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Genetic Susceptibility to Enteric Fever in Experimentally Challenged Human Volunteers
Amber Barton1,2, Jennifer Hill1, Sagida Bibi1
1Oxford Vaccine Group, Department of Paediatrics, University of Oxfordgrid.4991.5 and the NIHR Oxford Biomedical Research Centre, Oxford, United Kingdom.
Infection and Immunity
|March 7, 2022
Summary
Genetic factors influence susceptibility to enteric fever, a common Salmonella infection. The HLA-B*27:05 gene variant was strongly associated with increased risk and Salmonella Typhi replication, suggesting a role in disease development.
Area of Science:
- Genetics
- Immunology
- Infectious Diseases
Background:
- Enteric fever, caused by Salmonella Typhi and Paratyphi A, affects millions globally.
- Understanding genetic susceptibility is crucial for developing effective interventions.
Purpose of the Study:
- To identify genetic variants associated with enteric fever susceptibility using human challenge studies.
- To investigate the role of specific genetic factors, including Human Leukocyte Antigen (HLA) types, in disease development.
Main Methods:
- Genotyping (Illumina OmniExpress-24 BeadChip) and RNA sequencing of human challenge participants.
- Imputation of HLA types from genomic and transcriptomic data.
- Analysis of gene set enrichment and in vitro Salmonella Typhi replication in cells expressing HLA-B*27:05.
Main Results:
- Two single nucleotide polymorphisms (SNPs) in CAPN14 and MIATNB showed suggestive association with enteric fever symptoms or bacteremia.
- HLA-B*27:05 was the most strongly associated HLA type with enteric fever susceptibility.
- Gene sets related to the unfolded protein response were overrepresented in HLA-B*27:05 positive participants.
- Increased intracellular replication of Salmonella Typhi was observed in cells expressing HLA-B*27:05.
Conclusions:
- Genetic factors, particularly HLA-B*27:05, play a significant role in enteric fever susceptibility.
- HLA-B*27:05 may increase susceptibility by promoting Salmonella Typhi replication through unfolded protein response activation.
- Further research into HLA-B*27:05 and its role in Salmonella pathogenesis is warranted.
