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Genetic Susceptibility to Enteric Fever in Experimentally Challenged Human Volunteers
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...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Microbiology
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9022534/ https://www.ncbi.nlm.nih.gov/pubmed/35254093 http://dx.doi.org/10.1128/iai.00389-21 |
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author | Barton, Amber Hill, Jennifer Bibi, Sagida Chen, Liye Jones, Claire Jones, Elizabeth Camara, Susana Shrestha, Sonu Jin, Celina Gibani, Malick M. Dobinson, Hazel Waddington, Claire Darton, Thomas C. Blohmke, Christoph J. Pollard, Andrew J. |
author_facet | Barton, Amber Hill, Jennifer Bibi, Sagida Chen, Liye Jones, Claire Jones, Elizabeth Camara, Susana Shrestha, Sonu Jin, Celina Gibani, Malick M. Dobinson, Hazel Waddington, Claire Darton, Thomas C. Blohmke, Christoph J. Pollard, Andrew J. |
author_sort | Barton, Amber |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9022534 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Society for Microbiology |
record_format | MEDLINE/PubMed |
spelling | pubmed-90225342022-04-22 Genetic Susceptibility to Enteric Fever in Experimentally Challenged Human Volunteers Barton, Amber Hill, Jennifer Bibi, Sagida Chen, Liye Jones, Claire Jones, Elizabeth Camara, Susana Shrestha, Sonu Jin, Celina Gibani, Malick M. Dobinson, Hazel Waddington, Claire Darton, Thomas C. Blohmke, Christoph J. Pollard, Andrew J. Infect Immun Bacterial Infections 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. American Society for Microbiology 2022-03-07 /pmc/articles/PMC9022534/ /pubmed/35254093 http://dx.doi.org/10.1128/iai.00389-21 Text en Copyright © 2022 Barton et al. https://creativecommons.org/licenses/by/4.0/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/) . |
spellingShingle | Bacterial Infections Barton, Amber Hill, Jennifer Bibi, Sagida Chen, Liye Jones, Claire Jones, Elizabeth Camara, Susana Shrestha, Sonu Jin, Celina Gibani, Malick M. Dobinson, Hazel Waddington, Claire Darton, Thomas C. Blohmke, Christoph J. Pollard, Andrew J. Genetic Susceptibility to Enteric Fever in Experimentally Challenged Human Volunteers |
title | Genetic Susceptibility to Enteric Fever in Experimentally Challenged Human Volunteers |
title_full | Genetic Susceptibility to Enteric Fever in Experimentally Challenged Human Volunteers |
title_fullStr | Genetic Susceptibility to Enteric Fever in Experimentally Challenged Human Volunteers |
title_full_unstemmed | Genetic Susceptibility to Enteric Fever in Experimentally Challenged Human Volunteers |
title_short | Genetic Susceptibility to Enteric Fever in Experimentally Challenged Human Volunteers |
title_sort | genetic susceptibility to enteric fever in experimentally challenged human volunteers |
topic | Bacterial Infections |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9022534/ https://www.ncbi.nlm.nih.gov/pubmed/35254093 http://dx.doi.org/10.1128/iai.00389-21 |
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