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Basic Processes in -Host Interactions: Within-Host Evolution and the Transmission of the Virulent Genotype

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  • Authors: Médéric Diard1, Wolf-Dietrich Hardt2
  • Editors: Fernando Baquero3, Emilio Bouza4, J.A. Gutiérrez-Fuentes5, Teresa M. Coque6
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Institute of Microbiology, Department of Biology, ETH Zurich, Zurich, Switzerland; 2: Institute of Microbiology, Department of Biology, ETH Zurich, Zurich, Switzerland; 3: Hospital Ramón y Cajal (IRYCIS), Madrid, Spain; 4: Hospital Ramón y Cajal (IRYCIS), Madrid, Spain; 5: Complutensis University, Madrid, Spain; 6: Hospital Ramón y Cajal (IRYCIS), Madrid, Spain
  • Source: microbiolspec September 2017 vol. 5 no. 5 doi:10.1128/microbiolspec.MTBP-0012-2016
  • Received 17 February 2017 Accepted 26 June 2017 Published 07 September 2017
  • Wolf-Dietrich Hardt, hardt@micro.biol.ethz.ch
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  • Abstract:

    Transmission and virulence are central aspects of pathogen evolution. However, in many cases their interconnection has proven difficult to assess by experimentation. Here we discuss recent advances from a mouse model for diarrhea. Mouse models mimic the enhanced susceptibility of antibiotic-treated individuals to nontyphoidal salmonellosis. In streptomycin-pretreated mice, subspecies 1 serovar Typhimurium efficiently colonizes the gut lumen and elicits pronounced enteropathy. In the host’s gut, Typhimurium forms two subpopulations that cooperate to elicit disease and optimize transmission. The disease-causing subpopulation expresses a set of dedicated virulence factors (the type 3 secretion system 1 [TTSS-1]) that drive gut tissue invasion. The virulence factor expression is “costly” by retarding the growth rate and exposing the pathogen to innate immune defenses within the gut tissue. These costs are compensated by the gut inflammation (a “public good”) that is induced by the invading subpopulation. The inflamed gut lumen fuels Typhimurium growth, in particular that of the TTSS-1 “off” subpopulation. The latter grows up to very high densities and promotes transmission. Thus, both phenotypes cooperate to elicit disease and ensure transmission. This system has provided an experimental framework for studying within-host evolution of pathogen virulence, how cooperative virulence is stabilized, and how environmental changes (e.g., antibiotic therapy) affect the transmission of the virulent genotype.

  • Keywords: Salmonella Typhimurium; cooperative virulence; transmission; experimental evolution; division of labor; antibiotics; persisters; phenotypic variability

  • Citation: Diard M, Hardt W. 2017. Basic Processes in -Host Interactions: Within-Host Evolution and the Transmission of the Virulent Genotype. Microbiol Spectrum 5(5):MTBP-0012-2016. doi:10.1128/microbiolspec.MTBP-0012-2016.

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/content/journal/microbiolspec/10.1128/microbiolspec.MTBP-0012-2016
2017-09-07
2017-11-21

Abstract:

Transmission and virulence are central aspects of pathogen evolution. However, in many cases their interconnection has proven difficult to assess by experimentation. Here we discuss recent advances from a mouse model for diarrhea. Mouse models mimic the enhanced susceptibility of antibiotic-treated individuals to nontyphoidal salmonellosis. In streptomycin-pretreated mice, subspecies 1 serovar Typhimurium efficiently colonizes the gut lumen and elicits pronounced enteropathy. In the host’s gut, Typhimurium forms two subpopulations that cooperate to elicit disease and optimize transmission. The disease-causing subpopulation expresses a set of dedicated virulence factors (the type 3 secretion system 1 [TTSS-1]) that drive gut tissue invasion. The virulence factor expression is “costly” by retarding the growth rate and exposing the pathogen to innate immune defenses within the gut tissue. These costs are compensated by the gut inflammation (a “public good”) that is induced by the invading subpopulation. The inflamed gut lumen fuels Typhimurium growth, in particular that of the TTSS-1 “off” subpopulation. The latter grows up to very high densities and promotes transmission. Thus, both phenotypes cooperate to elicit disease and ensure transmission. This system has provided an experimental framework for studying within-host evolution of pathogen virulence, how cooperative virulence is stabilized, and how environmental changes (e.g., antibiotic therapy) affect the transmission of the virulent genotype.

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Figures

Image of FIGURE 1
FIGURE 1

Red arrows depict the potential for Typhimurium ( Tm) transmission to the next host during each step. Blue- and red-colored cells depict healthy and inflamed guts, respectively. PMN, polymorphonuclear neutrophils; DC, dendritic cells; MΦ, macrophages; IgA/G, immunoglobulin A/G produced as part of the host’s adaptive immune response 2 weeks postinfection—this follows the regrowth of (2nd bloom) after a population bottleneck inflicted by the innate immune response (at day 2 postinfection); IL-18, interleukin-18; Casp-1, caspase-1.

Source: microbiolspec September 2017 vol. 5 no. 5 doi:10.1128/microbiolspec.MTBP-0012-2016
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Image of FIGURE 2
FIGURE 2

(A) (Left) Bimodal expression of . The population of Typhimurium is divided into cells that express and cells that do not. (Right) Microscopy picture showing microcolonies on an agar pad of slow-growing “on” cells (expressing green fluorescent protein [GFP] under the control of P, the promoter controlling the SPI-1 operon ) and fast-growing “off” cells. Reproduced with permission from reference 49 . (B) The “on” cells enter into the mucosa and trigger inflammation. Most of these cells are killed by the mucosal innate immune response. Moreover, expression correlates with a substantial growth retardation. The “off” cells grow quickly in the lumen, ensuring the transmission of the virulent genotype. The inflammation is a public good shared among all cells in the lumen. (C) Colony blot obtained and described in reference 14 . Within-host evolution of Typhimurium leads to the rise of avirulent mutants (defectors), which are clones that do not express . The frequency of defectors was increasing between day 2 and day 10 postinfection (p.i.).

Source: microbiolspec September 2017 vol. 5 no. 5 doi:10.1128/microbiolspec.MTBP-0012-2016
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Image of FIGURE 3
FIGURE 3

(Left) In the absence of antibiotics, defectors can reach fixation and their transmission to the next host prevents disease. (Right) Antibiotics kill all cells in the lumen: defectors ( mutants) and virulent wild-type () cooperators. However, cells survive in the tissues and can reseed the lumen upon antibiotic withdrawal. This leads to successful transmission of the virulent genotype to the next hosts. Reproduced with permission from reference 73 .

Source: microbiolspec September 2017 vol. 5 no. 5 doi:10.1128/microbiolspec.MTBP-0012-2016
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Tables

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TABLE 1

Asymptomatic carriage of bona fide pathogenic bacteria in humans

Source: microbiolspec September 2017 vol. 5 no. 5 doi:10.1128/microbiolspec.MTBP-0012-2016

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