title: Role of disease-associated tolerance in infectious superspreaders.
abstract: Natural populations show striking heterogeneity in their ability to transmit disease. For example, a minority of infected individuals known as superspreaders carries out the majority of pathogen transmission events. In a mouse model of Salmonella infection, a subset of infected hosts becomes superspreaders, shedding high levels of bacteria (>10(8) cfu per g of feces) but remain asymptomatic with a dampened systemic immune state. Here we show that superspreader hosts remain asymptomatic when they are treated with oral antibiotics. In contrast, nonsuperspreader Salmonella-infected hosts that are treated with oral antibiotics rapidly shed superspreader levels of the pathogen but display signs of morbidity. This morbidity is linked to an increase in inflammatory myeloid cells in the spleen followed by increased production of acute-phase proteins and proinflammatory cytokines. The degree of colonic inflammation is similar in antibiotic-treated superspreader and nonsuperspreader hosts, indicating that the superspreader hosts are tolerant of antibiotic-mediated perturbations in the intestinal tract. Importantly, neutralization of acute-phase proinflammatory cytokines in antibiotic-induced superspreaders suppresses the expansion of inflammatory myeloid cells and reduces morbidity. We describe a unique disease-associated tolerance to oral antibiotics in superspreaders that facilitates continued transmission of the pathogen.
authors.affiliation: Departments of Microbiology and Immunology.
authors.forename: Smita
authors.initials: S
authors.lastname: Gopinath
authors.affiliation: Chemical and Systems Biology.
authors.forename: Joshua S
authors.initials: JS
authors.lastname: Lichtman
authors.affiliation: Comparative Medicine, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Bouley
authors.affiliation: Chemical and Systems Biology.
authors.forename: Joshua E
authors.initials: JE
authors.lastname: Elias
authors.affiliation: Departments of Microbiology and Immunology, dmonack@stanford.edu.
authors.forename: Denise M
authors.initials: DM
authors.lastname: Monack
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D016207:Cytokines / Q000276:immunology; D018562:Disease Transmission, Infectious; D024881:Drug Resistance, Bacterial; D051379:Mice; D022423:Myeloid Cells / Q000276:immunology / Q000473:pathology; D012480:Salmonella Infections / Q000188:drug therapy / Q000276:immunology / Q000635:transmission*; D012486:Salmonella typhimurium / Q000276:immunology / Q000472:pathogenicity*
chemical_list: D000900:Anti-Bacterial Agents; D016207:Cytokines
keywords: acute phase response; carriers; host-to-host transmission; pathogenesis