Lack of association between TLR4 polymorphism and severe gram-negative bacterial infection in neonates
Aim: Gram-negative microorganisms are responsible for a significant percentage of systemic bacterial infections in neonates, which tend to progress to sepsis. Toll-like receptor 4 (TLR4), one of the receptors in the innate immune system, binds to the lipopolysaccharide (LPS) present on gram-negative bacteria. Following ligation, a cascade of cellular signals leads to activation of NFkB, resulting in the generation of such proinflammatory cytokines as TNFa, IL-1, IL-2, and IL-6. These are the mediators of inflammation, which is the cellular response to activation of the innate immune system. As such, TLR4 appears to be a very likely candidate involved in the immediate immune response to gram-negative bacteria. Two polymorphisms in the TLR4 gene, Asp299Gly and Thr399Ile, cause a reduction in inflammatory cytokine response to LPS. We sought to determine if there was any correlation between these polymorphisms and severe gram-negative infection in neonates. Materials and Methods: The study included 17 neonates with severe gram-negative infection and 70 healthy controls. Results: No polymorphism was noted in the patient group. In all, 4 Asp299Gly and 7 Thr399Ile heterozygous polymorphisms were observed in the control group, and 4 subjects had both polymorphisms. Conclusion: There appeared to be no correlation between the 2 polymorphisms-Asp299Gly and Thr399Ile- and gram-negative infection.
Lack of association between TLR4 polymorphism and severe gram-negative bacterial infection in neonates
Aim: Gram-negative microorganisms are responsible for a significant percentage of systemic bacterial infections in neonates, which tend to progress to sepsis. Toll-like receptor 4 (TLR4), one of the receptors in the innate immune system, binds to the lipopolysaccharide (LPS) present on gram-negative bacteria. Following ligation, a cascade of cellular signals leads to activation of NFkB, resulting in the generation of such proinflammatory cytokines as TNFa, IL-1, IL-2, and IL-6. These are the mediators of inflammation, which is the cellular response to activation of the innate immune system. As such, TLR4 appears to be a very likely candidate involved in the immediate immune response to gram-negative bacteria. Two polymorphisms in the TLR4 gene, Asp299Gly and Thr399Ile, cause a reduction in inflammatory cytokine response to LPS. We sought to determine if there was any correlation between these polymorphisms and severe gram-negative infection in neonates. Materials and Methods: The study included 17 neonates with severe gram-negative infection and 70 healthy controls. Results: No polymorphism was noted in the patient group. In all, 4 Asp299Gly and 7 Thr399Ile heterozygous polymorphisms were observed in the control group, and 4 subjects had both polymorphisms. Conclusion: There appeared to be no correlation between the 2 polymorphisms-Asp299Gly and Thr399Ile- and gram-negative infection.
___
- Michel O, LeVan TD, Stern D, Dentener M, Thorn J, Gnat D et al. Systemic responsiveness to lipopolysaccharide and polymorphisms in the toll-like receptor 4 gene in human beings. J Allergy Clin Immunol 2003; 112: 923-929.
- Werner M, Topp R, Wimmer K, Richter K, Bischof W, Wjst M et al. TLR4 gene variants modify endotoxin effects on asthma. J Allergy Clin Immunol 2003; 112: 323-330.
- Agnese DM, Calvano JE, Hahm SJ, Coyle SM, Corbett SA, Calvano SE et al. Human toll-like receptor 4 mutations but not CD14 polymorphisms are associated with an increased risk of gram-negative infections. J Infect Dis 2002; 186: 1522- 1525.
- Lorenz E, Mira JP, Frees KL, Shwartz DA. Relevance of mutations in the TLR4 receptor in patients with gram- negative septic shock. Arch Intern Med 2002; 162: 1028-1032.
- Montes AH, Asensi V, Alvarez V, Valle E, Ocana MG, Meana A et al. The Toll-like receptor 4 (Asp299Gly) polymorphism is a risk factor for Gram-negative and hematogenous osteomyelitis. Clin Exp Immunol 2006; 143: 404-13.
- Smirnova I, Mann N, Dols A, Derkx HH, Hibberd ML, Levin M et al. Assay of locus-specific genetic load implicates rare Toll-like receptor 4 mutations in meningococcal susceptibility. Proc Nat Acad Sci USA 2003; 100: 6075-6080.
- Ahrens P, Kattner E, Kohler B, Hartel C, Seidenberg J, Segerer H et al. Genetic Factors in Neonatology Study Group. Mutations in the genes involved in the innate immune system as predictors of sepsis in very low birth weight infants. Pediatr Res 2004; 55: 652-656.
- Sackesen C, Karaaslan C, Keskin O, Tokol N, Tahan F, Civelek E et al. The effect of polymorphisms at the CD14 promoter and the TLR4 gene on asthma phenotypes in Turkish children with asthma. Allergy 2005; 60: 1485-92.
- Shimazu R, Akashi S, Ogata H, Nagai Y, Fukudome K, Miyake Y et al. MD-2, a molecule that confers lipopolysaccharide responsiveness on toll-like receptor 4. J. Exp. Med 1999; 189: 1777-1782.