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RORγt+ Treg to Th17 ratios correlate with susceptibility to Giardia infection

Yordanova, Ivet A., Cortés, Alba, Klotz, Christian, Kühl, Anja A., Heimesaat, Markus M., Cantacessi, Cinzia, Hartmann, Susanne, Rausch, Sebastian·2019·Scientific Reports
DOI 10.1038/s41598-019-56416-9PMC PMC6937251
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Abstract

Infections with Giardia are among the most common causes of food and water-borne diarrheal disease worldwide. Here, we investigated Th17, Treg and IgA responses, and alterations in gut microbiota in two mouse lines with varying susceptibility to Giardia muris infection. Infected BALB/c mice shed significantly more cysts compared with C57BL/6 mice. Impaired control of infection in BALB/c mice was associated with lower Th17 activity and lower IgA levels compared with C57BL/6 mice. The limited metabolic activity, proliferation and cytokine production of Th17 cells in BALB/c mice was associated with higher proportions of intestinal Foxp3 + RORγt + regulatory T cells and BALB/c mice developed increased RORγt + Treg:Th17 ratios in response to G. muris infection. Furthermore, G. muris colonization led to a significantly reduced evenness in the gut microbial communities of BALB/c mice. Our data indicate that differential susceptibility to Giardia infections may be related to RORγt + Treg controlling Th17 activity and that changes in the microbiota composition upon Giardia infection partially depend on the host background.

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Figure 1 Differential Th17 activity at steady state and during G. muris infection in BALB/c and C57BL/6 mice. Mice were orally infected with 1,000 G. muris cysts and surveyed for cyst excretion for six weeks and for intestinal Th17 cell activity 14 days post-infection. (a) Cyst shedding dynamics over the course of six weeks of G. muris infection in BALB/c and C57BL/6 mice. (b) Weight gain (relative to starting weight) of naïve and G. muris-infected BALB/c and C57BL/6 mice during a 14 day infection period. (c) Small intestinal enteritis score in duodenum, jejunum and ileum of naïve and G. muris-infected BALB/c and C57BL/6 mice. (d) Representative FACS plots of RORγt and IL-17A expression within CD4+ T cells in siLP of naïve and infected BALB/c and C57BL/6 mice following PMA/Ionomycin stimulation and frequencies of IL-17A+RORγt+ cells in CD4+ T cells in siLP and PP. (e) Frequencies of RORγt+Foxp3- Th17 cells in CD4+ cells in siLP and PP of naïve and infected BALB/c and C57BL/6 mice. (f) Ki-67 expression in RORγt+ Th17 cells in siLP. (g) IL-17A expression relative to the housekeeping gene β-glucuronidase (GUSB) as determined in small intestinal tissue samples. (h) Parasite-specific IL-17A expression by splenocytes of naïve and infected BALB/c and C57BL/6 mice stimulated with anti-CD3/CD28 antibodies or G. lamblia trophozoite GS or WB6 antigen. Signals from unstimulated control wells (all <36 pg/ml) were subtracted. Data in a, d, e, f and g are pooled from two-three independent experiments, with n = 3–5 mice/group. Weight gain was monitored once. Data in c and h are pooled from two independent experiments each performed with n = 3–4. Statistical analysis was done using Kruskal-Wallis test combined with Dunn’s or Tukey’s multiple comparison test (a-d) or unpaired t test (e). *p < 0.05, **p < 0.01, ***p < 0.001.
Figure 1 Differential Th17 activity at steady state and during G. muris infection in BALB/c and C57BL/6 mice. Mice were orally infected with 1,000 G. muris cysts and surveyed for cyst excretion for six weeks and for intestinal Th17 cell activity 14 days post-infection. (a) Cyst shedding dynamics over the course of six weeks of G. muris infection in BALB/c and C57BL/6 mice. (b) Weight gain (relative to starting weight) of naïve and G. muris-infected BALB/c and C57BL/6 mice during a 14 day infection period. (c) Small intestinal enteritis score in duodenum, jejunum and ileum of naïve and G. muris-infected BALB/c and C57BL/6 mice. (d) Representative FACS plots of RORγt and IL-17A expression within CD4+ T cells in siLP of naïve and infected BALB/c and C57BL/6 mice following PMA/Ionomycin stimulation and frequencies of IL-17A+RORγt+ cells in CD4+ T cells in siLP and PP. (e) Frequencies of RORγt+Foxp3- Th17 cells in CD4+ cells in siLP and PP of naïve and infected BALB/c and C57BL/6 mice. (f) Ki-67 expression in RORγt+ Th17 cells in siLP. (g) IL-17A expression relative to the housekeeping gene β-glucuronidase (GUSB) as determined in small intestinal tissue samples. (h) Parasite-specific IL-17A expression by splenocytes of naïve and infected BALB/c and C57BL/6 mice stimulated with anti-CD3/CD28 antibodies or G. lamblia trophozoite GS or WB6 antigen. Signals from unstimulated control wells (all <36 pg/ml) were subtracted. Data in a, d, e, f and g are pooled from two-three independent experiments, with n = 3–5 mice/group. Weight gain was monitored once. Data in c and h are pooled from two independent experiments each performed with n = 3–4. Statistical analysis was done using Kruskal-Wallis test combined with Dunn’s or Tukey’s multiple comparison test (a-d) or unpaired t test (e). *p < 0.05, **p < 0.01, ***p < 0.001.CC BY · PubMed Central
Figure 2 High Foxp3+RORγt+ Treg proportions correlate with poor intestinal Th17 activity in BALB/c mice. (a) Frequencies of Foxp3+ Treg in CD4+ cells isolated from the siLP of naïve and G. muris infected (day 14) BALB/c and C57BL/6 mice. (b) Representative FACS plots of RORγt and Foxp3 expression by small intestinal CD4+ T cells. Bold numbers report frequencies of Foxp3+RORγt+ Treg in BALB/c (orange) and C57BL/6 mice (black). (c) Representative histogram plots of RORγt expression in Foxp3+ Treg and frequencies of RORγt+ cells in the Foxp3+ Treg population isolated from siLP of naïve and infected BALB/c and C57BL/6 mice. (d) Uptake of fluorescently labelled palmitate (Bodipy FLC16) by CD4+ T cells isolated from the small intestine of mice infected with G. muris for two weeks. Left: representative overlays of unlabeled and labeled cells isolated from a C57BL/6 mouse at day 14 post infection. The demarcation of FL16high cells is indicated by the dashed line. Centre: gating of FL16high/low cells in CD4+ T cells isolated from BALB/c (B/c) and C57BL/6 (BL/6) mice at day 14 post infection. Right: expression profiles of Foxp3 and RORγt of FL16high/low cells overlayed onto the total CD4+ T cell population. (e) Representative overlays of Foxp3+RORγt+ Treg, RORγt+ Th17 and total CD4+ cells. Numbers report frequencies of RORγt+ Treg (orange) and Th17 cells (blue) in CD4+ T cells. The frequencies of FLC16hi cells within CD4+RORγt+ Th17 cells isolated from the small intestine are reported in the bar graph. (f) Ratio of RORγt+ Treg to Th17 cells in small intestinal CD4+ cells. (g,h) Correlation between RORγt+ Treg to Th17 cell ratios and (g) the frequency of FLC16hi Th17 cells or (h) Ki-67+ Th17 cells in small intestinal isolates of G. muris-infected BALB/c and C57BL/6 mice. Data are pooled from three (a,c,f) and two (e,g,h) independent experiments with n = 3–5/group. Statistical analysis was done using Kruskal-Wallis test combined with Dunn’s or Tukey’s multiple comparison test (a–f) and Spearman correlation test (g,h). *p < 0.05, **p < 0.01, ***p < 0.001.
Figure 2 High Foxp3+RORγt+ Treg proportions correlate with poor intestinal Th17 activity in BALB/c mice. (a) Frequencies of Foxp3+ Treg in CD4+ cells isolated from the siLP of naïve and G. muris infected (day 14) BALB/c and C57BL/6 mice. (b) Representative FACS plots of RORγt and Foxp3 expression by small intestinal CD4+ T cells. Bold numbers report frequencies of Foxp3+RORγt+ Treg in BALB/c (orange) and C57BL/6 mice (black). (c) Representative histogram plots of RORγt expression in Foxp3+ Treg and frequencies of RORγt+ cells in the Foxp3+ Treg population isolated from siLP of naïve and infected BALB/c and C57BL/6 mice. (d) Uptake of fluorescently labelled palmitate (Bodipy FLC16) by CD4+ T cells isolated from the small intestine of mice infected with G. muris for two weeks. Left: representative overlays of unlabeled and labeled cells isolated from a C57BL/6 mouse at day 14 post infection. The demarcation of FL16high cells is indicated by the dashed line. Centre: gating of FL16high/low cells in CD4+ T cells isolated from BALB/c (B/c) and C57BL/6 (BL/6) mice at day 14 post infection. Right: expression profiles of Foxp3 and RORγt of FL16high/low cells overlayed onto the total CD4+ T cell population. (e) Representative overlays of Foxp3+RORγt+ Treg, RORγt+ Th17 and total CD4+ cells. Numbers report frequencies of RORγt+ Treg (orange) and Th17 cells (blue) in CD4+ T cells. The frequencies of FLC16hi cells within CD4+RORγt+ Th17 cells isolated from the small intestine are reported in the bar graph. (f) Ratio of RORγt+ Treg to Th17 cells in small intestinal CD4+ cells. (g,h) Correlation between RORγt+ Treg to Th17 cell ratios and (g) the frequency of FLC16hi Th17 cells or (h) Ki-67+ Th17 cells in small intestinal isolates of G. muris-infected BALB/c and C57BL/6 mice. Data are pooled from three (a,c,f) and two (e,g,h) independent experiments with n = 3–5/group. Statistical analysis was done using Kruskal-Wallis test combined with Dunn’s or Tukey’s multiple comparison test (a–f) and Spearman correlation test (g,h). *p < 0.05, **p < 0.01, ***p < 0.001.CC BY · PubMed Central
Figure 3 Elevated frequencies, but poor activity of ILC3 in the small intestine of BALB/c mice. (a) Representative FACS plots of CD4 and RORγt expression by small intestinal cells in G. muris-infected BALB/c and C57BL/6 mice 14 days post-infection (left panel) and of IL-17A expression by CD4-RORγt+ cells in naïve and infected BALB/c and C57BL/6 mice (right panel). The histogram plot reports CD90 expression by CD4-RORγt+ cells. (b) Frequencies of CD4-RORγt+ cells in siLP cells. (c) Frequencies of IL-17A+ cells in CD4-RORγt+ cells after PMA/ionomycin stimulation. Data are pooled from three (b) or two (c) independent experiments with n = 3–5/group. Statistical analysis was done using Kruskal-Wallis test combined with Dunn’s multiple comparison test. *p < 0.05, **p < 0.01, ***p < 0.001. Further information on the phenotype of CD4-RORγt+ cells is available in Supplementary Fig. 2d–g.
Figure 3 Elevated frequencies, but poor activity of ILC3 in the small intestine of BALB/c mice. (a) Representative FACS plots of CD4 and RORγt expression by small intestinal cells in G. muris-infected BALB/c and C57BL/6 mice 14 days post-infection (left panel) and of IL-17A expression by CD4-RORγt+ cells in naïve and infected BALB/c and C57BL/6 mice (right panel). The histogram plot reports CD90 expression by CD4-RORγt+ cells. (b) Frequencies of CD4-RORγt+ cells in siLP cells. (c) Frequencies of IL-17A+ cells in CD4-RORγt+ cells after PMA/ionomycin stimulation. Data are pooled from three (b) or two (c) independent experiments with n = 3–5/group. Statistical analysis was done using Kruskal-Wallis test combined with Dunn’s multiple comparison test. *p < 0.05, **p < 0.01, ***p < 0.001. Further information on the phenotype of CD4-RORγt+ cells is available in Supplementary Fig. 2d–g.CC BY · PubMed Central
Figure 4 C57BL/6 mice display elevated small intestinal IgA+ plasma cells and serum IgA/IgG2b levels compared with BALB/c mice. (a) Representative FACS plots of IgA and B220 expression by siLP cells. Frequencies of B220-IgA+ plasma cells in siLP isolates are reported in the bar graph. (b) Representative FACS plots of IgA and IgM expression by B220+ B cells and frequencies of B220+IgA+ B cells in small intestinal Peyer’s patches (PP). (c,d) Serum levels of (c) IgA and (d) IgG2b antibodies. (e) IgA antibody levels in small intestinal tissue explant supernatants. (f,g) pIgR and TGF-β mRNA expression relative to GUSB determined in small intestinal tissue samples. Data are pooled from three (a–d) and two (e–g) independent experiments with n = 3–5/group. Statistical analysis was done using Kruskal-Wallis test combined with Dunn’s multiple comparison test. *p < 0.05, **p < 0.01, ***p < 0.001.
Figure 4 C57BL/6 mice display elevated small intestinal IgA+ plasma cells and serum IgA/IgG2b levels compared with BALB/c mice. (a) Representative FACS plots of IgA and B220 expression by siLP cells. Frequencies of B220-IgA+ plasma cells in siLP isolates are reported in the bar graph. (b) Representative FACS plots of IgA and IgM expression by B220+ B cells and frequencies of B220+IgA+ B cells in small intestinal Peyer’s patches (PP). (c,d) Serum levels of (c) IgA and (d) IgG2b antibodies. (e) IgA antibody levels in small intestinal tissue explant supernatants. (f,g) pIgR and TGF-β mRNA expression relative to GUSB determined in small intestinal tissue samples. Data are pooled from three (a–d) and two (e–g) independent experiments with n = 3–5/group. Statistical analysis was done using Kruskal-Wallis test combined with Dunn’s multiple comparison test. *p < 0.05, **p < 0.01, ***p < 0.001.CC BY · PubMed Central
Figure 5 Principle coordinates analysis (PCoA) and diversity of the fecal microbiota during G. muris infection. (a) Unsupervised Principal Coordinates Analysis (PCoA, on Bray-Curtis dissimilarities) of the fecal microbiota composition of naïve and infected (day 14) BALB/c and C57BL/6 mice. (b) Alpha diversity (measured by the Shannon index), species richness and evenness of the fecal microbiota of naïve and G. muris-infected BALB/c and C57BL/6 mice. Data are pooled from two independent experiments with n = 2–4 mice/group.
Figure 5 Principle coordinates analysis (PCoA) and diversity of the fecal microbiota during G. muris infection. (a) Unsupervised Principal Coordinates Analysis (PCoA, on Bray-Curtis dissimilarities) of the fecal microbiota composition of naïve and infected (day 14) BALB/c and C57BL/6 mice. (b) Alpha diversity (measured by the Shannon index), species richness and evenness of the fecal microbiota of naïve and G. muris-infected BALB/c and C57BL/6 mice. Data are pooled from two independent experiments with n = 2–4 mice/group.CC BY · PubMed Central
Figure 6 Populations of gut bacteria impacted by G. muris infection differ between BALB/c and C57BL/6 mice. (a) Microbial composition, at genus level, of naïve and G. muris-infected (day 14) mice of each line. Genera making up <0.5% of the overall microbiota are grouped under ‘others’. (b) Abundances of taxa varying significantly between naïve/infected BALB/c and/or naïve/infected C57BL/6 mice. Data are pooled from two independent experiments with n = 2–4 mice/group.
Figure 6 Populations of gut bacteria impacted by G. muris infection differ between BALB/c and C57BL/6 mice. (a) Microbial composition, at genus level, of naïve and G. muris-infected (day 14) mice of each line. Genera making up <0.5% of the overall microbiota are grouped under ‘others’. (b) Abundances of taxa varying significantly between naïve/infected BALB/c and/or naïve/infected C57BL/6 mice. Data are pooled from two independent experiments with n = 2–4 mice/group.CC BY · PubMed Central
Figure 7 Abundance of the main bacterial groups present in the murine intestinal microbiota detected by qPCR in naïve and G. muris infected BALB/c and C57BL/6 mice. Fecal gene numbers of the main bacterial groups abundant in the murine intestinal microbiota detected by qPCR in naïve and G. muris infected (day 14) BALB/c and C57BL/6 mice. Individual fecal loads of (a) total Eubacteria, (b) Enterobacteria, (c) Bifidobacteria, (d) Bacterides/Prevotella spp., (e) Mouse Intestinal Bacteroides (MIB), (f) Enterococci, (g) Lactobacilli, (h) Clostridium coccoides and (i) Clostridium leptum. Results are expressed as 16 R rRNA gene copy numbers per ng DNA. Data are pooled from two independent experiments with n = 3–5/group.
Figure 7 Abundance of the main bacterial groups present in the murine intestinal microbiota detected by qPCR in naïve and G. muris infected BALB/c and C57BL/6 mice. Fecal gene numbers of the main bacterial groups abundant in the murine intestinal microbiota detected by qPCR in naïve and G. muris infected (day 14) BALB/c and C57BL/6 mice. Individual fecal loads of (a) total Eubacteria, (b) Enterobacteria, (c) Bifidobacteria, (d) Bacterides/Prevotella spp., (e) Mouse Intestinal Bacteroides (MIB), (f) Enterococci, (g) Lactobacilli, (h) Clostridium coccoides and (i) Clostridium leptum. Results are expressed as 16 R rRNA gene copy numbers per ng DNA. Data are pooled from two independent experiments with n = 3–5/group.CC BY · PubMed Central

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Metadata

Authors
Yordanova, I. A., Cortés, A., Klotz, C., Kühl, A. A., Heimesaat, M. M., Cantacessi, C., Hartmann, S., & Rausch, S.
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2019-12-30
Volume
9
Issue
1
ISSN
2045-2322
DOI
10.1038/s41598-019-56416-9
PMC
PMC6937251
Cited by
22
References
3
Language
en
Licence
Funders
  • Fundacion Alfonso Martin Escudero
  • Deutsche Forschungsgemeinschaft (GRK2046)
  • Bundesministerium für Bildung und Forschung (IP7/01KI1725D)
  • RCUK | Biotechnology and Biological Sciences Research Council
  • Isaac Newton Trust

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CoChat. (2026). Citation check: RORγt+ Treg to Th17 ratios correlate with susceptibility to Giardia infection. https://app.cochat.ai/papers/10.1038/s41598-019-56416-9
The paper
Yordanova, I. A., Cortés, A., Klotz, C., Kühl, A. A., Heimesaat, M. M., Cantacessi, C., Hartmann, S., & Rausch, S. (2019). RORγt+ Treg to Th17 ratios correlate with susceptibility to Giardia infection. Scientific Reports. https://doi.org/10.1038/s41598-019-56416-9