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Open Access

Uremia Coupled with Mucosal Damage Predisposes Mice with Kidney Disease to Systemic Infection by Commensal Candida albicans

Chetan V. Jawale, De-Dong Li, Kritika Ramani, Li Lin, Kelvin Li, Barbara Methe and Partha Sarathi Biswas
ImmunoHorizons January 1, 2021, 5 (1) 16-24; DOI: https://doi.org/10.4049/immunohorizons.2000114
Chetan V. Jawale
*Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261; and
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De-Dong Li
*Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261; and
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Kritika Ramani
*Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261; and
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Li Lin
*Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261; and
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Kelvin Li
†Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261
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Barbara Methe
†Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261
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Partha Sarathi Biswas
*Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261; and
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  • FIGURE 1.
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    FIGURE 1.

    Increased gut barrier permeability in AAI-injected mice.

    C57BL/6 (WT) mice (n = 6–8) were either injected with AAI, PBS (control), or AAII. (A) Serum BUN and creatinine levels (n = 5) were measured at day 10 post–AAI injection. At (B) day 10 (n = 6–8) and (C) indicated time points post–AAI injection (n = 3–6), mice were gavaged with FITC–dextran and assessed for FITC–dextran concentration in the plasma. (D) Correlation between gut barrier permeability and BUN level (n = 8). (E) SI and colon sections were stained for ZO-1 expression. (F) Transcript expression of tight junction protein genes were evaluated by quantitative real-time PCR (n = 6–7). (G) H&E staining of SI and colon of uremic and control mice. Images from one of three mice/group for (E and G). Original magnification ×200. Data pooled from at least two independent experiments for (A–D and F) and expressed as mean ± SD (A, B, C, and F). Statistical analyses by Pearson correlation (D) and one-way ANOVA (A–C and F). **p < 0.01, ***p < 0.001, ****p < 0.0001.

  • FIGURE 2.
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    FIGURE 2.

    Uremia drives increased gut permeability.

    (A) Schematic diagram of the experimental design. WT mice (n = 5–6) were subjected to UUO. At day 7 postsurgery, UUO and non-UUO control mice were gavaged with FITC–dextran and assessed for barrier permeability. (B) Kidney histopathology following Masson trichome staining, (C) serum BUN level, and (D) plasma FITC–dextran concentration were measured at day 7 postsurgery. (E) Schematic diagram of the experimental design. Groups of uremic mice (n = 6–7) were either treated with probenecid (AAI+PRB) or left untreated (AAI). Control mice received probenecid only (PRB only). Mice were evaluated for (F) kidney fibrosis, (G) serum BUN level, and (H) gut barrier permeability. Images from one of three mice/group for (B and F). Original magnification ×200. The data are pooled from at least two independent experiments for (C, D, G, and H) and expressed as mean ± SD (C, D, G, and H). Statistical analyses by Student t test (C and D) and one-way ANOVA (G and H). ns, statistically not significant. ****p < 0.0001.

  • FIGURE 3.
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    FIGURE 3.

    Compromised gut mucosal immunity and dysbiosis in uremia.

    At day 10 post–AAI injection, SILP (n = 5–19) were evaluated for the frequency of (A) macrophages (liveCD45+CD11b+ F4/80+CX3CR1+CD11c+; liveCD45+CD11b+F4/80+CX3CR1+CD11c−), (B) dendritic cells (liveCD45+CD11b+CD103+CD11c+, liveCD45+CD11b−CD103+CD11c+; liveCD45+CD11b+ CD103−CD11c+), (C) neutrophils (liveCD45+CD11b+Ly6G+), (D) Th17 (liveCD45+CD4+IL-17+) and Th1 (liveCD45+CD4+IFN-γ+), (E) IgA-producing plasmablasts (liveCD45+CD11b+IgA+; liveCD45+CD11b−IgA+), and (F) Treg cells (liveCD4+Foxp3+) by FACS at day 10 post–AAI injection. (G) Percentages of Th17 and Th1 cells in the MLN (n = 8–12) were determined by intracellular cytokine staining following in vitro stimulation with PMA/ionomycin. (H) Frequency of Treg cells was determined in the MLN by FACS. (I) At day 10 post–AAI injection, fecal pellets from uremic and control (n = 5) mice were subjected to targeted 16S rRNA sequencing. Data pooled from at least two independent experiments for (A–H) and expressed as mean ± SD (A–H). Statistical analyses by one-way ANOVA (A–H) and pair-wise using Wilcoxon rank sum test (I). *p < 0.05, **p < 0.01, ***p < 0.001.

  • FIGURE 4.
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    FIGURE 4.

    Uremic mice exhibit translocation of gut microbiota.

    (A) Mice (n = 6) were subjected to AAN and evaluated for the translocation of gut microbiota in the liver and spleen at day 10 post–AAI injection. Images from one of six mice/group. (B) Uremic mice (n = 6) were either treated with probenecid (AAI+PRB) or left untreated (AAI) and assessed for microbiota translocation in the liver and spleen. Uremic and control groups (n = 6–9) were evaluated for the activation of T cells in the (C) MLN (liveCD4+CD44hi) and (D) spleen (liveCD4+CD62LloCD44hi and liveCD8+CD62LloCD44hi) by FACS. Pooled data from at least two experiments for (A–D) and expressed as mean ± SD (C and D). Statistical analyses by one-way ANOVA (C and D). *p < 0.05, **p < 0.01, ****p < 0.0001.

  • FIGURE 5.
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    FIGURE 5.

    Uremic mice exhibit translocation of C. rodentium.

    (A) Schematic diagram of the experimental design. AAI, control, and AAII-injected mice (n = 12) were gavaged with C. rodentium at day 3 post–AAI injection. At day 7, C. rodentium burden in the (B) fecal pellet and cecal content and (C) liver and spleen were measured. Pooled data from at least two experiments for (B and C) and expressed as mean ± SD (B and C). Statistical analyses by one-way ANOVA (B and C). *p < 0.05.

  • FIGURE 6.
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    FIGURE 6.

    Uremic mice show fungal translocation following DSS treatment.

    (A) Schematic representation of the experimental design. Mice (n = 10–15) were gavaged with C. albicans at day 2 post–AAI injection. At day 8, C. albicans and microbiota burden in the (B) fecal pellet and (C) liver and spleen were evaluated. (D) Schematic diagram of the experimental plan. Mice (n = 6–13) were fed with ampicillin in the drinking water throughout the experiment. At day 10 post–oral fungal infection, mice were either injected with AAI or PBS. Fungal and bacterial CFU in the (E) fecal pellet and (F) liver and spleen were determined. (G) Schematic representation of the experimental plan. Oral antibiotic–treated animals were fed with 2.5% DSS in water 3 d after AAI injection. (H) Survival (n = 4–8) was evaluated for 9 d post–AAI injection. (I) Mice were evaluated for the translocation of C. albicans in the liver. Pooled data from at least two experiments for (B, C, E, F, H, and I) and expressed as mean ± SD (B and E). Statistical analyses by one-way ANOVA (B), Mann–Whitney t test (E), and log-rank test (H). *p < 0.05, **p < 0.01.

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ImmunoHorizons: 5 (1)
ImmunoHorizons
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1 Jan 2021
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Uremia Coupled with Mucosal Damage Predisposes Mice with Kidney Disease to Systemic Infection by Commensal Candida albicans
Chetan V. Jawale, De-Dong Li, Kritika Ramani, Li Lin, Kelvin Li, Barbara Methe, Partha Sarathi Biswas
ImmunoHorizons January 1, 2021, 5 (1) 16-24; DOI: 10.4049/immunohorizons.2000114

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Uremia Coupled with Mucosal Damage Predisposes Mice with Kidney Disease to Systemic Infection by Commensal Candida albicans
Chetan V. Jawale, De-Dong Li, Kritika Ramani, Li Lin, Kelvin Li, Barbara Methe, Partha Sarathi Biswas
ImmunoHorizons January 1, 2021, 5 (1) 16-24; DOI: 10.4049/immunohorizons.2000114
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