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. 2016 Sep 16;353(6305):1249-53.
doi: 10.1126/science.aag3042. Epub 2016 Sep 15.

V体育平台登录 - Virulence factors enhance Citrobacter rodentium expansion through aerobic respiration

Christopher A Lopez  1 , Brittany M Miller  1 , Fabian Rivera-Chávez  1 , Eric M Velazquez  1 , Mariana X Byndloss  1 , Alfredo Chávez-Arroyo  1 , Kristen L Lokken  1 , Renée M Tsolis  1 , Sebastian E Winter  2 , Andreas J Bäumler  3
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VSports手机版 - Virulence factors enhance Citrobacter rodentium expansion through aerobic respiration

Christopher A Lopez et al. Science. .

Abstract

Citrobacter rodentium uses a type III secretion system (T3SS) to induce colonic crypt hyperplasia in mice, thereby gaining an edge during its competition with the gut microbiota through an unknown mechanism. Here, we show that by triggering colonic crypt hyperplasia, the C. rodentium T3SS induced an excessive expansion of undifferentiated Ki67-positive epithelial cells, which increased oxygenation of the mucosal surface and drove an aerobic C. rodentium expansion in the colon. Treatment of mice with the γ-secretase inhibitor dibenzazepine to diminish Notch-driven colonic crypt hyperplasia curtailed the fitness advantage conferred by aerobic respiration during C. rodentium infection. We conclude that C VSports手机版. rodentium uses its T3SS to induce histopathological lesions that generate an intestinal microenvironment in which growth of the pathogen is fueled by aerobic respiration. .

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Figures

Figure 1
Figure 1. Oxygen respiration supports C. rodentium expansion in the mouse colon
(A) C57BL/6 (C57) mice were infected with C. rodentium wild type (wt, DBS100) and either a moaA mutant (CAL142) or a napA narG narZ mutant (CAL93). (B) Conventional C57 or germ-free Swiss Webster (SW) mice were infected with wt C. rodentium and either a moaA mutant, a fdnG mutant (CAL210 [pWSK129]), or a fdoG mutant (CAL261). N is indicated in Fig. S3E. (C) Competitive in vitro growth (N =8) of C. rodentium wild type (wt) and a cydAB mutant (CAL247) for 16 hours in minimal medium in the presence of the indicated oxygen levels (% O2). (D) Conventional or germ-free mice were infected with an equal mixture of the C. rodentium wild type (wt) and a cydAB mutant. (A and D) N = 4. (E) C. rodentium was grown in minimal medium supplemented with mannose as a carbon source under either microaerobic or anaerobic conditions. (F) Bacterial RNA was isolated from either mucus scrapings or colon contents of C. rodentium-infected mice. (E–F) The transcript levels of sucA were quantified by real-time PCR, normalized to 16S rRNA levels and shown as fold-changes. N is shown in Fig. S4B and S4C. (G–I) Mice (N indicated in I) were either mock-treated, infected with the C. rodentium wild type (wt) or with a cydAB mutant (CAL247). (G) Enumeration of C. rodentium by plating on selective media. (A–G) Bars represent geometric mean ± standard error. (H) Boxes in Whisker plots represent the second and third quartiles of combined histopathology scores, while lines indicate the first and fourth quartiles. (I) Microbial representation at the class-level based on 16S rRNA gene sequencing of colon contents 7 days after infection. Color-coding for classes is shown on the right. *, P < 0.05; **, P < 0.01; ns, not statistically significantly different.
Figure 2
Figure 2. A functional T3SS increases epithelial oxygenation and drives a CydAB-dependent C. rodentium expansion
(A) Mice (N is indicated in Fig. S8A) were infected with the indicated C. rodentium strain mixtures. Bars represent geometric means of the competitive index (CI) ± standard error. (B) Representative images of colonic sections stained to detect pimonidazole hypoxia stain (red fluorescence) and counterstained with DAPI nuclear stain (blue fluorescence). Arrow heads point to the mucosal surface. E, epithelial cell; L, lumen. (C) Pimonidazole staining (PMDZ+) was quantified by flow cytometry in colonic epithelial (CD45− CD326+) cells. White bars indicate the level of background staining observed in mice that were not injected with PMDZ. Bars represent geometric mean ± standard error. **, P < 0.01; *, P < 0.05; ns, not statistically significantly different; wt, DBS100; cydAB, CAL247; cfcH, BMM12; cfcH cydAB, BMM11; eae, CAL290; eae cydAB, CAL291; escN, CAL286; escN cydAB, CAL287; espH cesF map, BMM30; espH cesF map cydAB, BMM40.
Figure 3
Figure 3. Colonic crypt hyperplasia drives a CydAB-dependent C. rodentium expansion
(A–C) C57BL/6 mice were mock infected or infected with the C. rodentium wild type (wt, DBS100) or an espH cesF map mutant (BMM30). (D–F) C57BL/6 mice were mock infected or infected with a 1:1 mixture of the C. rodentium wild type (wt) and a cydAB mutant (CAL247). Mice were either treated with dibenzazepine (DBZ) or with vehicle control. (A–F) Organs were collected seven days after infection. (A) CFU recovered from colon contents. (B and D) Representative images of colonic sections were stained to detect Ki67 (yellow fluorescence) and counterstained with DAPI nuclear stain (blue fluorescence). (C and E) Ki67 staining was quantified by image analysis. (F) Enumeration of wt and cydAB mutant recovered from colon contents was used to calculate the competitive index (CI). (A, C, E and F) Bars represent geometric mean ± standard error. **, P < 0.01; *, P < 0.05; ns, not statistically significantly different.
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References (V体育官网)

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