Toll-Interleukin 1 Receptor Domain-Containing Adaptor Protein 180L Single-Nucleotide Polymorphism Is Associated With Susceptibility to Recurrent Pneumococcal Lower Respiratory Tract Infections in Children.

Johan N Siebert,Lutz Hamann,Cécile Gameiro,Charlotte M Verolet,Claire-Anne Siegrist,Klara M Posfay-Barbe,Stéphane Grillet

doi:10.3389/fimmu.2018.01780

Abstract

Lower respiratory tract infections (LRTI) are often caused by Streptococcus pneumoniae (Spn) and can be recurrent in 8% of children older than 2 years of age. Spn is recognized by pattern-recognition receptors (PRRs) of the innate immune system, in particular toll-like receptors (TLRs) 2 and 4. To assess whether a defect somewhere along this TLR signaling pathway increases susceptibility to recurrent pneumococcal LRTI, we conducted a prospective case–control study with 88 healthy individuals and 45 children with recurrent LRTI aged 2–5 years old. We examined cell surface expression of TLR2 and TLR4, as well as eight genetic variants of these receptors or associated co-receptors TLR1 and TLR6. Interleukin-6 production was measured after whole blood stimulation assays with specific agonists and heat-killed Spn. Our findings reveal that single-nucleotide polymorphisms within toll-interleukin 1 receptor domain-containing adaptor protein (TIRAP) alone or in combination with TLR1 N248S, TLR1 I602S, or TLR6 S249P polymorphisms contributes to various degree of susceptibility to recurrent pneumococcal LRTI in children by modulating the inflammatory response. In that respect, carriage of the TIRAP S180L heterozygous trait increases the likelihood to protect against pneumococcal LRTI, whereas children carrying the mutant homozygous TIRAP 180L polymorphism might be more likely susceptible to recurrent pneumococcal LRTI.

Highlights

Lower respiratory tract infections (LRTI), such as pneumonia and bronchitis are major causes of hospitalization in young children less than 5 years old, and are associated with significant morbidity and mortality [1, 2]
To the best of our knowledge, this is the first study to show an association between single-nucleotide polymorphism (SNP) in toll-interleukin receptor domain-containing adaptor protein (TIRAP) and increased susceptibility to recurrent pneumococcal LRTI in children
The key finding was that the TIRAP S180L heterozygous trait contributes to protection to recurrent pneumococcal LRTI in children, whereas the 180L homozygous mutant trait, alone or in combination with TLR1 N248S, TLR1 I602S or TLR6 S249P polymorphisms, contributes to increased susceptibility by modulating the inflammatory response

Summary

Introduction

Lower respiratory tract infections (LRTI), such as pneumonia and bronchitis are major causes of hospitalization in young children less than 5 years old, and are associated with significant morbidity and mortality [1, 2]. Despite an early and high prevalence of nasopharyngeal pneumococcal colonization of the human upper respiratory tract, the immature immune system of young children responds poorly to the polysaccharidic antigens of Spn [7]. This is reflected by an incidence of invasive pneumococcal disease (IPD) as high in young infants as in the elderly [8]. Approximately 8% of children older than 2 years of age hospitalized for CAP are recognized as having recurrent LRTI [9], of which a significant proportion is caused by Spn [10,11,12,13,14]. While most children with recurrent infections probably have a normal immunity, it is important to recognize, and treat appropriately those with an underlying transient or permanent immune dysfunction

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Conclusion