype M1. Infect. Immun. 70:6206–14 [Google Scholar]
  97. Pence MA, Rooijakkers SHM, Cogen AL, Cole JN, Hollands A. 97.  et al. 2010. Streptococcal inhibitor of complement promotes innate immune resistance phenotypes of invasive M1T1 group A Streptococcus. J. Innate Immun. 2:587–95 [Google Scholar]
  98. Persson H, Vindebro R, von Pawel-Rammingen U. 98.  2013. The streptococcal cysteine protease SpeB is not a natural immunoglobulin-cleaving enzyme. Infect. Immun. 81:2236–41 [Google Scholar]
  99. Peschel A. 99.  1999. Inactivation of the dlt operon in Staphylococcus aureus confers sensitivity to defensins, protegrins, and other antimicrobial peptides. J. Biol. Chem. 274:8405–10 [Google Scholar]
  100. Poyart C, Pellegrini E, Marceau M, Baptista M, Jaubert F. 100.  et al. 2003. Attenuated virulence of Streptococcus agalactiae deficient in d-alanyl-lipoteichoic acid is due to an increased susceptibility to defensins and phagocytic cells. Mol. Microbiol. 49:1615–25 [Google Scholar]
  101. Prat C, Bestebroer J, de Haas CJ, van Strijp JA, van Kessel KP. 101.  2006. A new staphylococcal anti-inflammatory protein that antagonizes the formyl peptide receptor-like 1. J. Immunol. 177:8017–26 [Google Scholar]
  102. Prokesova L, Potuznikova B, Potempa J, Zikan J, Radl J. 102.  et al. 1992. Cleavage of human immunoglobulins by serine proteinase from Staphylococcus aureus. Immunol. Lett. 31:259–65 [Google Scholar]
  103. Ragle BE, Bubeck Wardenburg J. 103.  2009. Anti-alpha-hemolysin monoclonal antibodies mediate protection against Staphylococcus aureus pneumonia. Infect. Immun. 77:2712–18 [Google Scholar]
  104. Ragle BE, Karginov VA, Bubeck Wardenburg J. 104.  2010. Prevention and treatment of Staphylococcus aureus pneumonia with a β-cyclodextrin derivative. Antimicrob. Agents Chemother. 54:298–304 [Google Scholar]
  105. Ray A, Cot M, Puzo G, Gilleron M, Nigou J. 105.  2013. Bacterial cell wall macroamphiphiles: pathogen-/microbe-associated molecular patterns detected by mammalian innate immune system. Biochimie 95:33–42 [Google Scholar]
  106. Rooijakkers SH, Ruyken M, Roos A, Daha MR, Presanis JS. 106.  et al. 2005. Immune evasion by a staphylococcal complement inhibitor that acts on C3 convertases. Nat. Immunol. 6:920–27Staphylococcal virulence factor cripples a key step in complement activation. [Google Scholar]
  107. Rooijakkers SHM, van Strijp JAG. 107.  2007. Bacterial complement evasion. Mol. Immunol. 44:23–32 [Google Scholar]
  108. Rooijakkers SHM, van Wamel WJB, Ruyken M, van Kessel KPM, van Strijp JAG. 108.  2005. Anti-opsonic properties of staphylokinase. Microb. Infect. 7:476–84 [Google Scholar]
  109. Rosch JW, Boyd AR, Hinojosa E, Pestina T, Hu Y. 109.  et al. 2010. Statins protect against fulminant pneumococcal infection and cytolysin toxicity in a mouse model of sickle cell disease. J. Clin. Investig. 120:627–35 [Google Scholar]
  110. Saar-Dover R, Bitler A, Nezer R, Shmuel-Galia L, Firon A. 110.  et al. 2012. D-Alanylation of lipoteichoic acids confers resistance to cationic peptides in group B Streptococcus by increasing the cell wall density. PLoS Pathog. 8:e1002891 [Google Scholar]
  111. Sakoulas G, Okumura CY, Thienphrapa W, Olson J, Nonejuie P. 111.  et al. 2014. Nafcillin enhances innate immune-mediated killing of methicillin-resistant Staphylococcus aureus. J. Mol. Med. 92:139–49 [Google Scholar]
  112. Saleh M, Bartual SG, Abdullah MR. 112.  2013. Molecular architecture of Streptococcus pneumoniae surface thioredoxin-fold lipoproteins crucial for extracellular oxidative stress resistance and maintenance of virulence. EMBO Mol. Med. 12:1852–70 [Google Scholar]
  113. Shimada T, Park BG, Wolf AJ, Brikos C, Goodridge HS. 113.  et al. 2010. Staphylococcus aureus evades lysozyme-based peptidoglycan digestion that links phagocytosis, inflammasome activation, and IL-1β secretion. Cell Host Microbe 7:38–49Describes how S. aureus prevents lysozyme recognition to evade detection by intracellular PRRs and activation of the inflammatory response. [Google Scholar]
  114. Sieprawska-Lupa M, Mydel P, Krawczyk K, Wojcik K, Puklo M. 114.  et al. 2004. Degradation of human antimicrobial peptide LL-37 by Staphylococcus aureus-derived proteinases. Antimicrob. Agents Chemother. 48:4673–79 [Google Scholar]
  115. Sjögren J, Okumura CYM, Collin M, Nizet V, Hollands A. 115.  2011. Study of the IgG endoglycosidase EndoS in group A streptococcal phagocyte resistance and virulence. BMC Microbiol. 11:120 [Google Scholar]
  116. Staali L, Bauer S, Mörgelin M, Björck L, Tapper H. 116.  2006. Streptococcus pyogenes bacteria modulate membrane traffic in human neutrophils and selectively inhibit azurophilic granule fusion with phagosomes. Cell Microbiol. 8:690–703 [Google Scholar]
  117. Stafslien DK, Cleary PP. 117.  2000. Characterization of the streptococcal C5a peptidase using a C5a-green fluorescent protein fusion protein substrate. J. Bacteriol. 182:3254–58 [Google Scholar]
  118. Standish AJ, Weiser JN. 118.  2009. Human neutrophils kill Streptococcus pneumoniae via serine proteases. J. Immunol. 183:2602–9 [Google Scholar]
  119. Stemerding AM, Kohl J, Pandey MK, Kuipers A, Leusen JH. 119.  et al. 2013. Staphylococcus aureus formyl peptide receptor-like 1 inhibitor (FLIPr) and its homologue FLIPr-like are potent FcR antagonists that inhibit IgG-mediated effector functions. J. Immunol. 191:353–62 [Google Scholar]
  120. Sumby P, Barbian KD, Gardner DJ, Whitney AR, Welty DM. 120.  et al. 2005. Extracellular deoxyribonuclease made by group A Streptococcus assists pathogenesis by enhancing evasion of the innate immune response. Proc. Natl. Acad. Sci. USA 102:1679–84 [Google Scholar]
  121. Timmer AM, Timmer JC, Pence MA, Hsu LC, Ghochani M. 121.  et al. 2009. Streptolysin O promotes group A Streptococcus immune evasion by accelerated macrophage apoptosis. J. Biol. Chem. 284:862–71 [Google Scholar]
  122. Tsou CC, Chiang-Ni C, Lin YS, Chuang WJ, Lin MT. 122.  et al. 2008. An iron-binding protein, Dpr, decreases hydrogen peroxide stress and protects Streptococcus pyogenes against multiple stresses. Infect. Immun. 76:4038–45 [Google Scholar]
  123. Uchiyama S, Andreoni F, Schuepbach RA, Nizet V, Zinkernagel AS. 123.  2012. DNase Sda1 allows invasive M1T1 group A Streptococcus to prevent TLR9-dependent recognition. PLoS Pathog. 8:e1002736 [Google Scholar]
  124. Uhlemann AC, Otto M, Lowy FD, DeLeo FR. 124.  2013. Evolution of community- and healthcare-associated methicillin-resistant Staphylococcus aureus. Infect. Genet. Evol. 21:563–74 [Google Scholar]
  125. van Sorge NM, Beasley FC, Gusarov I, Gonzalez DJ, von Köckritz-Blickwede M. 125.  et al. 2013. Methicillin-resistant Staphylococcus aureus bacterial nitric-oxide synthase affects antibiotic sensitivity and skin abscess development. J. Biol. Chem. 288:6417–26 [Google Scholar]
  126. Verani JR, Schrag SJ. 126.  2010. Group B streptococcal disease in infants: progress in prevention and continued challenges. Clin. Perinatol. 37:375–92 [Google Scholar]
  127. Vollmer W. 127.  2000. The pgdA gene encodes for a peptidoglycan N-acetylglucosamine deacetylase in Streptococcus pneumoniae. J. Biol. Chem. 275:20496–501 [Google Scholar]
  128. von Köckritz-Blickwede M, Nizet V. 128.  2009. Innate immunity turned inside-out: antimicrobial defense by phagocyte extracellular traps. J. Mol. Med. 87:775–83 [Google Scholar]
  129. Walker MJ, Hollands A, Sanderson-Smith ML, Cole JN, Kirk JK. 129.  et al. 2007. DNase Sda1 provides selection pressure for a switch to invasive group A streptococcal infection. Nat. Med. 13:981–85 [Google Scholar]
  130. Wang R, Braughton KR, Kretschmer D, Bach TH, Queck SY. 130.  et al. 2007. Identification of novel cytolytic peptides as key virulence determinants for community-associated MRSA. Nat. Med. 13:1510–14Members of the phenol-soluble modulin family are recognized as key MRSA virulence determinants. [Google Scholar]
  131. Wiles KG, Panizzi P, Kroh HK, Bock PE. 131.  2010. Skizzle is a novel plasminogen- and plasmin-binding protein from Streptococcus agalactiae that targets proteins of human fibrinolysis to promote plasmin generation. J. Biol. Chem. 285:21153–64 [Google Scholar]
  132. Winterbourn CC, Kettle AJ. 132.  2013. Redox reactions and microbial killing in the neutrophil phagosome. Antioxid. Redox Signal. 18:642–60 [Google Scholar]
  133. Yamaguchi M, Terao Y, Mori Y, Hamada S, Kawabata S. 133.  2008. PfbA, a novel plasmin- and fibronectin-binding protein of Streptococcus pneumoniae, contributes to fibronectin-dependent adhesion and antiphagocytosis. J. Biol. Chem. 283:36272–79 [Google Scholar]
  134. Yesilkaya H, Andisi VF, Andrew PW, Bijlsma JJE. 134.  2013. Streptococcus pneumoniae and reactive oxygen species: an unusual approach to living with radicals. Trends Microbiol. 21:187–95 [Google Scholar]
  135. Yesilkaya H, Kadioglu A, Gingles N, Alexander JE, Mitchell TJ, Andrew PW. 135.  2000. Role of manganese-containing superoxide dismutase in oxidative stress and virulence of Streptococcus pneumoniae. Infect. Immun. 68:2819–26 [Google Scholar]
  136. Zinkernagel AS, Hruz P, Uchiyama S, von Köckritz-Blickwede M, Schuepbach RA. 136.  et al. 2012. Importance of toll-like receptor 9 in host defense against M1T1 group A Streptococcus infections. J. Innate Immun. 4:213–18 [Google Scholar]
  137. Zinkernagel AS, Timmer AM, Pence MA, Locke JB, Buchanan JT. 137.  et al. 2008. The IL-8 protease SpyCEP/ScpC of group A Streptococcus promotes resistance to neutrophil killing. Cell Host Microbe 4:170–78 [Google Scholar]
  138. Zysk G, Bejo L, Schneider-Wald BK, Nau R, Heinz H. 138.  2000. Induction of necrosis and apoptosis of neutrophil granulocytes by Streptococcus pneumoniae. Clin. Exp. Immunol. 122:61–66 [Google Scholar]

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error