Rapid transcriptional responses to serum exposure are associated with sensitivity and resistance to antibody-mediated complement killing in invasive Salmonella Typhimurium ST313.

Autor:	Ondari EM; Swiss Tropical and Public Health Institute, University of Basel, Basel, Switzerland.; University of Basel, Basel, Switzerland.; Novartis Vaccines Institute for Global Health, Siena, Italy.; Wellcome Trust Sanger Institute, Hinxton, UK., Klemm EJ; Wellcome Trust Sanger Institute, Hinxton, UK., Msefula CL; Wellcome Trust Sanger Institute, Hinxton, UK.; Malawi-Liverpool-Wellcome Trust Clinical Research Institute, Blantyre, Malawi.; Department of Microbiology, College of Medicine, University of Malawi, Blantyre, Malawi., El Ghany MA; Wellcome Trust Sanger Institute, Hinxton, UK.; The Westmead Institute for Medical Research and Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney, Westmead, Australia.; King Abdullah University of Science and Technology , Thuwal, Saudi Arabia., Heath JN; Institute of Immunology and Immuotherapy, University of Birmingham, Birmingham, UK., Pickard DJ; Wellcome Trust Sanger Institute, Hinxton, UK., Barquist L; Wellcome Trust Sanger Institute, Hinxton, UK.; Helmholtz Institute for RNA-based Infection Research , Würzburg, Germany.; Faculty of Medicine, University of Würzburg, Würzburg, Germany., Dougan G; Wellcome Trust Sanger Institute, Hinxton, UK.; Department of Medicine, University of Cambridge Addenbrooke's Hospital Cambridge, Cambridge, UK., Kingsley RA; Quadram Institute Bioscience, Norwich, UK., MacLennan CA; Institute of Immunology and Immuotherapy, University of Birmingham, Birmingham, UK.; Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
Jazyk:	angličtina
Zdroj:	Wellcome open research [Wellcome Open Res] 2019 Apr 25; Vol. 4, pp. 74. Date of Electronic Publication: 2019 Apr 25 (Print Publication: 2019).
DOI:	10.12688/wellcomeopenres.15059.1
Abstrakt:	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. Competing Interests: Competing interests: EMO and CAMacL are former employees of Novartis Vaccines Institute for Global Health (under ownership of GlaxoSmithKline at the time of data analysis and writing). CAMacL has been the recipient of a Clinical Research Fellowship from GlaxoSmithKline.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu