title: Persistent Infections by Nontyphoidal Salmonella in Humans: Epidemiology and Genetics.
abstract: BACKGROUND
  Although chronic infections by typhoidal Salmonella are well-known, prolonged human infections by nontyphoidal Salmonella (NTS) are poorly characterized.
  
  
  METHODS
  We retrospectively analyzed 48 345 culture-confirmed NTS infections that occurred in Israel 1995-2012. A case-control study was performed to identify risk factors associated with persistent infections. Whole-genome-sequencing, pulsed-field gel electrophoresis (PFGE), and a mouse infection model were used to study genetic and phenotypic differences between same-patient persistent, recurring isolates.
  
  
  RESULTS
  In total, 1047 cases of persistent NTS infections, comprising 2.2% of all reported cases of salmonellosis, were identified. The persistence periods ranged between 30 days to 8.3 years. The majority (93%) of the persistently infected patients were immunocompetent, and 65% were symptomatic with relapsing diarrhea, indicating a distinct clinical manifestation from the asymptomatic carriage of typhoidal Salmonella. Four NTS serovars (Mbandaka, Bredeney, Infantis and Virchow) were found to be significantly more frequently associated with persistence than others. Comparative genomics between early and later isolates obtained from the same patients confirmed clonal infection and showed 0 to 10 SNPs between persistent isolates. A different composition of mobile genetic elements (plasmids and phages) or amino acid substitutions in global regulators was identified in multiple cases. These changes resulted in differences in phenotype and virulence between early and later same-patient isolates.
  
  
  CONCLUSIONS
  These results illuminate the overlooked clinical manifestation of persistent salmonellosis that can serve as a human reservoir for NTS infections. Additionally, we demonstrate mechanisms of in-host microevolution and exhibit their potential to shape Salmonella pathogenicity, antimicrobial resistance and host-pathogen interactions.
authors.affiliation: Infectious Diseases Research Laboratory, Sheba Medical Center, Tel-Hashomer.|Department of Epidemiology and Preventive Medicine, Sackler Faculty of Medicine, Tel Aviv University, Israel.
authors.forename: Alex
authors.initials: A
authors.lastname: Marzel
authors.affiliation: Department of Microbiology and Molecular Genetics, University of California, Irvine.
authors.forename: Prerak T
authors.initials: PT
authors.lastname: Desai
authors.affiliation: Infectious Diseases Research Laboratory, Sheba Medical Center, Tel-Hashomer.|Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University.
authors.forename: Alina
authors.initials: A
authors.lastname: Goren
authors.affiliation: Ministry of Health Central Laboratories, Jerusalem.
authors.forename: Yosef Ilan
authors.initials: YI
authors.lastname: Schorr
authors.affiliation: Ministry of Health Central Laboratories, Jerusalem.
authors.forename: Israel
authors.initials: I
authors.lastname: Nissan
authors.affiliation: Department of Microbiology and Molecular Genetics, University of California, Irvine.
authors.forename: Steffen
authors.initials: S
authors.lastname: Porwollik
authors.affiliation: Ministry of Health Central Laboratories, Jerusalem.
authors.forename: Lea
authors.initials: L
authors.lastname: Valinsky
authors.affiliation: Department of Microbiology and Molecular Genetics, University of California, Irvine.
authors.forename: Michael
authors.initials: M
authors.lastname: McClelland
authors.affiliation: Infectious Diseases Research Laboratory, Sheba Medical Center, Tel-Hashomer.|Sackler Faculty of Medicine, Tel Aviv University, Israel.
authors.forename: Galia
authors.initials: G
authors.lastname: Rahav
authors.affiliation: Infectious Diseases Research Laboratory, Sheba Medical Center, Tel-Hashomer.|Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University.
authors.forename: Ohad
authors.initials: O
authors.lastname: Gal-Mor
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D002648:Child; D002675:Child, Preschool; D002908:Chronic Disease; D004269:DNA, Bacterial; D004195:Disease Models, Animal; D005260:Female; D016680:Genome, Bacterial / Q000235:genetics; D006801:Humans; D007223:Infant; D007557:Israel / Q000453:epidemiology; D008297:Male; D051379:Mice; D012189:Retrospective Studies; D012480:Salmonella Infections / Q000453:epidemiology* / Q000382:microbiology*; D019779:Salmonella enterica / Q000235:genetics* / Q000472:pathogenicity*; D017422:Sequence Analysis, DNA; D055815:Young Adult
chemical_list: D004269:DNA, Bacterial
keywords: Salmonella enterica; WGS; epidemiology; persistent infection; salmonellosis