Rapid transcriptional responses to serum exposure are associated with sensitivity and resistance to antibody-mediated complement killing in invasive Salmonella Typhimurium ST313 [version 1; peer review: 2 approved]
Background: Salmonella Typhimurium ST313 exhibits signatures of adaptation to invasive human infection, including higher resistance to humoral immune responses than gastrointestinal isolates. Full resistance to antibody-mediated complement killing (serum resistance) among nontyphoidal Salmonellae is...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wellcome
2019-04-01
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| Series: | Wellcome Open Research |
| Online Access: | https://wellcomeopenresearch.org/articles/4-74/v1 |
| _version_ | 1818875986980110336 |
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| author | Edna M. Ondari Elizabeth J. Klemm Chisomo L. Msefula Moataz Abd El Ghany Jennifer N. Heath Derek J. Pickard Lars Barquist Gordon Dougan Robert A. Kingsley Calman A. MacLennan |
| author_facet | Edna M. Ondari Elizabeth J. Klemm Chisomo L. Msefula Moataz Abd El Ghany Jennifer N. Heath Derek J. Pickard Lars Barquist Gordon Dougan Robert A. Kingsley Calman A. MacLennan |
| author_sort | Edna M. Ondari |
| collection | DOAJ |
| description | Background: Salmonella Typhimurium ST313 exhibits signatures of adaptation to invasive human infection, including higher resistance to humoral immune responses than gastrointestinal isolates. Full resistance to antibody-mediated complement killing (serum resistance) among nontyphoidal Salmonellae is uncommon, but selection of highly resistant strains could compromise vaccine-induced antibody immunity. Here, we address the hypothesis that serum resistance is due to a distinct genotype or transcriptome response in S. Typhimurium ST313. Methods: Six S. Typhimurium ST313 bloodstream isolates, three of which were antibody resistant, were studied. Genomic content (single nucleotide polymorphisms and larger chromosomal modifications) of the strains was determined by Illumina and PACBIO sequencing, and functionally characterized using RNA-seq, transposon directed insertion site sequencing (TraDIS), targeted gene deletion and transfer of selected point mutations in an attempt to identify features associated with serum resistance. Results: Sequence polymorphisms in genes from strains with atypical serum susceptibility when transferred from strains that were highly resistant or susceptible to a strain that exhibited intermediate susceptibility did not significantly alter serum killing phenotype. No large chromosomal modifications typified serum resistance or susceptibility. Genes required for resistance to serum identified by TraDIS and RNA-seq included those involved in exopolysaccharide synthesis, iron scavenging and metabolism. Most of the down-regulated genes were associated with membrane proteins. Resistant and susceptible strains had distinct transcriptional responses to serum, particularly related to genes responsible for polysaccharide biosynthesis. There was higher upregulation of wca locus genes, involved in the biosynthesis of colanic acid exopolysaccharide, in susceptible strains and increased expression of fepE, a regulator of very long-chain lipopolysaccharide in resistant strains. Conclusion: Clinical isolates of S. Typhimurium ST313 exhibit distinct antibody susceptibility phenotypes that may be associated with changes in gene expression on exposure to serum. |
| first_indexed | 2024-12-19T13:35:13Z |
| format | Article |
| id | doaj.art-e76cf5de64bc47299dbe1bae4d6deefa |
| institution | Directory Open Access Journal |
| issn | 2398-502X |
| language | English |
| last_indexed | 2024-12-19T13:35:13Z |
| publishDate | 2019-04-01 |
| publisher | Wellcome |
| record_format | Article |
| series | Wellcome Open Research |
| spelling | doaj.art-e76cf5de64bc47299dbe1bae4d6deefa2022-12-21T20:19:14ZengWellcomeWellcome Open Research2398-502X2019-04-01410.12688/wellcomeopenres.15059.116429Rapid transcriptional responses to serum exposure are associated with sensitivity and resistance to antibody-mediated complement killing in invasive Salmonella Typhimurium ST313 [version 1; peer review: 2 approved]Edna M. Ondari0Elizabeth J. Klemm1Chisomo L. Msefula2Moataz Abd El Ghany3Jennifer N. Heath4Derek J. Pickard5Lars Barquist6Gordon Dougan7Robert A. Kingsley8Calman A. MacLennan9Swiss Tropical and Public Health Institute, University of Basel, Basel, SwitzerlandWellcome Trust Sanger Institute, Hinxton, UKMalawi-Liverpool-Wellcome Trust Clinical Research Institute, Blantyre, MalawiWellcome Trust Sanger Institute, Hinxton, UKInstitute of Immunology and Immuotherapy, University of Birmingham, Birmingham, UKWellcome Trust Sanger Institute, Hinxton, UKWellcome Trust Sanger Institute, Hinxton, UKWellcome Trust Sanger Institute, Hinxton, UKQuadram Institute Bioscience, Norwich, UKJenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UKBackground: Salmonella Typhimurium ST313 exhibits signatures of adaptation to invasive human infection, including higher resistance to humoral immune responses than gastrointestinal isolates. Full resistance to antibody-mediated complement killing (serum resistance) among nontyphoidal Salmonellae is uncommon, but selection of highly resistant strains could compromise vaccine-induced antibody immunity. Here, we address the hypothesis that serum resistance is due to a distinct genotype or transcriptome response in S. Typhimurium ST313. Methods: Six S. Typhimurium ST313 bloodstream isolates, three of which were antibody resistant, were studied. Genomic content (single nucleotide polymorphisms and larger chromosomal modifications) of the strains was determined by Illumina and PACBIO sequencing, and functionally characterized using RNA-seq, transposon directed insertion site sequencing (TraDIS), targeted gene deletion and transfer of selected point mutations in an attempt to identify features associated with serum resistance. Results: Sequence polymorphisms in genes from strains with atypical serum susceptibility when transferred from strains that were highly resistant or susceptible to a strain that exhibited intermediate susceptibility did not significantly alter serum killing phenotype. No large chromosomal modifications typified serum resistance or susceptibility. Genes required for resistance to serum identified by TraDIS and RNA-seq included those involved in exopolysaccharide synthesis, iron scavenging and metabolism. Most of the down-regulated genes were associated with membrane proteins. Resistant and susceptible strains had distinct transcriptional responses to serum, particularly related to genes responsible for polysaccharide biosynthesis. There was higher upregulation of wca locus genes, involved in the biosynthesis of colanic acid exopolysaccharide, in susceptible strains and increased expression of fepE, a regulator of very long-chain lipopolysaccharide in resistant strains. Conclusion: Clinical isolates of S. Typhimurium ST313 exhibit distinct antibody susceptibility phenotypes that may be associated with changes in gene expression on exposure to serum.https://wellcomeopenresearch.org/articles/4-74/v1 |
| spellingShingle | Edna M. Ondari Elizabeth J. Klemm Chisomo L. Msefula Moataz Abd El Ghany Jennifer N. Heath Derek J. Pickard Lars Barquist Gordon Dougan Robert A. Kingsley Calman A. MacLennan Rapid transcriptional responses to serum exposure are associated with sensitivity and resistance to antibody-mediated complement killing in invasive Salmonella Typhimurium ST313 [version 1; peer review: 2 approved] Wellcome Open Research |
| title | Rapid transcriptional responses to serum exposure are associated with sensitivity and resistance to antibody-mediated complement killing in invasive Salmonella Typhimurium ST313 [version 1; peer review: 2 approved] |
| title_full | Rapid transcriptional responses to serum exposure are associated with sensitivity and resistance to antibody-mediated complement killing in invasive Salmonella Typhimurium ST313 [version 1; peer review: 2 approved] |
| title_fullStr | Rapid transcriptional responses to serum exposure are associated with sensitivity and resistance to antibody-mediated complement killing in invasive Salmonella Typhimurium ST313 [version 1; peer review: 2 approved] |
| title_full_unstemmed | Rapid transcriptional responses to serum exposure are associated with sensitivity and resistance to antibody-mediated complement killing in invasive Salmonella Typhimurium ST313 [version 1; peer review: 2 approved] |
| title_short | Rapid transcriptional responses to serum exposure are associated with sensitivity and resistance to antibody-mediated complement killing in invasive Salmonella Typhimurium ST313 [version 1; peer review: 2 approved] |
| title_sort | rapid transcriptional responses to serum exposure are associated with sensitivity and resistance to antibody mediated complement killing in invasive salmonella typhimurium st313 version 1 peer review 2 approved |
| url | https://wellcomeopenresearch.org/articles/4-74/v1 |
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