Gene Polymorphism of Toll-Like Receptors and Lung Function at Five to Seven Years of Age after Infant Bronchiolitis.

Eero Lauhkonen,Qiushui He,Merja Helminen,Juho Vuononvirta,Jyri O Toikka,Petri Koponen,Kirsi Nuolivirta,Johanna Teräsjärvi,Matti Korppi,Srinivasa M Srinivasula

doi:10.1371/journal.pone.0146526

Abstract

AimToll-like receptors (TLR) play a crucial role in innate immunity, protecting the host from pathogens such as viruses. Genetic variations in TLRs have been associated with the severity of viral bronchiolitis in infancy and with the later occurrence of post-bronchiolitis asthma. The aim of the present study was to evaluate if there are any exploratory associations between TLR gene polymorphisms and lung function at 5 to 7 years of age in former bronchiolitis patients.MethodsWe performed impulse oscillometry (IOS) at the median age of 6.3 years for 103 children who had been hospitalized for bronchiolitis at less than six months of age. The main parameters evaluated were airway resistance and reactance at 5Hz in baseline and post-exercise measurements. Data on single nucleotide polymorphisms (SNP) of TLR1 rs5743618, TLR2 rs5743708, TLR6 rs5743810 and TLR10 rs4129009 (TLR2 subfamily) and TLR3 rs3775291, TLR4 rs4986790, TLR7 rs179008, TLR8 rs2407992 and TLR 9 rs187084 were available for analyses.ResultsThe TLR4 rs4986790 wild genotype A/A was associated with a greater Rrs5 response (0.72 vs. -0.42, p = 0.03) to exercise. In TLR6 rs5743810, the minor allele T was associated with greater Rrs5 response (0.80 vs. -0.03, p = 0.04) to exercise. In TLR7 rs179008, the major allele A was associated with baseline decline in dRrs/df (-1.03 vs 0.61, p = 0.01) and increased Fres (2.28 vs. 0.89, p = 0.01) in girls.ConclusionAmong the nine studied TLRs, only TLR7 rs179008 showed some exploratory associations with post-bronchiolitis lung function deficiency, and polymorphisms of TLR4 rs4986790, and TLR6 rs5743810 in particular, with airway reactivity. These findings call for further confirmatory studies.

Highlights

[5] Bacterial lipopolysaccharide is the main ligand for Toll-like receptors (TLR) 4, and the F-protein of the respiratory syncytial virus (RSV) is recognized by TLR 4, being highly expressed in airway epithelium during RSV infection promoting inflammation. [5,8] The genetic alterations in TLRs were associated with the severity of bronchiolitis in infancy [8] and the later development of asthma
[10] On the other hand, attenuated TLR signaling could lead to repeated viral infections, which may further increase the risk of later atopy. [10,11] genetic differences in the TLR function might be associated with direct lung injury during bronchiolitis, or contribute to the development of later lung function reduction
Impulse oscillometry (IOS), [12] which measures lung function during tidal breathing, is a promising technique that can be used for preschool-aged children who are unable to perform the maximal expiratory blow needed in spirometry

Summary

Introduction

In a recent Finnish study, on average 37 per 1000 infants under the age of six months were annually admitted to the emergency room due to viral bronchiolitis and 70% of them were hospitalized. [1] At this age, respiratory syncytial virus (RSV) is the predominant cause of bronchiolitis, and most of the affected infants have no previous medical history. [2,3] Toll-like receptors (TLR), which recognize pathogens and initiate responses of both innate and adaptive immunity, are the gatekeepers of the immune system. [4] TLRs are important in airway mucosal responses to acute viral infections [5] and in later emergence and regulation of asthmatic inflammation. [6]In the respiratory epithelial cells, TLRs 1, 2, 4, 6 and 10 are expressed on the cell surfaces. In a recent Finnish study, on average 37 per 1000 infants under the age of six months were annually admitted to the emergency room due to viral bronchiolitis and 70% of them were hospitalized. [4] TLRs are important in airway mucosal responses to acute viral infections [5] and in later emergence and regulation of asthmatic inflammation. This study focused on children who had been hospitalized for bronchiolitis at less than 6 months of age The aim of this exploratory study was to see whether we could find any associations between the single nucleotide polymorphisms (SNP) at TLR1 rs5743618, TLR2 rs5743708, TLR3 rs3775291, TLR4 rs4986790, TLR6 rs5743810, TLR7 rs179008, TLR8 rs2407992, TLR9 rs187084 or TLR10 rs4129009 and lung function or airway reactivity measured by IOS at 5 to 7 years of age

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