title: Emergence of host-adapted Salmonella Enteritidis through rapid evolution in an immunocompromised host.
abstract: Host adaptation is a key factor contributing to the emergence of new bacterial, viral and parasitic pathogens. Many pathogens are considered promiscuous because they cause disease across a range of host species, while others are host-adapted, infecting particular hosts(1). Host adaptation can potentially progress to host restriction, where the pathogen is strictly limited to a single host species and is frequently associated with more severe symptoms. Host-adapted and host-restricted bacterial clades evolve from within a broader host-promiscuous species and sometimes target different niches within their specialist hosts, such as adapting from a mucosal to a systemic lifestyle. Genome degradation, marked by gene inactivation and deletion, is a key feature of host adaptation, although the triggers initiating genome degradation are not well understood. Here, we show that a chronic systemic non-typhoidal Salmonella infection in an immunocompromised human patient resulted in genome degradation targeting genes that are expendable for a systemic lifestyle. We present a genome-based investigation of a recurrent blood-borne Salmonella enterica serotype Enteritidis (S. Enteritidis) infection covering 15 years in an interleukin-12 β1 receptor-deficient individual that developed into an asymptomatic chronic infection. The infecting S. Enteritidis harboured a mutation in the mismatch repair gene mutS that accelerated the genomic mutation rate. Phylogenetic analysis and phenotyping of multiple patient isolates provides evidence for a remarkable level of within-host evolution that parallels genome changes present in successful host-restricted bacterial pathogens but never before observed on this timescale. Our analysis identifies common pathways of host adaptation and demonstrates the role that immunocompromised individuals can play in this process.
authors: The Wellcome Trust Sanger Institute, The Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
authors: Elizabeth J
authors: EJ
authors: Klemm
authors: Department of Infectious Diseases, Cambridge University Hospitals, Cambridge CB2 0QQ, UK.|Medical Research Council Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, UK.
authors: Effrossyni
authors: E
authors: Gkrania-Klotsas
authors: The Wellcome Trust Sanger Institute, The Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
authors: James
authors: J
authors: Hadfield
authors: The Wellcome Trust Sanger Institute, The Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
authors: Jessica L
authors: JL
authors: Forbester
authors: The Wellcome Trust Sanger Institute, The Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
authors: Simon R
authors: http://orcid.org/0000-0003-1512-6194
authors: SR
authors: Harris
authors: The Wellcome Trust Sanger Institute, The Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
authors: Christine
authors: C
authors: Hale
authors: School of Immunity and Infection, College of Medicine and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.
authors: Jennifer N
authors: JN
authors: Heath
authors: The Wellcome Trust Sanger Institute, The Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
authors: Thomas
authors: T
authors: Wileman
authors: The Wellcome Trust Sanger Institute, The Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
authors: Simon
authors: S
authors: Clare
authors: The Wellcome Trust Sanger Institute, The Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
authors: Leanne
authors: L
authors: Kane
authors: The Wellcome Trust Sanger Institute, The Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
authors: David
authors: D
authors: Goulding
authors: The Wellcome Trust Sanger Institute, The Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
authors: Thomas D
authors: TD
authors: Otto
authors: The Wellcome Trust Sanger Institute, The Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
authors: Sally
authors: S
authors: Kay
authors: Department of Clinical Biochemistry and Immunology, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors: Rainer
authors: R
authors: Doffinger
authors: Clinical Microbiology and Public Health Laboratory, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors: Fiona J
authors: FJ
authors: Cooke
authors: Department of Infectious Diseases, Cambridge University Hospitals, Cambridge CB2 0QQ, UK.
authors: Andrew
authors: A
authors: Carmichael
authors: Department of Medicine, University of Cambridge, Cambridge CB2 0SP, UK.
authors: Andrew M L
authors: AM
authors: Lever
authors: The Wellcome Trust Sanger Institute, The Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
authors: Julian
authors: http://orcid.org/0000-0002-7069-5958
authors: J
authors: Parkhill
authors: The Wellcome Trust Sanger Institute, The Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.|School of Immunity and Infection, College of Medicine and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.
authors: Calman A
authors: CA
authors: MacLennan
authors: Department of Clinical Biochemistry and Immunology, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors: Dinakantha
authors: D
authors: Kumararatne
authors: The Wellcome Trust Sanger Institute, The Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.|Department of Medicine, University of Cambridge, Cambridge CB2 0SP, UK.
authors: Gordon
authors: G
authors: Dougan
authors: The Wellcome Trust Sanger Institute, The Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.|The Institute of Food Research, Norwich Research Park, Norwich, Norfolk NR4 7UA, UK.
authors: Robert A
authors: RA
authors: Kingsley
mesh_terms: D000220:Adaptation, Biological; D016470:Bacteremia / Q000382:microbiology*; D019143:Evolution, Molecular; D017353:Gene Deletion; D014644:Genetic Variation; D016680:Genome, Bacterial; D054884:Host-Pathogen Interactions; D006801:Humans; D016867:Immunocompromised Host; D051719:MutS DNA Mismatch-Binding Protein / Q000172:deficiency; D059645:Mutation Rate; D010802:Phylogeny; D012480:Salmonella Infections / Q000382:microbiology*; D012477:Salmonella enteritidis / Q000145:classification / Q000235:genetics* / Q000302:isolation & purification*; D013997:Time Factors
chemical_list: D051719:MutS DNA Mismatch-Binding Protein