Rapid transcriptional responses to serum exposure are associated with sensitivity and resistance to antibody-mediated complement killing in invasive Salmonella Typhimurium ST313
AuthorsOndari, Edna M.
Klemm, Elizabeth J.
Msefula, Chisomo L.
Abd El Ghany, Moataz
Heath, Jennifer N.
Pickard, Derek J.
Kingsley, Robert A.
MacLennan, Calman A.
KAUST DepartmentBiological and Environmental Sciences and Engineering (BESE) Division
Computational Bioscience Research Center (CBRC)
Permanent link to this recordhttp://hdl.handle.net/10754/644878
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AbstractBackground: 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.
CitationOndari EM, Klemm EJ, Msefula CL, El Ghany MA, Heath JN, et al. (2019) Rapid transcriptional responses to serum exposure are associated with sensitivity and resistance to antibody-mediated complement killing in invasive Salmonella Typhimurium ST313. Wellcome Open Research 4: 74. Available: http://dx.doi.org/10.12688/wellcomeopenres.15059.1.
SponsorsThis work was supported by the Wellcome Trust . This research was supported by the European Community’s Seventh Framework Programme [FP7/2007-2013] Industry and Academia Partnerships and Pathways award  GENDRIVAX (Genome-Driven Vaccine Development for Bacterial Infections), through collaboration between the Novartis Vaccines Institute for Global Health, Wellcome Trust Sanger Institute, Swiss Tropical and Public Health Institute and the Kenya Medical Research Institute. Work at the Wellcome Trust Sanger Institute was supported by the Wellcome Trust . Work at the Quadram Institute was supported by BBSRC [BB/R012504/1]. GD was supported by Wellcome and the Cambridge BRC AMR theme.
PublisherF1000 ( Faculty of 1000 Ltd)
JournalWellcome Open Research
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