Meningococcal invasive isolates of the ST-11 clonal complex are most frequently associated with disease and rarely found in carriers. Unlike carriage isolates, invasive isolates induce apoptosis in epithelial cells through the TNF-α signaling pathway. While invasive and non-invasive isolates are both able to trigger the TLR4/MyD88 pathway in lipooligosaccharide (LOS)-dependant manner, we show that only non-invasive isolates were able to induce sustained NF-κB activity in infected epithelial cells. ST-11 invasive isolates initially triggered a strong NF-κB activity in infected epithelial cells that was abolished after 9h of infection and was associated with sustained activation of JNK, increased levels of membrane TNFR1, and induction of apoptosis. In contrast, infection with carriage isolates lead to prolonged activation of NF-κB that was associated with a transient activation of JNK increased TACE/ADAM17-mediated shedding of TNFR1 and protection against apoptosis. Our data provide insights to understand the meningococcal duality between invasiveness and asymptomatic carriage.
References
[1]
Peltola H (1983) Meningococcal disease: still with us. Rev Infect Dis 5: 71–91.
[2]
Schuchat A, Robinson K, Wenger JD, Harrison LH, Farley M, et al. (1997) Bacterial meningitis in the United States in 1995. Active Surveillance Team. N Engl J Med 337: 970–976.
[3]
van Deuren M, Brandtzaeg P, van der Meer JW (2000) Update on meningococcal disease with emphasis on pathogenesis and clinical management. Clin Microbiol Rev. 13. : 144–166. table of contents.
[4]
Cartwright KA, Stuart JM, Jones DM, Noah ND (1987) The Stonehouse survey: nasopharyngeal carriage of meningococci and Neisseria lactamica. Epidemiol Infect 99: 591–601.
[5]
Orr HJ, Gray SJ, Macdonald M, Stuart JM (2003) Saliva and meningococcal transmission. Emerg Infect Dis 9: 1314–1315.
[6]
Goldschneider I, Gotschlich EC, Artenstein MS (1969) Human immunity to the meningococcus. II. Development of natural immunity. J Exp Med 129: 1327–1348.
[7]
Densen P (1989) Interaction of complement with Neisseria meningitidis and Neisseria gonorrhoeae. Clin Microbiol Rev 2: SupplS11–17.
[8]
Emonts M, Hazelzet JA, de Groot R, Hermans PW (2003) Host genetic determinants of Neisseria meningitidis infections. Lancet Infect Dis 3: 565–577.
[9]
Maiden MC, Bygraves JA, Feil E, Morelli G, Russell JE, et al. (1998) Multilocus sequence typing: a portable approach to the identification of clones within populations of pathogenic microorganisms. Proc Natl Acad Sci U S A 95: 3140–3145.
[10]
Caugant DA (1998) Population genetics and molecular epidemiology of Neisseria meningitidis. Apmis 106: 505–525.
[11]
Yazdankhah SP, Kriz P, Tzanakaki G, Kremastinou J, Kalmusova J, et al. (2004) Distribution of serogroups and genotypes among disease-associated and carried isolates of Neisseria meningitidis from the Czech Republic, Greece, and Norway. J Clin Microbiol 42: 5146–5153.
[12]
Jolley KA, Kalmusova J, Feil EJ, Gupta S, Musilek M, et al. (2000) Carried meningococci in the Czech Republic: a diverse recombining population. J Clin Microbiol 38: 4492–4498.
[13]
Zarantonelli ML, Lancellotti M, Deghmane AE, Giorgini D, Hong E, et al. (2008) Hyperinvasive genotypes of Neisseria meningitidis in France. Clin Microbiol Infect 14: 467–472.
[14]
Schoen C, Blom J, Claus H, Schramm-Gluck A, Brandt P, et al. (2008) Whole-genome comparison of disease and carriage strains provides insights into virulence evolution in Neisseria meningitidis. Proc Natl Acad Sci U S A 105: 3473–3478.
[15]
Klein NJ, Ison CA, Peakman M, Levin M, Hammerschmidt S, et al. (1996) The influence of capsulation and lipooligosaccharide structure on neutrophil adhesion molecule expression and endothelial injury by Neisseria meningitidis. J Infect Dis 173: 172–179.
[16]
Virji M, Kayhty H, Ferguson DJ, Alexandrescu C, Heckels JE, et al. (1991) The role of pili in the interactions of pathogenic Neisseria with cultured human endothelial cells. Mol Microbiol 5: 1831–1841.
[17]
Mercier JC, Beaufils F, Hartmann JF, Azema D (1988) Hemodynamic patterns of meningococcal shock in children. Crit Care Med 16: 27–33.
[18]
Birkness KA, Swisher BL, White EH, Long EG, Ewing EP Jr, et al. (1995) A tissue culture bilayer model to study the passage of Neisseria meningitidis. Infect Immun 63: 402–409.
[19]
Stephens DS, Farley MM (1991) Pathogenic events during infection of the human nasopharynx with Neisseria meningitidis and Haemophilus influenzae. Rev Infect Dis 13: 22–33.
[20]
Read RC, Fox A, Miller K, Gray T, Jones N, et al. (1995) Experimental infection of human nasal mucosal explants with Neisseria meningitidis. J Med Microbiol 42: 353–361.
[21]
Warren HS Jr, Gonzalez RG, Tian D (2003) Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 38-2003. A 12-year-old girl with fever and coma. N Engl J Med 349: 2341–2349.
[22]
Deghmane AE, Veckerle C, Giorgini D, Hong E, Ruckly C, et al. (2009) Differential modulation of TNF-alpha-induced apoptosis by Neisseria meningitidis. PLoS Pathog 5: e1000405.
[23]
Barnes PJ, Karin M (1997) Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med 336: 1066–1071.
[24]
Rothwarf DM, Karin MThe NF-kappa B activation pathway: a paradigm in information transfer from membrane to nucleus. Sci STKE 1999: RE1.
[25]
Wang CY, Mayo MW, Korneluk RG, Goeddel DV, Baldwin AS Jr (1998) NF-kappaB antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation. Science 281: 1680–1683.
[26]
Rhen M, Eriksson S, Pettersson S (2000) Bacterial adaptation to host innate immunity responses. Curr Opin Microbiol 3: 60–64.
[27]
Kawai T, Akira S (2006) TLR signaling. Cell Death Differ 13: 816–825.
[28]
Medzhitov R, Preston-Hurlburt P, Kopp E, Stadlen A, Chen C, et al. (1998) MyD88 is an adaptor protein in the hToll/IL-1 receptor family signaling pathways. Mol Cell 2: 253–258.
[29]
Yamamoto M, Sato S, Mori K, Hoshino K, Takeuchi O, et al. (2002) Cutting edge: a novel Toll/IL-1 receptor domain-containing adapter that preferentially activates the IFN-beta promoter in the Toll-like receptor signaling. J Immunol 169: 6668–6672.
[30]
Yamamoto M, Sato S, Hemmi H, Sanjo H, Uematsu S, et al. (2002) Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4. Nature 420: 324–329.
[31]
Aderem A, Ulevitch RJ (2000) Toll-like receptors in the induction of the innate immune response. Nature 406: 782–787.
[32]
Jensen TJ, Loo MA, Pind S, Williams DB, Goldberg AL, et al. (1995) Multiple proteolytic systems, including the proteasome, contribute to CFTR processing. Cell 83: 129–135.
[33]
Rock KL, Gramm C, Rothstein L, Clark K, Stein R, et al. (1994) Inhibitors of the proteasome block the degradation of most cell proteins and the generation of peptides presented on MHC class I molecules. Cell 78: 761–771.
[34]
Beg AA, Baltimore D (1996) An essential role for NF-kappaB in preventing TNF-alpha-induced cell death. Science 274: 782–784.
[35]
Liu ZG, Hsu H, Goeddel DV, Karin M (1996) Dissection of TNF receptor 1 effector functions: JNK activation is not linked to apoptosis while NF-kappaB activation prevents cell death. Cell 87: 565–576.
[36]
Van Antwerp DJ, Martin SJ, Kafri T, Green DR, Verma IM (1996) Suppression of TNF-alpha-induced apoptosis by NF-kappaB. Science 274: 787–789.
[37]
Wang CY, Mayo MW, Baldwin AS Jr (1996) TNF- and cancer therapy-induced apoptosis: potentiation by inhibition of NF-kappaB. Science 274: 784–787.
[38]
Wu M, Lee H, Bellas RE, Schauer SL, Arsura M, et al. (1996) Inhibition of NF-kappaB/Rel induces apoptosis of murine B cells. Embo J 15: 4682–4690.
[39]
Mercurio F, Zhu H, Murray BW, Shevchenko A, Bennett BL, et al. (1997) IKK-1 and IKK-2: cytokine-activated IkappaB kinases essential for NF-kappaB activation. Science 278: 860–866.
[40]
Palombella VJ, Rando OJ, Goldberg AL, Maniatis T (1994) The ubiquitin-proteasome pathway is required for processing the NF-kappa B1 precursor protein and the activation of NF-kappa B. Cell 78: 773–785.
[41]
Black RA, Rauch CT, Kozlosky CJ, Peschon JJ, Slack JL, et al. (1997) A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells. Nature 385: 729–733.
[42]
Moss ML, Jin SL, Becherer JD, Bickett DM, Burkhart W, et al. (1997) Structural features and biochemical properties of TNF-alpha converting enzyme (TACE). J Neuroimmunol 72: 127–129.
[43]
Gallois C, Habib A, Tao J, Moulin S, Maclouf J, et al. (1998) Role of NF-kappaB in the antiproliferative effect of endothelin-1 and tumor necrosis factor-alpha in human hepatic stellate cells. Involvement of cyclooxygenase-2. J Biol Chem 273: 23183–23190.
[44]
Johnson SE, Dorman CM, Bolanowski SA (2002) Inhibition of myogenin expression by activated Raf is not responsible for the block to avian myogenesis. J Biol Chem 277: 28742–28748.
[45]
Bennett BL, Sasaki DT, Murray BW, O'Leary EC, Sakata ST, et al. (2001) SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase. Proc Natl Acad Sci U S A 98: 13681–13686.
[46]
Tang G, Minemoto Y, Dibling B, Purcell NH, Li Z, et al. (2001) Inhibition of JNK activation through NF-kappaB target genes. Nature 414: 313–317.
[47]
De Smaele E, Zazzeroni F, Papa S, Nguyen DU, Jin R, et al. (2001) Induction of gadd45beta by NF-kappaB downregulates pro-apoptotic JNK signalling. Nature 414: 308–313.
[48]
Coyne CB, Vanhook MK, Gambling TM, Carson JL, Boucher RC, et al. (2002) Regulation of airway tight junctions by proinflammatory cytokines. Mol Biol Cell 13: 3218–3234.
[49]
Schmitz H, Fromm M, Bentzel CJ, Scholz P, Detjen K, et al. (1999) Tumor necrosis factor-alpha (TNFalpha) regulates the epithelial barrier in the human intestinal cell line HT-29/B6. J Cell Sci 112 (Pt 1): 137–146.
[50]
Gitter AH, Bendfeldt K, Schulzke JD, Fromm M (2000) Leaks in the epithelial barrier caused by spontaneous and TNF-alpha-induced single-cell apoptosis. Faseb J 14: 1749–1753.
[51]
Mattila PS, Carlson P (1998) Pharyngolaryngitis caused by Neisseria meningitidis. Scand J Infect Dis 30: 198–200.
[52]
Hsu LC, Park JM, Zhang K, Luo JL, Maeda S, et al. (2004) The protein kinase PKR is required for macrophage apoptosis after activation of Toll-like receptor 4. Nature 428: 341–345.
[53]
Zhang Y, Bliska JB (2003) Role of Toll-like receptor signaling in the apoptotic response of macrophages to Yersinia infection. Infect Immun 71: 1513–1519.
[54]
Vogel SN, Fenton M (2003) Toll-like receptor 4 signalling: new perspectives on a complex signal-transduction problem. Biochem Soc Trans 31: 664–668.
Fitzgerald KA, Rowe DC, Barnes BJ, Caffrey DR, Visintin A, et al. (2003) LPS-TLR4 signaling to IRF-3/7 and NF-kappaB involves the toll adapters TRAM and TRIF. J Exp Med 198: 1043–1055.
[57]
Choi KB, Wong F, Harlan JM, Chaudhary PM, Hood L, et al. (1998) Lipopolysaccharide mediates endothelial apoptosis by a FADD-dependent pathway. J Biol Chem 273: 20185–20188.
[58]
Ruckdeschel K, Mannel O, Schrottner P (2002) Divergence of apoptosis-inducing and preventing signals in bacteria-faced macrophages through myeloid differentiation factor 88 and IL-1 receptor-associated kinase members. J Immunol 168: 4601–4611.
[59]
Klumpp DJ, Weiser AC, Sengupta S, Forrestal SG, Batler RA, et al. (2001) Uropathogenic Escherichia coli potentiates type 1 pilus-induced apoptosis by suppressing NF-kappaB. Infect Immun 69: 6689–6695.
[60]
Monack DM, Mecsas J, Bouley D, Falkow S (1998) Yersinia-induced apoptosis in vivo aids in the establishment of a systemic infection of mice. J Exp Med 188: 2127–2137.
Takamune Y, Ikebe T, Nagano O, Shinohara M (2008) Involvement of NF-kappaB-mediated maturation of ADAM-17 in the invasion of oral squamous cell carcinoma. Biochem Biophys Res Commun 365: 393–398.
[63]
Sokolova O, Heppel N, Jagerhuber R, Kim KS, Frosch M, et al. (2004) Interaction of Neisseria meningitidis with human brain microvascular endothelial cells: role of MAP- and tyrosine kinases in invasion and inflammatory cytokine release. Cell Microbiol 6: 1153–1166.
[64]
Johnson GL, Lapadat R (2002) Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 298: 1911–1912.
[65]
Szatanik M, Hong E, Ruckly C, Ledroit M, Giorgini D, et al. (2011) Experimental meningococcal sepsis in congenic transgenic mice expressing human transferrin. PLoS ONE 6: e22210.
[66]
Guinea-Viniegra J, Zenz R, Scheuch H, Hnisz D, Holcmann M, et al. (2009) TNFalpha shedding and epidermal inflammation are controlled by Jun proteins. Genes Dev 23: 2663–2674.
[67]
Derbigny WA, Hong SC, Kerr MS, Temkit M, Johnson RM (2007) Chlamydia muridarum infection elicits a beta interferon response in murine oviduct epithelial cells dependent on interferon regulatory factor 3 and TRIF. Infect Immun 75: 1280–1290.
[68]
Hanahan D (1983) Studies on transformation of Escherichia coli with plasmids. J Mol Biol 166: 557–580.
[69]
Kellogg DS Jr, Peacock WL Jr, Deacon WE, Brown L, Pirkle DI (1963) Neisseria Gonorrhoeae. I. Virulence Genetically Linked to Clonal Variation. J Bacteriol 85: 1274–1279.
[70]
Deghmane AE, Giorgini D, Larribe M, Alonso JM, Taha MK (2002) Down-regulation of pili and capsule of Neisseria meningitidis upon contact with epithelial cells is mediated by CrgA regulatory protein. Mol Microbiol 43: 1555–1564.
[71]
Taha MK, Morand PC, Pereira Y, Eugene E, Giorgini D, et al. (1998) Pilus-mediated adhesion of Neisseria meningitidis: the essential role of cell contact-dependent transcriptional upregulation of the PilC1 protein. Mol Microbiol 28: 1153–1163.
[72]
Jarvis GA, Li J, Swanson KV (1999) Invasion of human mucosal epithelial cells by Neisseria gonorrhoeae upregulates expression of intercellular adhesion molecule 1 (ICAM-1). Infect Immun 67: 1149–1156.
[73]
Philpott DJ, Belaid D, Troubadour P, Thiberge JM, Tankovic J, et al. (2002) Reduced activation of inflammatory responses in host cells by mouse-adapted Helicobacter pylory isolates. Cell Microbiol 4: 285–296.
[74]
Schmidt-Ullrich R, Memet S, Lilienbaum A, Feuillard J, Raphael M, et al. (1996) NF-kappaB activity in transgenic mice: developmental regulation and tissue specificity. Development 122: 2117–2128.
[75]
Deghmane AE, Petit S, Topilko A, Pereira Y, Giorgini D, et al. (2000) Intimate adhesion of Neisseria meningitidis to human epithelial cells is under the control of the crgA gene, a novel LysR-type transcriptional regulator. Embo J 19: 1068–1078.
