T cell-derived IL-22 directs mature colonocyte fate and upregulates host defense genes during Citrobacter rodentium infection.
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE227331 | GEO | 2024/04/11
REPOSITORIES: GEO
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Project description:T cell-derived IL-22 directs mature colonocyte fate and upregulates host defense genes during Citrobacter rodentium infection.
| PRJNA944665 | ENA
Project description:Citrobacter rodentium is an enteric bacterial pathogen of the mouse intestinal tract that triggers inflammatory responses resembling those of humans infected with enteropathogenic and enterohemorrhagic Escherichia coli. Inflammasome signaling is emerging as a central regulator of inflammatory and host responses to several pathogens, but the in vivo role of inflammasome signaling in host defense against C. rodentium has not been characterized. Here, we show that mice lacking the inflammasome components Nlrp3, Nlrc4, and caspase-1 were hypersusceptible to C. rodentium-induced gastrointestinal inflammation. This was due to defective interleukin (IL)-1? and IL-18 production given that il-1?(-/-) and il-18(-/-) mice also suffered from increased bacterial burdens and exacerbated histopathology. C. rodentium specifically activated the Nlrp3 inflammasome in in vitro-infected macrophages independently of a functional bacterial type III secretion system. Thus, production of IL-1? and IL-18 downstream of the Nlrp3 and Nlrc4 inflammasomes plays a critical role in host defense against enteric infections caused by C. rodentium.
| S-EPMC3351318 | biostudies-literature
Project description:Citrobacter rodentium is a gastrointestinal infection that requires early IL-22 from group 3 innate lymphoid cells (ILC3) for resistance. The role of vitamin D in the clearance of C. rodentium infection was tested in vitamin D sufficient (D+) and vitamin D deficient (D-) wildtype (WT) and Cyp27B1 (Cyp) KO mice (unable to produce the high affinity vitamin D ligand 1,25(OH)2D, 1,25D). Feeding Cyp KO mice D- diets reduced vitamin D levels and prevented synthesis of 1,25D. D- (WT and Cyp KO) mice had fewer ILC3 cells and less IL-22 than D+ mice. D- Cyp KO mice developed a severe infection that resulted in the lethality of the mice by d14 post-infection. T and B cell deficient D- Rag KO mice also developed a severe and lethal infection with C. rodentium compared to D+ Rag KO mice. D- WT mice survived the infection but took significantly longer to clear the C. rodentium infection than D+ WT or D+ Cyp KO mice. Treating infected D- Cyp KO mice with IL-22 protected the mice from lethality. Treating the D- WT mice with 1,25D reconstituted the ILC3 cells in the colon and protected the mice from C. rodentium. IL-22 treatment of D- WT mice eliminated the need for vitamin D to clear the C. rodentium infection. Vitamin D is required for early IL-22 production from ILC3 cells and protection from enteric infection with C. rodentium.
| S-EPMC6349822 | biostudies-literature
Project description:IBD is a complex autoimmune disease characterized by dysregulated interactions between host immune responses and microbiome at the intestinal epithelium interface. Here we identified shared protein alterations in intestinal epithelial differentiation and function between IBD and Citrobacter rodentium infected FVB mice. We discovered that prophylactic treatment with the mucosal healing therapy IL-22.Fc in the infected FVB mice reduced disease severity and rescued the mice from lethality. Notably, we observed an emergence of intermediate undifferentiated intestinal epithelial cells upon infection, with disrupted expression of the solute transporter machinery as well as components critical for intestinal barrier integrity. Multi-omics analyses revealed that with IL-22.Fc treatment several disease associated changes were prevented (including disruption of the solute transporter machinery), and proper physiological homeostatic functions of the intestine was restored. Taken together, we unveiled the disease relevance of the C. rodentium induced colitis model to IBD and demonstrated the protective role of the mucosal healing therapy IL-22.Fc in ameliorating the epithelial dysfunction.
2023-10-05 | PXD024688 | Pride
Project description:http://www.sanger.ac.uk/resources/downloads/bacteria/citrobacter-rodentium.htmlThis data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/
2013-10-07 | E-ERAD-168 | biostudies-arrayexpress
Project description:β2-integrins promote neutrophil recruitment to infected tissues and are crucial for host defense. Neutrophil recruitment is defective in leukocyte adhesion deficiency type-1 (LAD1), a condition caused by mutations in the CD18 (β2-integrin) gene. Using a model of Citrobacter rodentium (CR)-induced colitis, we show that CD18-/- mice display increased intestinal damage and systemic bacterial burden, compared to littermate controls, ultimately succumbing to infection. This phenotype is not attributed to defective neutrophil recruitment, as it is shared by CXCR2-/- mice that survive CR infection. CR-infected CD18-/- mice feature prominent upregulation of IL-17 and downregulation of IL-22. Exogenous IL-22 administration, but not endogenous IL-17 neutralization, protects CD18-/- mice from lethal colitis. β2-integrin expression on macrophages is mechanistically linked to Rac1/ROS-mediated induction of noncanonical-NLRP3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3) inflammasome-dependent IL-1β production, which promotes ILC3-derived IL-22. Therefore, β2-integrins are required for protective IL-1β-dependent IL-22 responses in colitis, and the identified mechanism may underlie the association of human LAD1 with colitis.
| S-EPMC6404229 | biostudies-literature
Project description:Innate immune cells, such as intestinal epithelial cells, dendritic cells (DCs), macrophages, granulocytes, and innate lymphoid cells provide a first line of defence to enteric pathogens. To study the role of CX(3)CR1(+) DCs and macrophages in host defence, we infected CX(3)CR1-GFP animals with Citrobacter rodentium. When transgenic CX(3)CR1-GFP animals are infected with the natural mouse pathogen C. rodentium, CX(3)CR1(-/-) animals showed a delayed clearance of C. rodentium as compared with (age- and sex-matched) wild-type B6 animals. The delayed clearance of C. rodentium is associated with reduced interleukin (IL)-22 expression. In C. rodentium-infected CX(3)CR1-GFP animals, IL-22 producing lymphoid-tissue inducer cells (LTi cells) were selectively reduced in the absence of CX(3)CR1. The reduced IL-22 expression correlates with decreased expression of the antimicrobial peptides RegIIIβ and RegIIIγ. The depletion of CX(3)CR1(+) cells by diphtheria toxin injection in CX(3)CR1-GFP × CD11c.DOG animals confirmed the role of CX(3)CR1(+) phagocytes in establishing IL-22 production, supporting the clearance of a C. rodentium infection.
| S-EPMC3534171 | biostudies-literature
Project description:The gut microbiota plays a crucial role in susceptibility to enteric pathogens, including Citrobacter rodentium, a model extracellular mouse pathogen that colonizes the colonic mucosa. C. rodentium infection outcomes vary between mouse strains, with C57BL/6 and C3H/HeN mice clearing and succumbing to the infection, respectively. Kanamycin (Kan) treatment at the peak of C57BL/6 mouse infection with Kan-resistant C. rodentium resulted in relocalization of the pathogen from the colonic mucosa and cecum to solely the cecal luminal contents; cessation of the Kan treatment resulted in rapid clearance of the pathogen. We now show that in C3H/HeN mice, following Kan-induced displacement of C. rodentium to the cecum, the pathogen stably colonizes the cecal lumens of 65% of the mice in the absence of continued antibiotic treatment, a phenomenon that we term antibiotic-induced bacterial commensalization (AIBC). AIBC C. rodentium was well tolerated by the host, which showed few signs of inflammation; passaged AIBC C. rodentium robustly infected naive C3H/HeN mice, suggesting that the AIBC state is transient and did not select for genetically avirulent C. rodentium mutants. Following withdrawal of antibiotic treatment, 35% of C3H/HeN mice were able to prevent C. rodentium commensalization in the gut lumen. These mice presented a bloom of a commensal species, Citrobacter amalonaticus, which inhibited the growth of C. rodentium in vitro in a contact-dependent manner and the luminal growth of AIBC C. rodentium in vivo. Overall, our data suggest that commensal species can confer colonization resistance to closely related pathogenic species. IMPORTANCE Gut bacterial infections involve three-way interactions between virulence factors, the host immune responses, and the microbiome. While the microbiome erects colonization resistance barriers, pathogens employ virulence factors to overcome them. Treating mice infected with kanamycin-resistant Citrobacter rodentium with kanamycin caused displacement of the pathogen from the colonic mucosa to the cecal lumen. Following withdrawal of the kanamycin treatment, 65% of the mice were persistently colonized by C. rodentium, which seemed to downregulate virulence factor expression. In this model of luminal gut colonization, 35% of mice were refractory to stable C. rodentium colonization, suggesting that their microbiotas were able to confer colonization resistance. We identify a commensal bacterium of the Citrobacter genus, C. amalonaticus, which inhibits C. rodentium growth in vitro and in vivo. These results show that the line separating commensal and pathogenic lifestyles is thin and multifactorial and that commensals may play a major role in combating enteric infection.
| S-EPMC8510533 | biostudies-literature
Project description:Citrobacter rodentium strain DBS100 causes an infection of the intestines in mice. It provides an important model for human gastrointestinal pathogens, such as enteropathogenic and enterohemorrhagic Escherichia coli, which cause life-threatening infections. To identify the genetic determinants that are common across the enteropathogenic bacteria, we sequenced the DBS100 genome.
| S-EPMC6588040 | biostudies-literature
Project description:Citrobacter rodentium is an enteropathogen that causes intestinal inflammatory responses in mice reminiscent of the pathology provoked by enteropathogenic and enterohemorrhagic Escherichia coli infections in humans. C. rodentium expresses various virulence factors that target specific signaling proteins involved in executing apoptotic, necroptotic and pyroptotic cell death, suggesting that each of these distinct cell death modes performs essential host defense functions that the pathogen aims to disturb. However, the relative contributions of apoptosis, necroptosis and pyroptosis in protecting the host against C. rodentium have not been elucidated. Here we used mice with single or combined deficiencies in essential signaling proteins controlling apoptotic, necroptotic or pyroptotic cell death to reveal the roles of these cell death modes in host defense against C. rodentium. Gastrointestinal C. rodentium infections in mice lacking GSDMD and/or MLKL showed that both pyroptosis and necroptosis were dispensable for pathogen clearance. In contrast, while RIPK3-deficient mice showed normal C. rodentium clearance, mice with combined caspase-8 and RIPK3 deficiencies failed to clear intestinal pathogen loads. Although this demonstrated a crucial role for caspase-8 signaling in establishing intestinal host defense, Casp8-/-Ripk3-/- mice remained capable of preventing systemic pathogen persistence. This systemic host defense relied on inflammasome signaling, as Casp8-/-Ripk3-/- mice with combined caspase-1 and -11 deletion succumbed to C. rodentium infection. Interestingly, although it is known that C. rodentium can activate the non-canonical caspase-11 inflammasome, selectively disabling canonical inflammasome signaling by single caspase-1 deletion sufficed to render Casp8-/-Ripk3-/- mice vulnerable to C. rodentium-induced lethality. Moreover, Casp8-/-Ripk3-/- mice lacking GSDMD survived a C. rodentium infection, suggesting that pyroptosis was not crucial for the protective functions of canonical inflammasomes in these mice. Taken together, our mouse genetic experiments revealed an essential cooperation between caspase-8 signaling and GSDMD-independent canonical inflammasome signaling to establish intestinal and systemic host defense against gastrointestinal C. rodentium infection.
| S-EPMC10119323 | biostudies-literature