Genetic Susceptibility to Enteric Fever in Experimentally Challenged Human Volunteers

Abstract

AbstractBackgroundInfection with Salmonella enterica serovars Typhi and Paratyphi A cause an estimated 14 million cases of enteric fever annually. Here the controlled nature of challenge studies is exploited to identify genetic variants associated with enteric fever susceptibility.MethodsHuman challenge participants were genotyped by Illumina OmniExpress-24 BeadChip array (n=176) and/or transcriptionally profiled by RNA-sequencing (n=178).ResultsTwo SNPs within CAPN14 and MIATNB were identified with p<10−5 for association with development of symptoms or bacteraemia following oral S. Typhi or S. Paratyphi A challenge. Imputation of classical human leukocyte antigen (HLA) types from genomic and transcriptomic data identified HLA-B*27:05, previously associated with non-typhoidal Salmonella-induced reactive arthritis, as the HLA type most strongly associated with enteric fever susceptibility (p=0.012). Genes related to the unfolded protein response and heat shock were over-represented in HLA-B*27:05+ participants following challenge (p=0.01). Furthermore, intracellular replication of S. Typhi is higher in C1R cells transfected with HLA-B*27:05 (p=0.02).ConclusionThese data suggest that activation of the unfolded protein response by HLA-B*27:05 misfolding may create an intracellular environment conducive to S. Typhi replication, increasing susceptibility to enteric fever.