Toll-Like Receptor 4 (TLR4) and Typhoid Fever in Vietnam

Nguyen Thi Hue,Sarah J Dunstan,Le Thi Phuong,Tran Tinh Hien,Nguyen T Hieu,Jeremy J Farrar,Nguyen Tran Chinh,Ha Vinh,Mai Ngoc Lanh,Jörg Hermann Fritz

doi:10.1371/journal.pone.0004800

Abstract

Understanding the host genetic susceptibility to typhoid fever may provide a better understanding of pathogenesis and help in the development of new therapeutics and vaccines. Here we determine the genetic variation within the human TLR4 gene encoding the principal receptor for bacterial endotoxin recognition in typhoid fever patients. It is possible that genetic variants of TLR4 could detrimentally affect the innate immune response against S. typhi infection. Mutation detection and genotyping of TLR4 was performed on DNA from 414 Vietnamese typhoid fever patients and 372 population controls. dHPLC detected a total of 10 polymorphisms within the upstream and exonic regions of TLR4, of which 7 are novel. Two SNPs, T4025A and C4215G, were more frequent in typhoid cases than in controls however due to their low allele frequencies they showed borderline significance (T4025A: OR 1.9, 95%CI 0.9–4.3, P 0.07 and C4215G: OR 6.7, 95%CI 0.8–307, P 0.04). Six missense mutations were identified, with 5/6 positioned in the ectoplasmic domain. Four missense mutations and one promoter SNP (A-271G) were only present in typhoid cases, albeit at low allele frequencies. Here we determined the extent of genetic variation within TLR4 in a Vietnamese population and suggest that TLR4 may be involved in defense against typhoid fever in this population.

Highlights

IntroductionTyphi), is a Gram negative bacterium that can cause typhoid fever [1]
As this polymorphism was not common in the Vietnamese we chose to identify which Toll-Like Receptor 4 (TLR4) polymorphisms exist in the Vietnamese Kinh population
Occurring genetic variations in the genes that control innate immunity may play an important role in human susceptibility to a variety of diseases that require an adequate and appropriate immune response

Summary

Introduction

Typhi), is a Gram negative bacterium that can cause typhoid fever [1]. Worldwide typhoid fever is a serious public health problem, with an estimated 22 million cases, resulting in 200,000 deaths [2]. The burden of disease lies mainly in developing countries where the provision of sanitary conditions can be inadequate. Typhi are emerging, posing a real threat to the current antimicrobial treatment of typhoid [1]. To be in a position to develop novel therapeutic agents or new vaccines for typhoid it is imperative that the immunological mechanisms of disease protection are thoroughly understood. The availability of the human genome sequence and advances in molecular technologies allows the study of protective disease mechanisms using a genetic approach

Methods

Results

Conclusion