Advertisement

Classification and Pathogenesis of Meningococcal Infections

  • Petter Brandtzaeg
  • Marcel van Deuren
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 799)

Abstract

The clinical symptoms induced by Neisseria meningitidis reflect compartmentalized intravascular and intracranial bacterial growth and inflammation. In this chapter, we describe a classification system for meningococcal disease based on the nature of the clinical symptoms. Meningococci invade the subarachnoid space and cause meningitis in as many as 50–70% of patients. The bacteremic phase is moderate in patients with meningitis and mild systemic meningococcemia but graded high in patients with septic shock. Three landmark studies using this classification system and comprising 862 patients showed that 37–49% developed meningitis without shock, 10–18% shock without meningitis, 7–12% shock and meningitis, and 18–33% had mild meningococcemia without shock or meningitis. N. meningitidis lipopolysaccharide (LPS) is the principal trigger of the innate immune system via activation of the Toll-like receptor 4-MD2 cell surface receptor complex on myeloid and nonmyeloid human cells. The intracellular signals are conveyed via MyD88-dependent and -independent pathways altering the expression of >4,600 genes in target cells such as monocytes. However, non-LPS molecules contribute to inflammation, but 10–100-fold higher concentrations are required to reach the same responses as induced by LPS. Activation of the complement and coagulation systems is related to the bacterial load in the circulation and contributes to the development of shock, organ dysfunction, thrombus formation, bleeding, and long-term complications in patients. Despite rapid intervention and advances in patient intensive care, why as many as 30% of patients with systemic meningococcal disease develop massive meningococcemia leading to shock and death is still not understood.

Key words

Meningococcal meningitis Septicemia Classification Lipopolysaccharide Shock 

Notes

Acknowledgments

Peter Kierulf, Reidun Övstebö, Berit Brusletto, Tom Eirik Mollnes, Bernt Christian Hellerud, Arne Höiby, Anne Marie Siebke Tröseid, Tom Sprong, Chris Neeleman, and Sabine de Greeff have all contributed extensively to the studies.

The studies have been financed by Ullevål University Hospital, Oslo, the Reginal Health Authority Helse Söröst, Norway, and the Dutch Organisation for Scientific Research, the Netherlands. A particular thank you to all patients, parents, and relatives who consented to participate in the studies.

References

  1. 1.
    Caugant DA, Maiden MC (2009) Meningo-coccal carriage and disease-population biology and evolution. Vaccine 27 Suppl 2:B64–B70PubMedCrossRefGoogle Scholar
  2. 2.
    Virji M (2009) Pathogenic neisseriae: surface modulation, pathogenesis and infection control. Nat Rev Microbiol 7:274–286PubMedCrossRefGoogle Scholar
  3. 3.
    Stephens DS, Farley MM (1991) Pathogenic events during infection of the human nasopharynx with Neisseria meningitidis and Haemophilus influenzae. Rev Infect Dis 13:22–33PubMedCrossRefGoogle Scholar
  4. 4.
    Flexner S (1913) The results of serum treatment in thirteen hundred cases of epidemic meningitis. J Exp Med 17:553–576PubMedCrossRefGoogle Scholar
  5. 5.
    Brooks R, Woods CW, Benjamin DK Jr et al (2006) Increased case-fatality rate associated with outbreaks of Neisseria meningitidis infection, compared with sporadic meningococcal disease, in the United States, 1994-2002. Clin Infect Dis 43:49–54PubMedCrossRefGoogle Scholar
  6. 6.
    de Greeff SC, de Melker HE, Schouls LM et al (2008) Pre-admission clinical course of meningococcal disease and opportunities for the earlier start of appropriate intervention: a prospective epidemiological study on 752 patients in the Netherlands, 2003-2005. Eur J Clin Microbiol Infect Dis 27:985–992PubMedCrossRefGoogle Scholar
  7. 7.
    Rosenstein NE, Perkins BA, Stephens DS et al (1999) The changing epidemiology of meningococcal disease in the United States, 1992-1996. J Infect Dis 180:1894–1901PubMedCrossRefGoogle Scholar
  8. 8.
    Gedde-Dahl TW, Hoiby EA, Schillinger A et al (1983) An epidemiological, clinical and microbiological follow-up study of incident meningococcal disease cases in Norway, winter 1981-1982. Material and epidemiology in the MenOPP project. NIPH Ann 6:155–168PubMedGoogle Scholar
  9. 9.
    Halstensen A, Pedersen SH, Haneberg B et al (1987) Case fatality of meningococcal disease in western Norway. Scand J Infect Dis 19:35–42PubMedCrossRefGoogle Scholar
  10. 10.
    Brandtzaeg P, Kierulf P, Gaustad P et al (1989) Plasma endotoxin as a predictor of multiple organ failure and death in systemic meningococcal disease. J Infect Dis 159:195–204PubMedCrossRefGoogle Scholar
  11. 11.
    van Deuren M, Brandtzaeg P, van der Meer JW (2000) Update on meningococcal disease with emphasis on pathogenesis and clinical management. Clin Microbiol Rev 13:144–66PubMedCrossRefGoogle Scholar
  12. 12.
    Boisier P, Mainassara HB, Sidikou F et al (2007) Case-fatality ratio of bacterial meningitis in the African meningitis belt: we can do better. Vaccine 25 Suppl 1:A24–A29PubMedCrossRefGoogle Scholar
  13. 13.
    Rosenstein NE, Perkins BA, Stephens DS et al (2001) Meningococcal disease. N Engl J Med 344:1378–1388PubMedCrossRefGoogle Scholar
  14. 14.
    Stephens DS, Greenwood B, Brandtzaeg P (2007) Epidemic meningitis, meningococcaemia, and Neisseria meningitidis. Lancet 369:2196–2210PubMedCrossRefGoogle Scholar
  15. 15.
    Davila S, Wright VJ, Khor CC et al (2010) Genome-wide association study identifies variants in the CFH region associated with host susceptibility to meningococcal disease. Nat Genet 42:772–776PubMedCrossRefGoogle Scholar
  16. 16.
    Haralambous E, Dolly SO, Hibberd ML et al (2006) Factor H, a regulator of complement activity, is a major determinant of meningococcal disease susceptibility in UK Caucasian patients. Scand J Infect Dis 38:764–771PubMedCrossRefGoogle Scholar
  17. 17.
    Brouwer MC, Read RC, van de Beek D (2010) Host genetics and outcome in meningococcal disease: a systematic review and meta-analysis. Lancet Infect Dis 10:262–274PubMedCrossRefGoogle Scholar
  18. 18.
    Stiehm ER, Damrosch DS (1966) Factors in the prognosis of meningococcal infection. Review of 63 cases with emphasis on recognition and management of the severely ill patient. J Pediatr 68:457–467PubMedCrossRefGoogle Scholar
  19. 19.
    Brandtzaeg P (2006) Pathogenesis and pathophysiology of invasive meningococcal disease. In: Frosch M, Maiden CJ (eds) Handbook of meningococcal disease. Wiley-VCH, Weinheim, pp 427–480CrossRefGoogle Scholar
  20. 20.
    Brandtzaeg P (2010) Meningococcal Infections. In: Warrell DA, Cox TM, Firth JD (eds) Oxford Textbook of Medicine, 5th edn. Oxford University Press, Oxford, pp 709–722Google Scholar
  21. 21.
    Hackett SJ, Guiver M, Marsh J et al (2002) Meningococcal bacterial DNA load at presentation correlates with disease severity. Arch Dis Child 86:44–46PubMedCrossRefGoogle Scholar
  22. 22.
    Darton T, Guiver M, Naylor S et al (2009) Severity of meningococcal disease associated with genomic bacterial load. Clin Infect Dis 48:587–594PubMedCrossRefGoogle Scholar
  23. 23.
    Ovstebo R, Brandtzaeg P, Brusletto B et al (2004) Use of robotized DNA isolation and real-time PCR to quantify and identify close correlation between levels of Neisseria meningitidis DNA and lipopolysaccharides in plasma and cerebrospinal fluid from patients with systemic meningococcal disease. J Clin Microbiol 42:2980–2987PubMedCrossRefGoogle Scholar
  24. 24.
    Harrison OB, Robertson BD, Faust SN et al (2002) Analysis of pathogen-host cell interactions in purpura fulminans: expression of capsule, type IV pili, and PorA by Neisseria meningitidis in vivo. Infect Immun 70:5193–5201PubMedCrossRefGoogle Scholar
  25. 25.
    van Deuren M, van Dijke BJ, Koopman RJ et al (1993) Rapid diagnosis of acute meningococcal infections by needle aspiration or biopsy of skin lesions. BMJ 306:1229–1232PubMedCrossRefGoogle Scholar
  26. 26.
    van Deuren M, Brandtzaeg P (2005) Myocardial dysfunction in meningococcal septic shock: no clear answer yet. Crit Care Med 33:1884–1886PubMedCrossRefGoogle Scholar
  27. 27.
    Baines PB, Stanford S, Bishop-Bailey D et al (1999) Nitric oxide production in meningococcal disease is directly related to disease severity. Crit Care Med 27:1187–1190PubMedCrossRefGoogle Scholar
  28. 28.
    Bjerre A, Brusletto B, Rosenqvist E et al (2000) Cellular activating properties and morphology of membrane-bound and purified meningococcal lipopolysaccharide. J Endotoxin Res 6:437–445PubMedGoogle Scholar
  29. 29.
    Brandtzaeg P, Bjerre A, Ovstebo R et al (2001) Neisseria meningitidis lipopolysaccharides in human pathology. J Endotoxin Res 7:401–420PubMedGoogle Scholar
  30. 30.
    Bjerre A, Brusletto B, Ovstebo R et al (2003) Identification of meningococcal LPS as a major monocyte activator in IL-10 depleted shock plasmas and CSF by blocking the CD14-TLR4 receptor complex. J Endotoxin Res 9:155–163PubMedGoogle Scholar
  31. 31.
    Hellerud BC, Stenvik J, Espevik T et al (2008) Stages of meningococcal sepsis simulated in vitro, with emphasis on complement and Toll-like receptor activation. Infect Immun 76:4183–4189PubMedCrossRefGoogle Scholar
  32. 32.
    Sprong T, Stikkelbroeck N, van der Ley P et al (2001) Contributions of Neisseria meningitidis LPS and non-LPS to proinflammatory cytokine response. J Leukoc Biol 70:283–288Google Scholar
  33. 33.
    Girardin SE, Travassos LH, Herve M et al (2003) Peptidoglycan molecular requirements allowing detection by Nod1 and Nod2. J Biol Chem 278:41702–41708PubMedCrossRefGoogle Scholar
  34. 34.
    Ingalls RR, Lien E, Golenbock DT (2001) Membrane-associated proteins of a lipopolysaccharide-deficient mutant of Neisseria meningitidis activate the inflammatory response through toll-like receptor 2. Infect Immun 69:2230–2236PubMedCrossRefGoogle Scholar
  35. 35.
    Massari P, Ram S, Macleod H et al (2003) The role of porins in neisserial pathogenesis and immunity. Trends Microbiol 11:87–93PubMedCrossRefGoogle Scholar
  36. 36.
    Mogensen TH, Paludan SR, Kilian M et al (2006) Live Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis activate the inflammatory response through Toll-like receptors 2, 4, and 9 in species-specific patterns. J Leukoc Biol 80:267–277PubMedCrossRefGoogle Scholar
  37. 37.
    Pridmore AC, Wyllie DH, Abdillahi F et al (2001) A lipopolysaccharide-deficient mutant of Neisseria meningitidis elicits attenuated cytokine release by human macrophages and signals via toll-like receptor (TLR) 2 but not via TLR4/MD2. J Infect Dis 183:89–96PubMedCrossRefGoogle Scholar
  38. 38.
    Kahler CM, Stephens DS (1998) Genetic basis for biosynthesis, structure, and function of meningococcal lipooligosaccharide (endotoxin). Crit Rev Microbiol 24:281–334PubMedGoogle Scholar
  39. 39.
    Kulshin VA, Zahringer U, Lindner B et al (1992) Structural characterization of the lipid A component of pathogenic Neisseria meningitidis. J Bacteriol 174:1793–1800PubMedGoogle Scholar
  40. 40.
    Zughaier S, Agrawal S, Stephens DS et al (2006) Hexa-acylation and KDO(2)-glycosylation determine the specific immunostimulatory activity of Neisseria meningitidis lipid A for human monocyte derived dendritic cells. Vaccine 24:1291–1297PubMedCrossRefGoogle Scholar
  41. 41.
    Scholten RJ, Kuipers B, Valkenburg HA et al (1994) Lipo-oligosaccharide immunotyping of Neisseria meningitidis by a whole-cell ELISA with monoclonal antibodies. J Med Microbiol 41:236–243PubMedCrossRefGoogle Scholar
  42. 42.
    van der Ley P, Steeghs L, Hamstra HJ et al (2001) Modification of lipid A biosynthesis in Neisseria meningitidis lpxL mutants: influence on lipopolysaccharide structure, toxicity, and adjuvant activity. Infect Immun 69:5981–5990PubMedCrossRefGoogle Scholar
  43. 43.
    Fransen F, Heckenberg SG, Hamstra HJ et al (2009) Naturally occurring lipid A mutants in Neisseria meningitidis from patients with invasive meningococcal disease are associated with reduced coagulopathy. PLoS Pathog 5:e1000396PubMedCrossRefGoogle Scholar
  44. 44.
    John CM, Liu M, Jarvis GA (2009) Natural phosphoryl and acyl variants of lipid A from Neisseria meningitidis strain 89I differentially induce tumor necrosis factor-alpha in human monocytes. J Biol Chem 284:21515–21525PubMedCrossRefGoogle Scholar
  45. 45.
    Zhang Y, Gaekwad J, Wolfert MA et al (2008) Innate immune responses of synthetic lipid A derivatives of Neisseria meningitidis. Chemistry 14:558–569PubMedCrossRefGoogle Scholar
  46. 46.
    Zimmer SM, Zughaier SM, Tzeng YL et al (2007) Human MD-2 discrimination of meningococcal lipid A structures and activation of TLR4. Glycobiology 17:847–856PubMedCrossRefGoogle Scholar
  47. 47.
    Steeghs L, den Hartog R, den Boer A et al (1998) Meningitis bacterium is viable without endotoxin. Nature 392:449–450Google Scholar
  48. 48.
    Albiger B, Johansson L, Jonsson AB (2003) Lipooligosaccharide-deficient Neisseria meningitidis shows altered pilus-associated characteristics. Infect Immun 71:155–162PubMedCrossRefGoogle Scholar
  49. 49.
    Brandtzaeg P (2003) Host response to Neisseria meningitidis lacking lipopolysaccharides. Expert Rev Anti Infect Ther 1:589–596PubMedCrossRefGoogle Scholar
  50. 50.
    Brandtzaeg P, Mollnes TE, Kierulf P (1989) Complement activation and endotoxin levels in systemic meningococcal disease. J Infect Dis 160:58–65PubMedCrossRefGoogle Scholar
  51. 51.
    Bjerre A, Brusletto B, Mollnes TE et al (2002) Complement activation induced by purified Neisseria meningitidis lipopolysaccharide (LPS), outer membrane vesicles, whole bacteria, and an LPS-free mutant. J Infect Dis 185:220–228PubMedCrossRefGoogle Scholar
  52. 52.
    Ovstebo R, Olstad OK, Brusletto B et al (2008) Identification of genes particularly sensitive to lipopolysaccharide (LPS) in human monocytes induced by wild-type versus LPS-deficient Neisseria meningitidis strains. Infect Immun 76:2685–2695PubMedCrossRefGoogle Scholar
  53. 53.
    Schubert-Unkmeir A, Sokolova O, Panzner U et al (2007) Gene expression pattern in human brain endothelial cells in response to Neisseria meningitidis. Infect Immun 75:899–914PubMedCrossRefGoogle Scholar
  54. 54.
    Christodoulides M, Heckels JE, Weller RO (2002). The role of the leptomeninges in meningococcal meningitis. In: Ferreiros C, Criado MT, and Vavquez J (eds) Emerging strategies in the fight against meningitis: molecular and cellular aspects. Horizon Scientific Press, Norfolk: pp1–34Google Scholar
  55. 55.
    Join-Lambert O, Morand PC, Carbonnelle E et al (2010) Mechanisms of meningeal invasion by a bacterial extracellular pathogen, the example of Neisseria meningitidis. Prog Neurobiol 91:130–139PubMedCrossRefGoogle Scholar
  56. 56.
    Wells DB, Tighe PJ, Wooldridge KG et al (2001) Differential gene expression during meningeal-meningococcal interaction: evidence for self-defense and early release of cytokines and chemokines. Infect Immun 69:2718–2722PubMedCrossRefGoogle Scholar
  57. 57.
    Zughaier SM, Zimmer SM, Datta A et al (2005) Differential induction of the toll-like receptor 4-MyD88-dependent and -independent signaling pathways by endotoxins. Infect Immun 73:2940–2950PubMedCrossRefGoogle Scholar
  58. 58.
    Nielsen EW, Hellerud BC, Thorgersen EB et al (2009) A new dynamic porcine model of meningococcal shock. Shock 32:302–309PubMedCrossRefGoogle Scholar
  59. 59.
    Hellerud BC, Nielsen EW, Thorgersen EB et al (2010) Dissecting the effects of lipopolysaccharides from nonlipopolysaccharide molecules in experimental porcine meningococcal sepsis. Crit Care Med 38:1467–1474PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Departments of Pediatrics and Medical BiochemistryUniversity of OsloOsloNorway
  2. 2.Department of Internal Medicine and Nijmegen Institute for Infection, Inflammation and ImmunityRadboud University Nijmegen Medical CentreNijmegenThe Netherlands

Personalised recommendations