Genetic susceptibility to invasive nontyphoidal Salmonella disease in African children
<p>Nontyphoidal <em>Salmonella</em> (NTS) causes invasive, and frequently fatal, disease in African children. The burden of disease secondary to NTS reflects inadequacy of <em>Salmonella</em>-control strategies in Africa, with expanding antibiotic resistance, and no lic...
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| Formatua: | Thesis |
| Hizkuntza: | English |
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2016
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| _version_ | 1826297201741004800 |
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| author | Gilchrist, J |
| author2 | Hill, A |
| author_facet | Hill, A Gilchrist, J |
| author_sort | Gilchrist, J |
| collection | OXFORD |
| description | <p>Nontyphoidal <em>Salmonella</em> (NTS) causes invasive, and frequently fatal, disease in African children. The burden of disease secondary to NTS reflects inadequacy of <em>Salmonella</em>-control strategies in Africa, with expanding antibiotic resistance, and no licensed anti-NTS vaccine. The delivery of improved interventions to prevent, diagnose, and treat invasive NTS (iNTS) infection, will be facilitated by an improved understanding of the biological determinants of susceptibility to iNTS, including host genetic factors.</p> <p>To identify host genetic determinants of iNTS disease, we performed a GWAS and replication analysis of NTS bacteraemia in African children. This analysis identified and validated a common genetic variant in <em>STAT4</em> associated with increased iNTS risk. </p> <p>To characterise the function of the NTS-associated <em>STAT4</em> variant, we utilised a genotype-selectable bioresource of healthy European adults and samples from African children with iNTS disease. In these experiments, the risk genotype at <em>STAT4</em> is associated with reduced <em>STAT4</em> RNA expression in stimulated leukocytes, and reduced IFNγ production in both <em>ex vivo</em> stimulated natural killer cells and in the serum of African children with acute NTS bacteraemia.</p> <p>To validate genetic variation suggestively associated with NTS bacteraemia in the GWAS, NTS-associated loci with evidence of regulatory function were prioritised for functional characterisation. Using <em>in vitro</em> models of intracellular <em>Salmonella</em> infection and RNA interference, I characterise the role of a candidate NTS-susceptibility determinant, EVI5L, in <em>Salmonella</em> infections.</p> <p>Finally, applying a pathway enrichment analysis to the NTS bacteraemia GWAS demonstrated that NTS-associated genetic variation in African children is enriched for methionine salvage enzymes. I further investigate the potential for host-pathogen interaction in this pathway, generating and characterising <em>Salmonella</em> mutants deficient in methionine metabolism.</p> <p>Taken together, these data represent the first unbiased assessment of genetic susceptibility to iNTS disease in unselected populations. These results have important implications for the design of <em>Salmonella</em>-control strategies for use in Africa.</p> |
| first_indexed | 2024-03-07T04:27:58Z |
| format | Thesis |
| id | oxford-uuid:cd5097bf-1279-423b-a5e5-5cda104dae7f |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T04:27:58Z |
| publishDate | 2016 |
| record_format | dspace |
| spelling | oxford-uuid:cd5097bf-1279-423b-a5e5-5cda104dae7f2022-03-27T07:27:51ZGenetic susceptibility to invasive nontyphoidal Salmonella disease in African childrenThesishttp://purl.org/coar/resource_type/c_db06uuid:cd5097bf-1279-423b-a5e5-5cda104dae7fhuman geneticsinvasive salmonella infectiongenome-wide association studiesEnglishORA Deposit2016Gilchrist, JHill, AMacLennan, C<p>Nontyphoidal <em>Salmonella</em> (NTS) causes invasive, and frequently fatal, disease in African children. The burden of disease secondary to NTS reflects inadequacy of <em>Salmonella</em>-control strategies in Africa, with expanding antibiotic resistance, and no licensed anti-NTS vaccine. The delivery of improved interventions to prevent, diagnose, and treat invasive NTS (iNTS) infection, will be facilitated by an improved understanding of the biological determinants of susceptibility to iNTS, including host genetic factors.</p> <p>To identify host genetic determinants of iNTS disease, we performed a GWAS and replication analysis of NTS bacteraemia in African children. This analysis identified and validated a common genetic variant in <em>STAT4</em> associated with increased iNTS risk. </p> <p>To characterise the function of the NTS-associated <em>STAT4</em> variant, we utilised a genotype-selectable bioresource of healthy European adults and samples from African children with iNTS disease. In these experiments, the risk genotype at <em>STAT4</em> is associated with reduced <em>STAT4</em> RNA expression in stimulated leukocytes, and reduced IFNγ production in both <em>ex vivo</em> stimulated natural killer cells and in the serum of African children with acute NTS bacteraemia.</p> <p>To validate genetic variation suggestively associated with NTS bacteraemia in the GWAS, NTS-associated loci with evidence of regulatory function were prioritised for functional characterisation. Using <em>in vitro</em> models of intracellular <em>Salmonella</em> infection and RNA interference, I characterise the role of a candidate NTS-susceptibility determinant, EVI5L, in <em>Salmonella</em> infections.</p> <p>Finally, applying a pathway enrichment analysis to the NTS bacteraemia GWAS demonstrated that NTS-associated genetic variation in African children is enriched for methionine salvage enzymes. I further investigate the potential for host-pathogen interaction in this pathway, generating and characterising <em>Salmonella</em> mutants deficient in methionine metabolism.</p> <p>Taken together, these data represent the first unbiased assessment of genetic susceptibility to iNTS disease in unselected populations. These results have important implications for the design of <em>Salmonella</em>-control strategies for use in Africa.</p> |
| spellingShingle | human genetics invasive salmonella infection genome-wide association studies Gilchrist, J Genetic susceptibility to invasive nontyphoidal Salmonella disease in African children |
| title | Genetic susceptibility to invasive nontyphoidal Salmonella disease in African children |
| title_full | Genetic susceptibility to invasive nontyphoidal Salmonella disease in African children |
| title_fullStr | Genetic susceptibility to invasive nontyphoidal Salmonella disease in African children |
| title_full_unstemmed | Genetic susceptibility to invasive nontyphoidal Salmonella disease in African children |
| title_short | Genetic susceptibility to invasive nontyphoidal Salmonella disease in African children |
| title_sort | genetic susceptibility to invasive nontyphoidal salmonella disease in african children |
| topic | human genetics invasive salmonella infection genome-wide association studies |
| work_keys_str_mv | AT gilchristj geneticsusceptibilitytoinvasivenontyphoidalsalmonelladiseaseinafricanchildren |