#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Leukocidin A/B (LukAB) Kills Human Monocytes via Host NLRP3 and ASC when Extracellular, but Not Intracellular


Staphylococcus aureus infections are becoming increasingly common, aggressive, and difficult to manage clinically. S. aureus produces a number of pore-forming toxins that target and kill immune cells. In this study, we demonstrate that LukAB is primarily responsible for S. aureus-mediated targeting and killing of human monocytes. We show that the NLRP3-ASC inflammasome, a sensor of cell membrane damage and trigger of inflammation, is critical for this response. S. aureus uses LukAB to kill immune cells both through external interactions (LukAB on the cell surface) and through internal interactions (LukAB secretion after S. aureus is engulfed by the immune cell). Interestingly, we show that the mechanism by which LukAB kills immune cells in these two settings differs. This is the first report of a S. aureus toxin manipulating unique immune signaling pathways depending on the cellular site of contact. Understanding the multitude of ways by which S. aureus evades the immune response is critical for our ability to treat infections with this pathogen.


Vyšlo v časopise: Leukocidin A/B (LukAB) Kills Human Monocytes via Host NLRP3 and ASC when Extracellular, but Not Intracellular. PLoS Pathog 11(6): e32767. doi:10.1371/journal.ppat.1004970
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004970

Souhrn

Staphylococcus aureus infections are becoming increasingly common, aggressive, and difficult to manage clinically. S. aureus produces a number of pore-forming toxins that target and kill immune cells. In this study, we demonstrate that LukAB is primarily responsible for S. aureus-mediated targeting and killing of human monocytes. We show that the NLRP3-ASC inflammasome, a sensor of cell membrane damage and trigger of inflammation, is critical for this response. S. aureus uses LukAB to kill immune cells both through external interactions (LukAB on the cell surface) and through internal interactions (LukAB secretion after S. aureus is engulfed by the immune cell). Interestingly, we show that the mechanism by which LukAB kills immune cells in these two settings differs. This is the first report of a S. aureus toxin manipulating unique immune signaling pathways depending on the cellular site of contact. Understanding the multitude of ways by which S. aureus evades the immune response is critical for our ability to treat infections with this pathogen.


Zdroje

1. Klevens RM, Morrison MA, Nadle J, Petit S, Gershman K, et al. (2007) Invasive methicillin-resistant Staphylococcus aureus infections in the United States. JAMA 298: 1763–1771. 17940231

2. Alonzo F 3rd, Torres VJ (2014) The Bicomponent Pore-Forming Leucocidins of Staphylococcus aureus. Microbiol Mol Biol Rev 78: 199–230. doi: 10.1128/MMBR.00055-13 24847020

3. DuMont AL, Torres VJ (2014) Cell targeting by the Staphylococcus aureus pore-forming toxins: it's not just about lipids. Trends Microbiol 22: 21–27. doi: 10.1016/j.tim.2013.10.004 24231517

4. Bramley AJ, Patel AH, O'Reilly M, Foster R, Foster TJ (1989) Roles of alpha-toxin and beta-toxin in virulence of Staphylococcus aureus for the mouse mammary gland. Infect Immun 57: 2489–2494. 2744856

5. Bubeck Wardenburg J, Bae T, Otto M, Deleo FR, Schneewind O (2007) Poring over pores: alpha-hemolysin and Panton-Valentine leukocidin in Staphylococcus aureus pneumonia. Nat Med 13: 1405–1406. 18064027

6. Bubeck Wardenburg J, Patel RJ, Schneewind O (2007) Surface proteins and exotoxins are required for the pathogenesis of Staphylococcus aureus pneumonia. Infect Immun 75: 1040–1044. 17101657

7. Girgis DO, Sloop GD, Reed JM, O'Callaghan RJ (2005) Effects of toxin production in a murine model of Staphylococcus aureus keratitis. Invest Ophthalmol Vis Sci 46: 2064–2070. 15914624

8. Kennedy AD, Bubeck Wardenburg J, Gardner DJ, Long D, Whitney AR, et al. (2010) Targeting of alpha-hemolysin by active or passive immunization decreases severity of USA300 skin infection in a mouse model. J Infect Dis 202: 1050–1058. doi: 10.1086/656043 20726702

9. Rauch S, DeDent AC, Kim HK, Bubeck Wardenburg J, Missiakas DM, et al. (2012) Abscess formation and alpha-hemolysin induced toxicity in a mouse model of Staphylococcus aureus peritoneal infection. Infect Immun 80: 3721–3732. doi: 10.1128/IAI.00442-12 22802349

10. Bubeck Wardenburg J, Palazzolo-Ballance AM, Otto M, Schneewind O, DeLeo FR (2008) Panton-Valentine leukocidin is not a virulence determinant in murine models of community-associated methicillin-resistant Staphylococcus aureus disease. J Infect Dis 198: 1166–1170. doi: 10.1086/592053 18729780

11. Labandeira-Rey M, Couzon F, Boisset S, Brown EL, Bes M, et al. (2007) Staphylococcus aureus Panton-Valentine leukocidin causes necrotizing pneumonia. Science 315: 1130–1133. 17234914

12. Tseng CW, Kyme P, Low J, Rocha MA, Alsabeh R, et al. (2009) Staphylococcus aureus Panton-Valentine leukocidin contributes to inflammation and muscle tissue injury. PLoS One 4: e6387. doi: 10.1371/journal.pone.0006387 19633710

13. Zaidi T, Zaidi T, Yoong P, Pier GB (2013) Staphylococcus aureus corneal infections: effect of the Panton-Valentine leukocidin (PVL) and antibody to PVL on virulence and pathology. Invest Ophthalmol Vis Sci 54: 4430–4438. doi: 10.1167/iovs.13-11701 23737477

14. Cremieux AC, Dumitrescu O, Lina G, Vallee C, Cote JF, et al. (2009) Panton-valentine leukocidin enhances the severity of community-associated methicillin-resistant Staphylococcus aureus rabbit osteomyelitis. PLoS One 4: e7204. doi: 10.1371/journal.pone.0007204 19779608

15. Lipinska U, Hermans K, Meulemans L, Dumitrescu O, Badiou C, et al. (2011) Panton-Valentine leukocidin does play a role in the early stage of Staphylococcus aureus skin infections: a rabbit model. PLoS One 6: e22864. doi: 10.1371/journal.pone.0022864 21850240

16. Diep BA, Palazzolo-Ballance AM, Tattevin P, Basuino L, Braughton KR, et al. (2008) Contribution of Panton-Valentine leukocidin in community-associated methicillin-resistant Staphylococcus aureus pathogenesis. PLoS One 3: e3198. doi: 10.1371/journal.pone.0003198 18787708

17. Diep BA, Chan L, Tattevin P, Kajikawa O, Martin TR, et al. (2010) Polymorphonuclear leukocytes mediate Staphylococcus aureus Panton-Valentine leukocidin-induced lung inflammation and injury. Proc Natl Acad Sci U S A 107: 5587–5592. doi: 10.1073/pnas.0912403107 20231457

18. Loffler B, Hussain M, Grundmeier M, Bruck M, Holzinger D, et al. (2010) Staphylococcus aureus panton-valentine leukocidin is a very potent cytotoxic factor for human neutrophils. PLoS Pathog 6: e1000715. doi: 10.1371/journal.ppat.1000715 20072612

19. Spaan AN, Henry T, van Rooijen WJ, Perret M, Badiou C, et al. (2013) The staphylococcal toxin panton-valentine leukocidin targets human c5a receptors. Cell Host Microbe 13: 584–594. doi: 10.1016/j.chom.2013.04.006 23684309

20. DuMont AL, Nygaard TK, Watkins RL, Smith A, Kozhaya L, et al. (2011) Characterization of a new cytotoxin that contributes to Staphylococcus aureus pathogenesis. Mol Microbiol 79: 814–825. doi: 10.1111/j.1365-2958.2010.07490.x 21255120

21. Ventura CL, Malachowa N, Hammer CH, Nardone GA, Robinson MA, et al. (2010) Identification of a novel Staphylococcus aureus two-component leukotoxin using cell surface proteomics. PLoS One 5: e11634. doi: 10.1371/journal.pone.0011634 20661294

22. DuMont AL, Yoong P, Day CJ, Alonzo F 3rd, McDonald WH, et al. (2013) Staphylococcus aureus LukAB cytotoxin kills human neutrophils by targeting the CD11b subunit of the integrin Mac-1. Proc Natl Acad Sci U S A 110: 10794–10799. doi: 10.1073/pnas.1305121110 23754403

23. Malachowa N, Kobayashi SD, Braughton KR, Whitney AR, Parnell MJ, et al. (2012) Staphylococcus aureus Leukotoxin GH Promotes Inflammation. J Infect Dis 206: 1185–1193. 22872735

24. DuMont AL, Yoong P, Liu X, Day CJ, Chumbler NM, et al. (2014) Identification of a crucial residue required for Staphylococcus aureus LukAB cytotoxicity and receptor recognition. Infect Immun 82: 1268–1276. doi: 10.1128/IAI.01444-13 24379286

25. DuMont AL, Yoong P, Surewaard BG, Benson MA, Nijland R, et al. (2013) Staphylococcus aureus elaborates leukocidin AB to mediate escape from within human neutrophils. Infect Immun 81: 1830–1841. doi: 10.1128/IAI.00095-13 23509138

26. Kebaier C, Chamberland RR, Allen IC, Gao X, Broglie PM, et al. (2012) Staphylococcus aureus alpha-hemolysin mediates virulence in a murine model of severe pneumonia through activation of the NLRP3 inflammasome. J Infect Dis 205: 807–817. doi: 10.1093/infdis/jir846 22279123

27. Davis B, Wen H, Ting J (2011) The inflammasome NLRs in immunity, inflammation, and associated diseases. Annual review of immunology 29: 707–735. doi: 10.1146/annurev-immunol-031210-101405 21219188

28. Craven R, Gao X, Allen I, Gris D, Bubeck Wardenburg J, et al. (2009) Staphylococcus aureus alpha-hemolysin activates the NLRP3-inflammasome in human and mouse monocytic cells. PloS one 4.

29. Holzinger D, Gieldon L, Mysore V, Nippe N, Taxman D, et al. (2012) Staphylococcus aureus Panton-Valentine leukocidin induces an inflammatory response in human phagocytes via the NLRP3 inflammasome. Journal of leukocyte biology 92: 1069–1081. doi: 10.1189/jlb.0112014 22892107

30. Mariathasan S, Weiss DS, Newton K, McBride J, O'Rourke K, et al. (2006) Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 440: 228–232. 16407890

31. Hanamsagar R, Torres V, Kielian T (2011) Inflammasome activation and IL-1beta/IL-18 processing are influenced by distinct pathways in microglia. J Neurochem 119: 736–748. doi: 10.1111/j.1471-4159.2011.07481.x 21913925

32. Cho JS, Guo Y, Ramos RI, Hebroni F, Plaisier SB, et al. (2012) Neutrophil-derived IL-1beta is sufficient for abscess formation in immunity against Staphylococcus aureus in mice. PLoS Pathog 8: e1003047. doi: 10.1371/journal.ppat.1003047 23209417

33. Confalonieri M, Annane D, Antonaglia C, Santagiuliana M, Borriello EM, et al. (2013) Is prolonged low-dose glucocorticoid treatment beneficial in community-acquired pneumonia? Curr Infect Dis Rep 15: 158–166. doi: 10.1007/s11908-013-0322-8 23371407

34. Willingham SB, Bergstralh DT, O'Connor W, Morrison AC, Taxman DJ, et al. (2007) Microbial pathogen-induced necrotic cell death mediated by the inflammasome components CIAS1/cryopyrin/NLRP3 and ASC. Cell Host Microbe 2: 147–159. 18005730

35. Martinon F, Burns K, Tschopp J (2002) The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell 10: 417–426. 12191486

36. Duthie ES, Lorenz LL (1952) Staphylococcal coagulase; mode of action and antigenicity. J Gen Microbiol 6: 95–107. 14927856

37. Munoz-Planillo R, Franchi L, Miller LS, Nunez G (2009) A critical role for hemolysins and bacterial lipoproteins in Staphylococcus aureus-induced activation of the Nlrp3 inflammasome. J Immunol 183: 3942–3948. doi: 10.4049/jimmunol.0900729 19717510

38. Duprez L, Wirawan E, Vanden Berghe T, Vandenabeele P (2009) Major cell death pathways at a glance. Microbes Infect 11: 1050–1062. doi: 10.1016/j.micinf.2009.08.013 19733681

39. Edinger AL, Thompson CB (2004) Death by design: apoptosis, necrosis and autophagy. Curr Opin Cell Biol 16: 663–669. 15530778

40. Bergsbaken T, Fink SL, Cookson BT (2009) Pyroptosis: host cell death and inflammation. Nat Rev Microbiol 7: 99–109. doi: 10.1038/nrmicro2070 19148178

41. Scaffidi P, Misteli T, Bianchi ME (2002) Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 418: 191–195. 12110890

42. Bedner E, Smolewski P, Amstad P, Darzynkiewicz Z (2000) Activation of caspases measured in situ by binding of fluorochrome-labeled inhibitors of caspases (FLICA): correlation with DNA fragmentation. Exp Cell Res 259: 308–313. 10942603

43. Munoz-Planillo R, Kuffa P, Martinez-Colon G, Smith BL, Rajendiran TM, et al. (2013) K(+) efflux is the common trigger of NLRP3 inflammasome activation by bacterial toxins and particulate matter. Immunity 38: 1142–1153. doi: 10.1016/j.immuni.2013.05.016 23809161

44. Warny M, Kelly CP (1999) Monocytic cell necrosis is mediated by potassium depletion and caspase-like proteases. Am J Physiol 276: C717–724. 10070000

45. Wannamaker W, Davies R, Namchuk M, Pollard J, Ford P, et al. (2007) (S)-1-((S)-2-{[1-(4-amino-3-chloro-phenyl)-methanoyl]-amino}-3,3-dimethyl-butanoy l)-pyrrolidine-2-carboxylic acid ((2R,3S)-2-ethoxy-5-oxo-tetrahydro-furan-3-yl)-amide (VX-765), an orally available selective interleukin (IL)-converting enzyme/caspase-1 inhibitor, exhibits potent anti-inflammatory activities by inhibiting the release of IL-1beta and IL-18. J Pharmacol Exp Ther 321: 509–516. 17289835

46. Thornberry NA, Bull HG, Calaycay JR, Chapman KT, Howard AD, et al. (1992) A novel heterodimeric cysteine protease is required for interleukin-1 beta processing in monocytes. Nature 356: 768–774. 1574116

47. Schindler CA, Schuhardt VT (1964) Lysostaphin: A New Bacteriolytic Agent for the Staphylococcus. Proc Natl Acad Sci U S A 51: 414–421. 14171453

48. Thomsen IP, Dumont AL, James DB, Yoong P, Saville BR, et al. (2014) Children with invasive Staphylococcus aureus disease exhibit a potently neutralizing antibody response to the cytotoxin LukAB. Infect Immun 82: 1234–1242. doi: 10.1128/IAI.01558-13 24379282

49. Yazdi AS, Drexler SK, Tschopp J (2010) The role of the inflammasome in nonmyeloid cells. J Clin Immunol 30: 623–627. doi: 10.1007/s10875-010-9437-y 20582456

50. Gross O, Thomas CJ, Guarda G, Tschopp J (2011) The inflammasome: an integrated view. Immunol Rev 243: 136–151. doi: 10.1111/j.1600-065X.2011.01046.x 21884173

51. Spaan AN, Surewaard BG, Nijland R, van Strijp JA (2013) Neutrophils Versus Staphylococcus aureus: A Biological Tug of War. Annu Rev Microbiol.

52. Bakele M, Joos M, Burdi S, Allgaier N, Poschel S, et al. (2014) Localization and functionality of the inflammasome in neutrophils. J Biol Chem 289: 5320–5329. doi: 10.1074/jbc.M113.505636 24398679

53. Mankan AK, Dau T, Jenne D, Hornung V (2012) The NLRP3/ASC/Caspase-1 axis regulates IL-1beta processing in neutrophils. Eur J Immunol 42: 710–715. doi: 10.1002/eji.201141921 22213227

54. Karmakar M, Katsnelson M, Malak HA, Greene NG, Howell SJ, et al. (2015) Neutrophil IL-1beta processing induced by pneumolysin is mediated by the NLRP3/ASC inflammasome and caspase-1 activation and is dependent on K+ efflux. J Immunol 194: 1763–1775. doi: 10.4049/jimmunol.1401624 25609842

55. Motani K, Kushiyama H, Imamura R, Kinoshita T, Nishiuchi T, et al. (2011) Caspase-1 protein induces apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC)-mediated necrosis independently of its catalytic activity. J Biol Chem 286: 33963–33972. doi: 10.1074/jbc.M111.286823 21832064

56. Feng Q, Li P, Leung PC, Auersperg N (2004) Caspase-1zeta, a new splice variant of the caspase-1 gene. Genomics 84: 587–591. 15498465

57. Badarau A, Rouha H, Malafa S, Logan DT, Hakansson M, et al. (2015) Structure-function analysis of heterodimer formation, oligomerization, and receptor binding of the Staphylococcus aureus bi-component toxin LukGH. J Biol Chem 290: 142–156. doi: 10.1074/jbc.M114.598110 25371205

58. Hamon MA, Cossart P (2011) K+ efflux is required for histone H3 dephosphorylation by Listeria monocytogenes listeriolysin O and other pore-forming toxins. Infect Immun 79: 2839–2846. doi: 10.1128/IAI.01243-10 21482680

59. Sauer JD, Witte CE, Zemansky J, Hanson B, Lauer P, et al. (2010) Listeria monocytogenes triggers AIM2-mediated pyroptosis upon infrequent bacteriolysis in the macrophage cytosol. Cell Host Microbe 7: 412–419. doi: 10.1016/j.chom.2010.04.004 20417169

60. Sokolovska A, Becker CE, Ip WK, Rathinam VA, Brudner M, et al. (2013) Activation of caspase-1 by the NLRP3 inflammasome regulates the NADPH oxidase NOX2 to control phagosome function. Nat Immunol 14: 543–553. doi: 10.1038/ni.2595 23644505

61. Reyes-Robles T, Alonzo F 3rd, Kozhaya L, Lacy DB, Unutmaz D, et al. (2013) Staphylococcus aureus leukotoxin ED targets the chemokine receptors CXCR1 and CXCR2 to kill leukocytes and promote infection. Cell Host Microbe 14: 453–459. doi: 10.1016/j.chom.2013.09.005 24139401

62. Benson MA, Lilo S, Nygaard T, Voyich JM, Torres VJ (2012) Rot and SaeRS cooperate to activate expression of the staphylococcal superantigen-like exoproteins. J Bacteriol 194: 4355–4365. doi: 10.1128/JB.00706-12 22685286

63. Gillaspy AF, Hickmon SG, Skinner RA, Thomas JR, Nelson CL, et al. (1995) Role of the accessory gene regulator (agr) in pathogenesis of staphylococcal osteomyelitis. Infect Immun 63: 3373–3380. 7642265

64. Centers for Disease C, Prevention (1999) Four pediatric deaths from community-acquired methicillin-resistant Staphylococcus aureus—Minnesota and North Dakota, 1997–1999. MMWR Morb Mortal Wkly Rep 48: 707–710. 21033181

65. Supersac G, Piemont Y, Kubina M, Prevost G, Foster TJ (1998) Assessment of the role of gamma-toxin in experimental endophthalmitis using a hlg-deficient mutant of Staphylococcus aureus. Microb Pathog 24: 241–251. 9533895

66. Benson MA, Ohneck EA, Ryan C, Alonzo F 3rd, Smith H, et al. (2014) Evolution of hypervirulence by a MRSA clone through acquisition of a transposable element. Mol Microbiol 93: 664–681. doi: 10.1111/mmi.12682 24962815

67. Diep BA, Gill SR, Chang RF, Phan TH, Chen JH, et al. (2006) Complete genome sequence of USA300, an epidemic clone of community-acquired meticillin-resistant Staphylococcus aureus. Lancet 367: 731–739. 16517273

Štítky
Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

Článok vyšiel v časopise

PLOS Pathogens


2015 Číslo 6
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Získaná hemofilie - Povědomí o nemoci a její diagnostika
nový kurz

Eozinofilní granulomatóza s polyangiitidou
Autori: doc. MUDr. Martina Doubková, Ph.D.

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa

#ADS_BOTTOM_SCRIPTS#