article · 01/12/2014
Granulocytes Impose a Tight Bottleneck upon the Gut Luminal Pathogen Population during Salmonella Typhimurium Colitis
Résumé
Topological, chemical and immunological barriers are thought to limit infection by enteropathogenic bacteria. However, in many cases these barriers and their consequences for the infection process remain incompletely understood. Here, we employed a mouse model for Salmonella colitis and a mixed inoculum approach to identify barriers limiting the gut luminal pathogen population. Mice were infected via the oral route with wild type S. Typhimurium (S. Tm) and/or mixtures of phenotypically identical but differentially tagged S. Tm strains ({''}WITS'', wild-type isogenic tagged strains), which can be individually tracked by quantitative real-time PCR. WITS dilution experiments identified a substantial loss in tag/genetic diversity within the gut luminal S. Tm population by days 2-4 post infection. The diversity-loss was not attributable to overgrowth by S. Tm mutants, but required inflammation, Gr-1(+) cells (mainly neutrophilic granulocytes) and most likely NADPH-oxidase-mediated defense, but not iNOS. Mathematical modelling indicated that inflammation inflicts a bottleneck transiently restricting the gut luminal S. Tm population to approximately 6000 cells and plating experiments verified a transient, inflammation-and Gr-1(+) cell-dependent dip in the gut luminal S. Tm population at day 2 post infection. We conclude that granulocytes, an important clinical hallmark of S. Tm-induced inflammation, impose a drastic bottleneck upon the pathogen population. This extends the current view of inflammation-fuelled gut-luminal Salmonella growth by establishing the host response in the intestinal lumen as a double-edged sword, fostering and diminishing colonization in a dynamic equilibrium. Our work identifies a potent immune defense against gut infection and reveals a potential Achilles' heel of the infection process which might be targeted for therapy.
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Maier, L., Diard, M., Sellin, M.-E., Chouffane, E.-S., Trautwein-Weidner, K., Periaswamy, B., Slack, E., Dolowschiak, T., Stecher, B., Loverdo, C., Regoes, R.-R., & Hardt, W.-D. (2014). Granulocytes Impose a Tight Bottleneck upon the Gut Luminal Pathogen Population during Salmonella Typhimurium Colitis. PLoS Pathog., 10(12). https://doi.org/10.1371/journal.ppat.1004557@article{Maier2014_298,
author = {Maier, Lisa and Diard, Mederic and Sellin, Mikael E. and Chouffane, Elsa-Sarah and Trautwein-Weidner, Kerstin and Periaswamy, Balamurugan and Slack, Emma and Dolowschiak, Tamas and Stecher, Baerbel and Loverdo, Claude and Regoes, Roland R. and Hardt, Wolf-Dietrich},
year = {2014},
month = {12},
title = {Granulocytes Impose a Tight Bottleneck upon the Gut Luminal Pathogen Population during Salmonella Typhimurium Colitis},
journal = {PLoS Pathog.},
publisher = {PUBLIC LIBRARY SCIENCE},
volume = {10},
number = {12},
address = {1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA},
abstract = {Topological, chemical and immunological barriers are thought to limit infection by enteropathogenic bacteria. However, in many cases these barriers and their consequences for the infection process remain incompletely understood. Here, we employed a mouse model for Salmonella colitis and a mixed inoculum approach to identify barriers limiting the gut luminal pathogen population. Mice were infected via the oral route with wild type S. Typhimurium (S. Tm) and/or mixtures of phenotypically identical but differentially tagged S. Tm strains (\{''\}WITS'', wild-type isogenic tagged strains), which can be individually tracked by quantitative real-time PCR. WITS dilution experiments identified a substantial loss in tag/genetic diversity within the gut luminal S. Tm population by days 2-4 post infection. The diversity-loss was not attributable to overgrowth by S. Tm mutants, but required inflammation, Gr-1(+) cells (mainly neutrophilic granulocytes) and most likely NADPH-oxidase-mediated defense, but not iNOS. Mathematical modelling indicated that inflammation inflicts a bottleneck transiently restricting the gut luminal S. Tm population to approximately 6000 cells and plating experiments verified a transient, inflammation-and Gr-1(+) cell-dependent dip in the gut luminal S. Tm population at day 2 post infection. We conclude that granulocytes, an important clinical hallmark of S. Tm-induced inflammation, impose a drastic bottleneck upon the pathogen population. This extends the current view of inflammation-fuelled gut-luminal Salmonella growth by establishing the host response in the intestinal lumen as a double-edged sword, fostering and diminishing colonization in a dynamic equilibrium. Our work identifies a potent immune defense against gut infection and reveals a potential Achilles' heel of the infection process which might be targeted for therapy.},
url = {http://www.dx.doi.org/10.1371/journal.ppat.1004557},
doi = {10.1371/journal.ppat.1004557},
issn = {1553-7366},
}TY - JOUR
AU - Maier, Lisa
AU - Diard, Mederic
AU - Sellin, Mikael E.
AU - Chouffane, Elsa-Sarah
AU - Trautwein-Weidner, Kerstin
AU - Periaswamy, Balamurugan
AU - Slack, Emma
AU - Dolowschiak, Tamas
AU - Stecher, Baerbel
AU - Loverdo, Claude
AU - Regoes, Roland R.
AU - Hardt, Wolf-Dietrich
PY - 2014
DA - 2014/12/01
TI - Granulocytes Impose a Tight Bottleneck upon the Gut Luminal Pathogen Population during Salmonella Typhimurium Colitis
JO - PLoS Pathog.
VL - 10
IS - 12
PB - PUBLIC LIBRARY SCIENCE
SN - 1553-7366
AB - Topological, chemical and immunological barriers are thought to limit infection by enteropathogenic bacteria. However, in many cases these barriers and their consequences for the infection process remain incompletely understood. Here, we employed a mouse model for Salmonella colitis and a mixed inoculum approach to identify barriers limiting the gut luminal pathogen population. Mice were infected via the oral route with wild type S. Typhimurium (S. Tm) and/or mixtures of phenotypically identical but differentially tagged S. Tm strains ({''}WITS'', wild-type isogenic tagged strains), which can be individually tracked by quantitative real-time PCR. WITS dilution experiments identified a substantial loss in tag/genetic diversity within the gut luminal S. Tm population by days 2-4 post infection. The diversity-loss was not attributable to overgrowth by S. Tm mutants, but required inflammation, Gr-1(+) cells (mainly neutrophilic granulocytes) and most likely NADPH-oxidase-mediated defense, but not iNOS. Mathematical modelling indicated that inflammation inflicts a bottleneck transiently restricting the gut luminal S. Tm population to approximately 6000 cells and plating experiments verified a transient, inflammation-and Gr-1(+) cell-dependent dip in the gut luminal S. Tm population at day 2 post infection. We conclude that granulocytes, an important clinical hallmark of S. Tm-induced inflammation, impose a drastic bottleneck upon the pathogen population. This extends the current view of inflammation-fuelled gut-luminal Salmonella growth by establishing the host response in the intestinal lumen as a double-edged sword, fostering and diminishing colonization in a dynamic equilibrium. Our work identifies a potent immune defense against gut infection and reveals a potential Achilles' heel of the infection process which might be targeted for therapy.
DO - 10.1371/journal.ppat.1004557
UR - http://www.dx.doi.org/10.1371/journal.ppat.1004557
ER -