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Schistosoma mansoni-Mediated Suppression of Allergic Airway Inflammation Requires Patency and Foxp3+ Treg Cells

Layland, Laura E., Straubinger, Kathrin, Ritter, Manuel, Loffredo-Verde, Eva, Garn, Holger, Sparwasser, Tim, Prazeres da Costa, Clarissa·2013·PLoS Neglected Tropical Diseases
DOI 10.1371/journal.pntd.0002379PMC PMC3744427
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Figure 1 Experimental models for examining S. mansoni-mediated suppression of AAI. A Patent Infected Protection (PiP). Groups of BALB/c female mice were infected with S. mansoni. Inf/OVA and OVA groups of mice were then sensitised with OVA either i.p. with Alum or s.c. without adjuvant at the indicated timepoints. Challenge occurred over three consecutive days in the 9th week of infection and analysis 5 days thereafter. B Prepatent (PP). Sensitizations were started in Inf/OVA and OVA groups during the first weeks of infection, before eggs are released from fecund females. Challenge and analysis were performed as in A. C Early Phase (EP). AAI was performed entirely over the first 5 weeks of infection. D Praziquantel therapy. During the 6th week of infection, mice were orally treated with PZQ for 5 consecutive days. AAI was then begun after either 2 weeks (upper track) or 6 weeks (lower track). E Depletion of Treg. Groups of C57BL/6 DEREG mice were infected with S. mansoni. In some groups, Treg were depleted using DT injections prior to OVA sensitization at the indicated timepoints. Challenge and analysis occurred in the 12th week of infection.
Figure 1 Experimental models for examining S. mansoni-mediated suppression of AAI. A Patent Infected Protection (PiP). Groups of BALB/c female mice were infected with S. mansoni. Inf/OVA and OVA groups of mice were then sensitised with OVA either i.p. with Alum or s.c. without adjuvant at the indicated timepoints. Challenge occurred over three consecutive days in the 9th week of infection and analysis 5 days thereafter. B Prepatent (PP). Sensitizations were started in Inf/OVA and OVA groups during the first weeks of infection, before eggs are released from fecund females. Challenge and analysis were performed as in A. C Early Phase (EP). AAI was performed entirely over the first 5 weeks of infection. D Praziquantel therapy. During the 6th week of infection, mice were orally treated with PZQ for 5 consecutive days. AAI was then begun after either 2 weeks (upper track) or 6 weeks (lower track). E Depletion of Treg. Groups of C57BL/6 DEREG mice were infected with S. mansoni. In some groups, Treg were depleted using DT injections prior to OVA sensitization at the indicated timepoints. Challenge and analysis occurred in the 12th week of infection.CC BY · PubMed Central
Figure 2 Suppression of AAI in S. mansoni-infected mice requires patency. Groups of BALB/c female mice were infected with S. mansoni. Left PiP experiments: After the 5th week of infection, OVA sensitizations were administered either i.p. with alum or s.c. in the absence of adjuvant (Figure 1A). Middle PP experiments: sensitizations were given during the first weeks of infection (before patency) but challenge was performed at the same time-point of infection as in PiP investigations (Figure 1B). Right EP studies: both sensitizations and challenge were performed before the onset of patency (Figure 1C). Upon AAI analysis, individual mice were assessed for leucocyte numbers (A–C) and eosinophil levels (D–F). Lung sections were also scored for inflammation (G–I). In i.p.+Alum experiments displayed in A, D and G, bars show mean + SD of individual mice from 5 independent infection/allergy experiments (PBS, n = 21; OVA, n = 34; Inf/OVA, n = 29 and Inf., n = 28). In s.c.-Alum experiments OVA, n = 8 and Inf/OVA, n = 7. In PP experiments B, E and H, bars show mean + SD of individual mice from 2 independent infection/allergy experiments (PBS, n = 2; OVA, n = 14; Inf/OVA, n = 13 and Inf., n = 10). In EP experiments C, F and I, bars show mean + SD of individual mice from 1 or 3 similar independent infection/allergy experiments (PBS, n = 2; OVA, n = 10; Inf/OVA, n = 10 and Inf., n = 4). Asterisks show statistical differences (ANOVA or Student's t test) between the groups indicated by the brackets (*p<0.05, **p<0.01, ***p<0.001).
Figure 2 Suppression of AAI in S. mansoni-infected mice requires patency. Groups of BALB/c female mice were infected with S. mansoni. Left PiP experiments: After the 5th week of infection, OVA sensitizations were administered either i.p. with alum or s.c. in the absence of adjuvant (Figure 1A). Middle PP experiments: sensitizations were given during the first weeks of infection (before patency) but challenge was performed at the same time-point of infection as in PiP investigations (Figure 1B). Right EP studies: both sensitizations and challenge were performed before the onset of patency (Figure 1C). Upon AAI analysis, individual mice were assessed for leucocyte numbers (A–C) and eosinophil levels (D–F). Lung sections were also scored for inflammation (G–I). In i.p.+Alum experiments displayed in A, D and G, bars show mean + SD of individual mice from 5 independent infection/allergy experiments (PBS, n = 21; OVA, n = 34; Inf/OVA, n = 29 and Inf., n = 28). In s.c.-Alum experiments OVA, n = 8 and Inf/OVA, n = 7. In PP experiments B, E and H, bars show mean + SD of individual mice from 2 independent infection/allergy experiments (PBS, n = 2; OVA, n = 14; Inf/OVA, n = 13 and Inf., n = 10). In EP experiments C, F and I, bars show mean + SD of individual mice from 1 or 3 similar independent infection/allergy experiments (PBS, n = 2; OVA, n = 10; Inf/OVA, n = 10 and Inf., n = 4). Asterisks show statistical differences (ANOVA or Student's t test) between the groups indicated by the brackets (*p<0.05, **p<0.01, ***p<0.001).CC BY · PubMed Central
Figure 3 Increased Foxp3+ Treg frequency in the draining lymph nodes of Inf/OVA mice is not reflected in lung sections. A) Total cell counts and B) the number of CD4+Foxp3+ T cells in the draining lymph nodes of individual mice on the day of analysis in PiP studies. Symbols depict the levels in each mouse and data shows values from 5 independent infection studies (PBS, n = 21; OVA, n = 34; Inf/OVA, n = 29 and Inf., n = 28). CD3+Foxp3+ T cells in the lung sections of C) OVA mice, D) Inf/OVA mice and E) control groups (PBS) were determined by immunohistochemical staining. Arrows depict positive cells. F) Quantification of CD3+Foxp3+ T cells in individual lung sections was determined within a 1 mm2 area. Asterisks show statistical differences (ANOVA) between the groups indicated by the brackets (*p<0.05, **p<0.01, ***p<0.001).
Figure 3 Increased Foxp3+ Treg frequency in the draining lymph nodes of Inf/OVA mice is not reflected in lung sections. A) Total cell counts and B) the number of CD4+Foxp3+ T cells in the draining lymph nodes of individual mice on the day of analysis in PiP studies. Symbols depict the levels in each mouse and data shows values from 5 independent infection studies (PBS, n = 21; OVA, n = 34; Inf/OVA, n = 29 and Inf., n = 28). CD3+Foxp3+ T cells in the lung sections of C) OVA mice, D) Inf/OVA mice and E) control groups (PBS) were determined by immunohistochemical staining. Arrows depict positive cells. F) Quantification of CD3+Foxp3+ T cells in individual lung sections was determined within a 1 mm2 area. Asterisks show statistical differences (ANOVA) between the groups indicated by the brackets (*p<0.05, **p<0.01, ***p<0.001).CC BY · PubMed Central
Figure 4 Depletion of Treg during sensitization reverts schistosome-mediated dampening of AAI. As depicted in Figure 1F, groups of C57BL/6 DEREG mice were infected with S. mansoni. On the 9th and 10th week of infection mice were sensitized i.p. with OVA in the presence of alum. Prior to sensitization, Treg were depleted by the administration of DT. During the 12th week of infection, mice were challenged and assessed for the number of leucocytes (A) and eosinophils (B) in the BAL. Levels of inflammation were also scored using lung sections stained with PAS (C–G). OVA-specific IgE levels were measured in the sera of individual mice via ELISA (H). OVA-specific responses were measured following stimulation of spleen cells (2×105) with 10 µg/ml OVA (I). In addition, schistosome-specific responses were evaluated upon re-stimulation of spleen cells with SEA (25 µg/ml) (J). After 72 hours, IL-5 levels were determined in the culture supernatant by ELISA (I and J). Egg burden was measured in livers of individually infected mice (K). Bars show data from one of two similar experiments (OVA, n = 7; OVADT, n = 7; Inf/OVADT, n = 5; Inf/OVA n = 8; PBSDT n = 3). Asterisks show statistical differences (ANOVA or Student's t test) between the groups indicated by the brackets (*p<0.05, p<0.01, ***p<0.001).
Figure 4 Depletion of Treg during sensitization reverts schistosome-mediated dampening of AAI. As depicted in Figure 1F, groups of C57BL/6 DEREG mice were infected with S. mansoni. On the 9th and 10th week of infection mice were sensitized i.p. with OVA in the presence of alum. Prior to sensitization, Treg were depleted by the administration of DT. During the 12th week of infection, mice were challenged and assessed for the number of leucocytes (A) and eosinophils (B) in the BAL. Levels of inflammation were also scored using lung sections stained with PAS (C–G). OVA-specific IgE levels were measured in the sera of individual mice via ELISA (H). OVA-specific responses were measured following stimulation of spleen cells (2×105) with 10 µg/ml OVA (I). In addition, schistosome-specific responses were evaluated upon re-stimulation of spleen cells with SEA (25 µg/ml) (J). After 72 hours, IL-5 levels were determined in the culture supernatant by ELISA (I and J). Egg burden was measured in livers of individually infected mice (K). Bars show data from one of two similar experiments (OVA, n = 7; OVADT, n = 7; Inf/OVADT, n = 5; Inf/OVA n = 8; PBSDT n = 3). Asterisks show statistical differences (ANOVA or Student's t test) between the groups indicated by the brackets (*p<0.05, p<0.01, ***p<0.001).CC BY · PubMed Central

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Metadata

Authors
Layland, L. E., Straubinger, K., Ritter, M., Loffredo-Verde, E., Garn, H., Sparwasser, T., & Prazeres da Costa, C.
Venue
PLoS Neglected Tropical Diseases
Publisher
Public Library of Science (PLoS)
Published
2013-08-15
Volume
7
Issue
8
Pages
e2379
ISSN
1935-2735
DOI
10.1371/journal.pntd.0002379
PMC
PMC3744427
Cited by
65
References
0
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (unspecified)

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