title: Intraspecies variation in the emergence of hyperinfectious bacterial strains in nature.
abstract: Salmonella is a principal health concern because of its endemic prevalence in food and water supplies, the rise in incidence of multi-drug resistant strains, and the emergence of new strains associated with increased disease severity. Insights into pathogen emergence have come from animal-passage studies wherein virulence is often increased during infection. However, these studies did not address the prospect that a select subset of strains undergo a pronounced increase in virulence during the infective process- a prospect that has significant implications for human and animal health. Our findings indicate that the capacity to become hypervirulent (100-fold decreased LD(50)) was much more evident in certain S. enterica strains than others. Hyperinfectious salmonellae were among the most virulent of this species; restricted to certain serotypes; and more capable of killing vaccinated animals. Such strains exhibited rapid (and rapidly reversible) switching to a less-virulent state accompanied by more competitive growth ex vivo that may contribute to maintenance in nature. The hypervirulent phenotype was associated with increased microbial pathogenicity (colonization; cytotoxin production; cytocidal activity), coupled with an altered innate immune cytokine response within infected cells (IFN-β; IL-1β; IL-6; IL-10). Gene expression analysis revealed that hyperinfectious strains display altered transcription of genes within the PhoP/PhoQ, PhoR/PhoB and ArgR regulons, conferring changes in the expression of classical virulence functions (e.g., SPI-1; SPI-2 effectors) and those involved in cellular physiology/metabolism (nutrient/acid stress). As hyperinfectious strains pose a potential risk to human and animal health, efforts toward mitigation of these potential food-borne contaminants may avert negative public health impacts and industry-associated losses.
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, California, United States of America.
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Heithoff
authors.forename: William R
authors.initials: WR
authors.lastname: Shimp
authors.forename: John K
authors.initials: JK
authors.lastname: House
authors.forename: Yi
authors.initials: Y
authors.lastname: Xie
authors.forename: Bart C
authors.initials: BC
authors.lastname: Weimer
authors.forename: Robert L
authors.initials: RL
authors.lastname: Sinsheimer
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Mahan
mesh_terms: D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015964:Gene Expression Regulation, Bacterial; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D051379:Mice; D018085:Regulon; D012475:Salmonella / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000472:pathogenicity*; D012480:Salmonella Infections / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000635:transmission; D037521:Virulence Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D016207:Cytokines; D037521:Virulence Factors