Background Carriage of Neisseria meningitidis occurs approximately in 10% of the population, onset of invasive meningococcal disease (IMD) cannot be predicted and differs between ages. It remains unclear, which host factors determine invasion of the bloodstream by the bacteria. Innate immunity has a very important role in the first recognition of invading pathogens. The functional single nucleotide polymorphisms (SNPs) CD14 C-159T and toll-like receptor 4 (TLR4) Asp299Gly have been associated with the risk of gram-negative infections. However, their role in development of IMD still remains unclear. Our aim was to investigate the influence of CD14 C-159T and TLR4 Asp299Gly polymorphisms on the risk of IMD. Methodology/Principal Findings It was a retrospective case control study. Surviving Austrian meningococcal disease patients were enrolled by sending buccal swabs for DNA analysis. 185 cases with a proven meningococcal infection and 770 healthy controls were enrolled. In surviving meningococcal disease patients DNA analysis of CD14 C-159T and TLR 4 Asp299Gly polymorphisms was performed, as they are part of the innate immune response to bacterial determinants. CD14 C-159T and TLR4 Asp299Gly SNPs were not significantly associated with the presence of IMD when compared to healthy controls. The odds ratio for CD14 C-159T SNP was 1.14 (95% confidence interval (CI) 0.91–1.43; p = 0.266). In TLR4 Asp 299 Gly SNP the odds ratio was 0.78 (CI 0.47–1.43; p = 0.359). Conclusion/Significance We could not observe a significant influence of CD14 C-159T and TLR4 Asp299Gly polymorphisms on the risk of developing IMD in surviving meningococcal disease patients. To our knowledge, this is the first study investigating the influence of the CD14 C-159T SNP on the susceptibility to IMD.
References
[1]
ACIP (2005) Prevention and control of meningococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 07: 1–21.
[2]
Gardner P (2006) Clinical practice. Prevention of meningococcal disease. N Engl J Med 355: 1466–1473.
[3]
Trotter CL, Gay NJ, Edmunds WJ (2006) The natural history of meningococcal carriage and disease. Epidemiol Infect 134: 556–566.
[4]
Caroff M, Karibian D, Cavaillon JM, Haeffner-Cavaillon N (2002) Structural and functional analyses of bacterial lipopolysaccharides. Microbes Infect 4: 9159–9126.
[5]
Pugin J, Heumann ID, Tomasz A, Kravchenko VV, Akamatsu Y, et al. (1994) CD14 is a pattern recognition receptor. Immunity 1: 509–516.
[6]
Labeta MO, Durieux JJ, Fernandez N, Herrman R, Ferrara P (1993) Release from a human monocyte-like cell line of two different soluble forms of the lipopolysaccharide receptor, CD14. Eur J Immunol 23: 2144–2151.
[7]
Wright SD, Ramos RA, Tobias PS, Ulvitch RJ, Mathison JC (1990) CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein. Science 249: 1431–1433.
[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]
LeVan TD, Bloom JW, Bailey TJ, Karp CL, Halonen M, et al. (2001) A common single nucleotide polymorphism in the CD14 promoter decreases the affinity of Sp protein binding and enhances transcriptional activity. J Immunol 167: 5838–5844.
[10]
Baldini M, Lohman IC, Halonen M, Erickson RP, Holt PG, et al. (1999) A Polymorphism in the 5′ flanking region of the CD14 gene is associated with circulating soluble CD14 levels and with total serum immunoglobulin E. Am J Respir Cell Mol Biol 20: 976–983.
T polymorphism in the promoter of the CD14 monocyte receptor gene as a risk factor for myocardial infarction. Circulation 99: 3218–3220. -->
[11]
Hubacek JA, Rothe G, Pitha J, Skodova Z, Stanek V, et al. (1999) C (？260)-->T polymorphism in the promoter of the CD14 monocyte receptor gene as a risk factor for myocardial infarction. Circulation 99: 3218–3220.
[12]
Burgmann H, Winkler S, Locker GJ, Presterl E, Laczika K, et al. (1996) Increased serum concentration of soluble CD14 is a prognostic marker in gram-positive sepsis. Clin Immunol Immunopathol 80: 307–310.
[13]
Agnese DM, Calvano JE, Hahm SJ, Coyle SM, Corbett SA, et al. (2002) Human toll-like receptor 4 mutations but not CD14 polymorphisms are associated with an increased risk of gram-negative infections. J Infect Dis 186: 1522–1525.
[14]
Jessen KM, Lindboe SB, Petersen AL, Eugen-Olsen J, Benfield T (2007) Common TNF-alpha, IL-1 beta, PAI-1, CD14 and TLR4 polymorphisms are not associated with disease severity or outcome from Gram negative sepsis. BMC Infect Dis 7: 108.
[15]
Rupp J, Goepel W, Kramme E, Jahn J, Solbach W, et al. (2004) CD14 promoter polymorphism -159C>T is associated with susceptibility to chronic Chlamydia pneumoniae infection in peripheral blood monocytes. Genes Immun 5: 435–438.
[16]
Sutherland AM, Walley KR, Russell JA (2005) Polymorphisms in CD14, mannose-binding lectin, and Toll-like receptor-2 are associated with increased prevalence of infection in critically ill adults. Crit Care Med 33: 638–644.
[17]
Faber J, Meyer CU, Gemmer C, Russo A, Finn A, et al. (2006) Human toll-like receptor 4 mutations are associated with susceptibility to invasive meningococcal disease in infancy. Pediatr Infect Dis J 25: 80–81.
[18]
Read RC, Pullin J, Gregory S, Borrow R, Kaczmarsk EB, et al. (2001) A functional polymorphism of toll-like receptor 4 is not associated with likelihood or severity of meningococcal disease. J Infect Dis 184: 640–642.
[19]
Illi S, von Mutius E, Lau S, Bergmann R, Niggemann B, et al. (2001) Early childhood infectious diseases and the development of asthma up to school age: a birth cohort study. BMJ 322: 390–395.
[20]
Sengler C, Haider A, Sommerfeld C, Lau S, Baldini M, et al. (2003) Evaluation of the CD14 C-159 T polymorphism in the German Multicenter Allergy Study cohort. Clin Exp Allergy 33: 166–169.
[21]
Bunker-Wiersma HE, Koopmans RP, Kuipers TW, Knoester H, Bos AP (2008) Single nucleotide polymorphisms in genes of circulatory homeostasis in surviving pediatric intensive care patients with meningococcal infection. Pediatr Crit Care Med 9: 517–523.
[22]
Read RC, Teare DM, Pridmore AC, Naylor SC, Timms JM, et al. (2009) The tumor necrosis factor polymorphism TNF (？308) is associated with susceptibility to meningococcal sepsis, but not with lethality. Crit Care Med 37: 1237–1243.
[23]
Smirnova I, Mann N, Dols A, Derkx HH, Hibberd ML, et al. (2003) Assay of locus-specific genetic load implicates rare Toll-like receptor 4 mutations in meningococcal susceptibility. Proc Natl Acad Sci 100: 6075–6080.
