Barton, A., Hill, J., Bibi, S. et al. (12 more authors) (2022) Genetic susceptibility to enteric fever in experimentally challenged human volunteers. Infection and Immunity, 90 (4). ISSN 0019-9567
Abstract
Infections 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. Human challenge participants were genotyped by Illumina OmniExpress-24 BeadChip array (n = 176) and/or transcriptionally profiled by RNA sequencing (n = 174). While the study was underpowered to detect any single nucleotide polymorphisms (SNPs) significant at the whole-genome level, two SNPs within CAPN14 and MIATNB were identified with P < 10−5 for association with development of symptoms or bacteremia 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 nontyphoidal Salmonella-induced reactive arthritis, as the HLA type most strongly associated with enteric fever susceptibility (P = 0.011). Gene sets relating to the unfolded protein response/heat shock and endoplasmic reticulum-associated protein degradation were overrepresented in HLA-B*27:05+ participants following challenge. Furthermore, intracellular replication of S. Typhi is higher in C1R cells transfected with HLA-B*27:05 (P = 0.02). These 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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2022 Barton et al. This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International license. (https://creativecommons.org/licenses/by/4.0/) |
Keywords: | typhoid fever; single nucleotide polymorphism; transcriptome; Salmonella Typhi; genomics; unfolded protein response; HLA antigens |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Sheffield Teaching Hospitals |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 14 Mar 2022 17:46 |
Last Modified: | 13 Feb 2023 15:37 |
Status: | Published |
Publisher: | American Society for Microbiology |
Refereed: | Yes |
Identification Number: | 10.1128/iai.00389-21 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:184758 |