PMID- 35254093
OWN - NLM
STAT- MEDLINE
DCOM- 20220425
LR  - 20240214
IS  - 1098-5522 (Electronic)
IS  - 0019-9567 (Print)
IS  - 0019-9567 (Linking)
VI  - 90
IP  - 4
DP  - 2022 Apr 21
TI  - Genetic Susceptibility to Enteric Fever in Experimentally Challenged Human 
      Volunteers.
PG  - e0038921
LID - 10.1128/iai.00389-21 [doi]
LID - e00389-21
AB  - 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.
FAU - Barton, Amber
AU  - Barton A
AUID- ORCID: 0000-0001-8313-8643
AD  - Oxford Vaccine Group, Department of Paediatrics, University of Oxfordgrid.4991.5 
      and the NIHR Oxford Biomedical Research Centre, Oxford, United Kingdom.
AD  - Clinical Research Department, London School of Hygiene and Tropical Medicine, 
      London, United Kingdom.
FAU - Hill, Jennifer
AU  - Hill J
AD  - Oxford Vaccine Group, Department of Paediatrics, University of Oxfordgrid.4991.5 
      and the NIHR Oxford Biomedical Research Centre, Oxford, United Kingdom.
FAU - Bibi, Sagida
AU  - Bibi S
AD  - Oxford Vaccine Group, Department of Paediatrics, University of Oxfordgrid.4991.5 
      and the NIHR Oxford Biomedical Research Centre, Oxford, United Kingdom.
FAU - Chen, Liye
AU  - Chen L
AD  - Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, 
      University of Oxfordgrid.4991.5, Oxford, United Kingdom.
FAU - Jones, Claire
AU  - Jones C
AD  - Oxford Vaccine Group, Department of Paediatrics, University of Oxfordgrid.4991.5 
      and the NIHR Oxford Biomedical Research Centre, Oxford, United Kingdom.
FAU - Jones, Elizabeth
AU  - Jones E
AD  - Oxford Vaccine Group, Department of Paediatrics, University of Oxfordgrid.4991.5 
      and the NIHR Oxford Biomedical Research Centre, Oxford, United Kingdom.
FAU - Camara, Susana
AU  - Camara S
AD  - Oxford Vaccine Group, Department of Paediatrics, University of Oxfordgrid.4991.5 
      and the NIHR Oxford Biomedical Research Centre, Oxford, United Kingdom.
FAU - Shrestha, Sonu
AU  - Shrestha S
AD  - Oxford Vaccine Group, Department of Paediatrics, University of Oxfordgrid.4991.5 
      and the NIHR Oxford Biomedical Research Centre, Oxford, United Kingdom.
FAU - Jin, Celina
AU  - Jin C
AD  - Oxford Vaccine Group, Department of Paediatrics, University of Oxfordgrid.4991.5 
      and the NIHR Oxford Biomedical Research Centre, Oxford, United Kingdom.
FAU - Gibani, Malick M
AU  - Gibani MM
AD  - Oxford Vaccine Group, Department of Paediatrics, University of Oxfordgrid.4991.5 
      and the NIHR Oxford Biomedical Research Centre, Oxford, United Kingdom.
AD  - Department of Infectious Disease, Imperial College London, London, United 
      Kingdom.
FAU - Dobinson, Hazel
AU  - Dobinson H
AD  - Oxford Vaccine Group, Department of Paediatrics, University of Oxfordgrid.4991.5 
      and the NIHR Oxford Biomedical Research Centre, Oxford, United Kingdom.
FAU - Waddington, Claire
AU  - Waddington C
AD  - Oxford Vaccine Group, Department of Paediatrics, University of Oxfordgrid.4991.5 
      and the NIHR Oxford Biomedical Research Centre, Oxford, United Kingdom.
AD  - Department of Medicine, University of Cambridge, Cambridge, United Kingdom.
FAU - Darton, Thomas C
AU  - Darton TC
AD  - Oxford Vaccine Group, Department of Paediatrics, University of Oxfordgrid.4991.5 
      and the NIHR Oxford Biomedical Research Centre, Oxford, United Kingdom.
AD  - Department of Infection, Immunity and Cardiovascular Disease, University of 
      Sheffield, Sheffield, United Kingdom.
AD  - Florey Institute for Host-Pathogen Interactions, University of Sheffield, 
      Sheffield, United Kingdom.
FAU - Blohmke, Christoph J
AU  - Blohmke CJ
AD  - Oxford Vaccine Group, Department of Paediatrics, University of Oxfordgrid.4991.5 
      and the NIHR Oxford Biomedical Research Centre, Oxford, United Kingdom.
FAU - Pollard, Andrew J
AU  - Pollard AJ
AD  - Oxford Vaccine Group, Department of Paediatrics, University of Oxfordgrid.4991.5 
      and the NIHR Oxford Biomedical Research Centre, Oxford, United Kingdom.
LA  - eng
GR  - WT_/Wellcome Trust/United Kingdom
GR  - 090532/Z/09/Z/WT_/Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220307
PL  - United States
TA  - Infect Immun
JT  - Infection and immunity
JID - 0246127
SB  - IM
MH  - Genetic Predisposition to Disease
MH  - Healthy Volunteers
MH  - Humans
MH  - *Paratyphoid Fever
MH  - *Salmonella enterica
MH  - Salmonella paratyphi A
MH  - Salmonella typhi
MH  - *Typhoid Fever/genetics
PMC - PMC9022534
OTO - NOTNLM
OT  - HLA antigens
OT  - Salmonella Typhi
OT  - genomics
OT  - single nucleotide polymorphism
OT  - transcriptome
OT  - typhoid fever
OT  - unfolded protein response
COIS- The authors declare a conflict of interest. A.J.P. is Chair of the UK Department 
      of Health and Social Care's (DHSC) Joint Committee on Vaccination & Immunisation 
      (JCVI) and is a member of the WHO's Strategic Advisory Group of Experts. C.J.B. 
      is currently employed by GlaxoSmithKline.
EDAT- 2022/03/08 06:00
MHDA- 2022/04/26 06:00
PMCR- 2022/03/07
CRDT- 2022/03/07 12:15
PHST- 2022/03/08 06:00 [pubmed]
PHST- 2022/04/26 06:00 [medline]
PHST- 2022/03/07 12:15 [entrez]
PHST- 2022/03/07 00:00 [pmc-release]
AID - 00389-21 [pii]
AID - iai.00389-21 [pii]
AID - 10.1128/iai.00389-21 [doi]
PST - ppublish
SO  - Infect Immun. 2022 Apr 21;90(4):e0038921. doi: 10.1128/iai.00389-21. Epub 2022 
      Mar 7.