Card9 mediates susceptibility to intestinal pathogens through microbiota modulation and control of bacterial virulence

Bruno Lamas 1, 2 Marie-Laure Michel 2 Nadine Waldschmitt 3 Hang-Phuong Pham 4 Vassiliki Zacharioudaki 3 Louise Dupraz 2 Myriam Delacre 3 Jane M Natividad 2 Gregory Da Costa 2 Julien Planchais 2 Bruno Sovran 2 Chantal Bridonneau 2 Adrien Six 5 Philippe Langella 2 Mathias Richard 2 Mathias Chamaillard 3 Harry Sokol 6, 1, 2, *
* Auteur correspondant
1 LBM-E4 - Microorganismes, Molécules Bioactives et Physiopathologie Intestinale
INSERM - Institut National de la Santé et de la Recherche Médicale : U1057, UPMC - Université Pierre et Marie Curie - Paris 6
2 MICALIS - MICrobiologie de l'ALImentation au Service de la Santé humaine
3 CIIL - Centre d’Infection et d’Immunité de Lille (CIIL) - U1019 - UMR 8204
4 ILTOO Pharma
5 I3 - Immunologie - Immunopathologie - Immunothérapie
6 Service de Gastroentérologie et nutrition [CHU Saint-Antoine]
Abstract : Objective: In association with innate and adaptive immunity, the microbiota controls the colonisation resistance against intestinal pathogens. Caspase recruitment domain 9 (CARD9), a key innate immunity gene, is required to shape a normal gut microbiota. Card9–/– mice are more susceptible to the enteric mouse pathogen Citrobacter rodentium that mimics human infections with enteropathogenic and enterohaemorrhagic Escherichia coli. Here, we examined how CARD9 controls C. rodentium infection susceptibility through microbiota-dependent and microbiota-independent mechanisms. Design: C. rodentium infection was assessed in conventional and germ-free (GF) wild-type (WT) and Card9–/– mice. To explore the impact of Card9–/–microbiota in infection susceptibility, GF WT mice were colonised with WT (WT→GF) or Card9–/– (Card9–/–→GF) microbiota before C. rodentium infection. Microbiota composition was determined by 16S rDNA gene sequencing. Inflammation severity was determined by histology score and lipocalin level. Microbiota–host immune system interactions were assessed by quantitative PCR analysis. Results: CARD9 controls pathogen virulence in a microbiota-independent manner by supporting a specific humoral response. Higher susceptibility to C. rodentium-induced colitis was observed in Card9–/–→GF mice. The microbiota of Card9–/– mice failed to outcompete the monosaccharide-consuming C. rodentium, worsening the infection severity. A polysaccharide-enriched diet counteracted the ecological advantage of C. rodentium and the defective pathogen-specific antibody response in Card9–/– mice. Conclusions: CARD9 modulates the susceptibility to intestinal infection by controlling the pathogen virulence in a microbiota-dependent and microbiota-independent manner. Genetic susceptibility to intestinal pathogens can be overridden by diet intervention that restores humoural immunity and a competing microbiota.
Keywords : mono-and polysaccharides IBD germfree mice Citrobacter rodentium pathogen-specific antibody microbiota
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Article dans une revue
Gut, BMJ Publishing Group, 2017, pp.314195. 〈10.1136/gutjnl-2017-314195〉
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Bruno Lamas, Marie-Laure Michel, Nadine Waldschmitt, Hang-Phuong Pham, Vassiliki Zacharioudaki, et al.. Card9 mediates susceptibility to intestinal pathogens through microbiota modulation and control of bacterial virulence. Gut, BMJ Publishing Group, 2017, pp.314195. 〈10.1136/gutjnl-2017-314195〉. 〈hal-01586076〉

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