Role of Toll-Like Receptors 2 and 4 Genes Polymorphisms in Neonatal Sepsis in a Developing Country: A Pilot Study

Abstract

Objective Toll-like receptors (TLR) are one of the key molecules that alert the immune system to the presence of microbial infections. This study attempts to elucidate the role of TLR2 and TLR4 polymorphisms in neonatal sepsis.

Methods A case–control study including 30 neonates with confirmed sepsis compared with 20 neonates in a control group. TLR2 and TLR24 gene polymorphisms were confirmed by polymerase chain reaction.

Results The majority of infections were attributed to gram-negative organisms (72.5%) namely Klebsiella pneumoniae, Pseudomonas aeruginosa, and Escherichia coli. Results also revealed that incidence of TLR polymorphism was significantly different between the sepsis and control groups (p = 0.016). The most common polymorphism was TLR2; Arg 753 Gln (16.7%). Presence of TLR polymorphism was also associated with a longer duration of therapy (a median of 10 days for cases with positive polymorphism compared with 6.5 days for negative cases; p = 0.001).

Conclusion This pilot study suggests that any polymorphisms in TLR2 and TLR4 might have a role that interferes with the innate immune response of newborn.

Keywords

neonatal sepsis - polymorphism - toll-like receptors - TLR-2 and TLR-4

Ethical Approval

The study was approved by Alexandria University Ethics Committee, Egypt (institutional review board number: 00007555).

Publication History

Received: 07 March 2020

Accepted: 15 June 2020

Article published online:
20 August 2020

• References

• 1 Abu-Maziad A, Schaa K, Bell EF. et al. Role of polymorphic variants as genetic modulators of infection in neonatal sepsis. Pediatr Res 2010; 68 (04) 323-329
• 2 Levy O. Innate immunity of the newborn: basic mechanisms and clinical correlates. Nat Rev Immunol 2007; 7 (05) 379-390
• 3 Lemaitre B, Nicolas E, Michaut L, Reichhart JM, Hoffmann JA. The dorsoventral regulatory gene cassette spätzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 1996; 86 (06) 973-983
• 4 Santhanam S, Steele RW. Pediatric sepsis 2017. Available at: https://emedicine.medscape.com/article/972559-overview . Accessed December 14, 2014
• 5 Kang TJ, Chae GT. Detection of Toll-like receptor 2 (TLR2) mutation in the lepromatous leprosy patients. FEMS Immunol Med Microbiol 2001; 31 (01) 53-58
• 6 Arbour NC, Lorenz E, Schutte BC. et al. TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat Genet 2000; 25 (02) 187-191
• 7 Henckaerts L, Nielsen KR, Steffensen R. et al. Polymorphisms in innate immunity genes predispose to bacteremia and death in the medical intensive care unit. Crit Care Med 2009; 37 (01) 192-201 , e1–e3
• 8 Arcaroli J, Fessler MB, Abraham E. Genetic polymorphisms and sepsis. Shock 2005; 24 (04) 300-312
• 9 Garcia PCR, Eulmesekian P, Branco RG. et al. External validation of the paediatric logistic organ dysfunction score. Intensive Care Med 2010; 36 (01) 116-122
• 10 Tesini BL. Neonatal sepsis. MSD manual (professional version, last full review 2018). Available at: www.msdmanuals.com/professional/pediatrics/infections-in-neonates/neonatal-sepsis/ . Accessed July 2018
• 11 Schoonjans F, Zalata A, Depuydt CE, Comhaire FH. MedCalc: a new computer program for medical statistics. Comput Methods Programs Biomed 1995; 48 (03) 257-262
• 12 Kirchner M, Sonnenschein A, Schoofs S, Schmidtke P, Umlauf VN, Mannhardt-Laakmann W. Surface expression and genotypes of Toll-like receptors 2 and 4 in patients with juvenile idiopathic arthritis and systemic lupus erythematosus. Pediatr Rheumatol Online J 2013; 11 (01) 9-18
• 13 Marambe-Lazarte CC, Bunyi MA, Gallardo EE, Lim LG, Lobo JJ, Aguilar CY. Etiology of neonatal sepsis in five urban hospitals in the Philippines. PIDSP J 2011; 12 (02) 75-85
• 14 Bhat Y R, Lewis LE. , K e V. Bacterial isolates of early-onset neonatal sepsis and their antibiotic susceptibility pattern between 1998 and 2004: an audit from a center in India. Ital J Pediatr 2011; 37: 32-37
• 15 Mohsen L, Ramy N, Saied D. et al. Emerging antimicrobial resistance in early and late-onset neonatal sepsis. Antimicrob Resist Infect Control 2017; 6: 63-71
• 16 Raha BK, Baki MA, Begum T, Nahar N, Begum M. Clinical, bacteriological profile & outcome of neonatal sepsis in a tertiary care hospital. Med Today 2014; 26 (01) 18-21
• 17 Yoon HJ, Choi JY, Kim CO. et al. Lack of Toll-like receptor 4 and 2 polymorphisms in Korean patients with bacteremia. J Korean Med Sci 2006; 21 (06) 979-982
• 18 Gao JW, Zhang AQ, Wang X. et al. Association between the TLR2 Arg753Gln polymorphism and the risk of sepsis: a meta-analysis. Crit Care 2015; 19: 416
• 19 Lorenz E, Mira JP, Frees KL, Schwartz DA. Relevance of mutations in the TLR4 receptor in patients with gram-negative septic shock. Arch Intern Med 2002; 162 (09) 1028-1032
• 20 Nachtigall I, Tamarkin A, Tafelski S. et al. Polymorphisms of the toll-like receptor 2 and 4 genes are associated with faster progression and a more severe course of sepsis in critically ill patients. J Int Med Res 2014; 42 (01) 93-110
• 21 Esposito S, Zampiero A, Pugni L. et al. Genetic polymorphisms and sepsis in premature neonates. PLoS One 2014; 9 (07) e101248
• 22 Wang XL, Zhang L, Li YW, Hou HM, Sun HB. [Association between toll-like receptors 2 and 5 polymorphisms and neonatal sepsis]. Zhongguo Dang Dai Er Ke Za Zhi 2015; 17 (12) 1316-1321
• 23 Elek N, Sandor S, Balazs G, Dahlem P. Pediatric sepsis: genetic considerations. J Child Sci 2017; 7 (01) e76-e88
• 24 Bannister EG, Smith C, Visvanathan K, Thompson A, Hardikar W. TLR2 and TLR4 in healthy children: age and gender differences. J Paediatr Child Health 2013; 49 (12) 1082-1083
• 25 Roberts BJ, Dragon JA, Moussawi M, Huber SA. Sex-specific signaling through toll-like receptors 2 and 4 contributes to survival outcome of coxsackievirus B3 infection in C57Bl/6 mice. Biol Sex Differ 2012; 3 (01) 25-38
• 26 Mockenhaupt FP, Hammann L, von Gartner C. et al. Common polymorphisms of TLR 4 and 9 are associated with the clinical manifestation of malaria. J Infect Dis 2006; 194 (02) 184-189
• 27 Sutherland AM, Walley KR, Russell JA. 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 2005; 33 (03) 638-644
• 28 Stappers MH, Thys Y, Oosting M. et al. TLR1, TLR2, and TLR6 gene polymorphisms are associated with increased susceptibility to complicated skin and skin structure infections. J Infect Dis 2014; 210 (02) 311-318
• 29 Agnese DM, Calvano JE, Hahm SJ. 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 (10) 1522-1525
• 30 Chantratita N, Tandhavanant S, Seal S. et al. TLR4 genetic variation is associated with inflammatory responses in Gram-positive sepsis. Clin Microbiol Infect 2017; 23 (01) 47.e1-47.e10
• 31 Khaertynov K, Anokhin VA, Rizvanov AA, Daviduk YN, Lubin SA. Genetic polymorphisms and bacterial infections in neonates. Bionanoscience 2017; 7 (01) 78-84