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Review
. 2021 Oct:63:142-149.
doi: 10.1016/j.mib.2021.07.003. Epub 2021 Aug 3.

Regulation of Citrobacter rodentium colonization: virulence, immune response and microbiota interactions

Gustavo Caballero-Flores  1 , Joseph M Pickard  2 , Gabriel Núñez  3
Affiliations
Review

Regulation of Citrobacter rodentium colonization: virulence, immune response and microbiota interactions

Gustavo Caballero-Flores et al. Curr Opin Microbiol. 2021 Oct.

Abstract

Citrobacter rodentium is a mouse-specific pathogen commonly used to model infection by human Enteropathogenic Escherichia coli, an important cause of infant diarrhea and mortality worldwide. In the early phase of infection, C. rodentium overcomes competition by the gut microbiota for successful replication. Then, the pathogen uses a type three secretion system (T3SS) to inject effector proteins into intestinal epithelial cells and induce metabolic and inflammatory conditions that promote colonization of the intestinal epithelium. C. rodentium also elicits highly coordinated innate and adaptive immune responses in the gut that regulate pathogen colonization and eradication. In this review, we highlight recent work on the regulation and function of the C. rodentium T3SS, the mechanisms employed by the pathogen to evade competition by the microbiota, and the function of the host immune response against infection.

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Conflict of interest statement

Conflict of interest statement Nothing declared.

Figures

Figure 1.
Figure 1.. Regulation of C. rodentium virulence and pathogen-microbiota interactions in the gut.
Depletion of dietary amino acids (AAs) by the gut microbiota limits C. rodentium early expansion, while the pathogen subverts AA depletion through induction of AA biosynthesis. Increased levels of dietary AA promote pathogen colonization. Pectin-derived Galacturonic acid (GA) is used as a carbon source for initial pathogen expansion whereas reduced levels of GA induce LEE expression later during infection. Various microbiota-derived molecules influence C. rodentium colonization and/or LEE virulence expression including butyrate, indole, and succinate. Host-derived molecules also modulate pathogen colonization through regulation of LEE, including membrane-derived endocannabinoid 2-arachidonoyl glycerol (2-AG), the neurotransmitters Epinephrine (Epi), Norepinephrine (NE) and serotonin, and the mucus layer component fucose. C. rodentium relies on anaerobic (H2O2) respiration for initial colonization of the mucosa, a process dependent on the expression of the LEE-encoded T3SS. At the onset of acute inflammation, the pathogen attaches to the intestinal epithelial cells (IECs) and uses the T3SS to inject several effector proteins, which exhibit context-dependent essentiality. This leads to a shift from oxidative phosphorylation (OXPHOS) to aerobic glycolysis in IECs and increased oxygenation of the mucosa, thereby promoting expansion of C. rodentium and symbiotic facultative anaerobes through aerobic respiration. Pre-infection with Yersinia pseudotuberculosis protects against C. rodentium infection through microbiota production of taurine-derived sulfide (H2S), an inhibitor of pathogen aerobic respiration. Dietary L-Serine (L-Ser) is utilized by the pathogen as a carbon source in the inflamed gut, whereas L-Arginine (L-Arg) may play a dual role during acute and late phases of infection. Under normal circumstances, C. rodentium relocates to the intestinal lumen and is eradicated from the gut through various mechanisms including competition for nutrients by symbiotic bacteria. Administration of a high fat/low fiber diet can lead to persistent infection with low grade inflammation. EC, Enterochromaffin cell (EC).
Figure 2.
Figure 2.. Innate and adaptive immune responses elicited by C. rodentium.
During early infection, maternal IgG against TSS3 proteins are transferred from the mother to the offspring in breast milk, coating the pathogen in the intestinal lumen and reducing its attachment to the intestinal epithelium. Lypd8, produced by intestinal epithelial cells (IECs), also inhibits pathogen attachment through binding to the C. rodentium surface adhesin, Intimin. IL-22 is essential for host survival during the onset of C. rodentium-induced inflammation. IL-36γ promotes production of IL-23, which subsequently induces ILC3-dependent IL-22 release. IL-1β and IL-6 also induce IL-22, which in turn triggers secretion of anti-microbial peptides (AMP) by IECs. The microbiota-derived SCFAs, acetate and butyrate also promote IL-22 production by ILC3, intraepithelial lymphocytes (IELs) and T cells. IL-22 production can also be augmented by dietary vitamin D in ILC3s. Likewise, vitamin A enhances the protective function of IECs, phagocytes and T cells. ChAT+ T cells produce acetylcholine (ACh), a neurotransmitter inducing protective Nitric oxide (NO) by IECs. Conversely, IL-33 reduces the numbers of Th17 cells and protective IL-17, resulting in a worsened disease. At late stages of infection, IL-1R signaling in Grem1+ mesenchymal cells promote epithelial healing through production R-spondin 3 that stimulate by intestinal stem cells. An adaptive, pathogen-specific IgG immune response specifically targets T3SS surface proteins of virulent C. rodentium and marks it for elimination by neutrophils. Neutrophils promote pathogen eradication by phagocytosis of opsonized bacteria, secretion of enzymes, reactive oxygen and nitrogen species, and/or NET formation at the epithelial surface. Finally, the gut microbiota outcompetes and eradicates remaining avirulent C. rodentium from the lumen by various ways, including nutrient competition. During secondary infection, pathogen-specific memory T cells in the gut can be reactivated to produce IL-22.
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