Skip to main content
Top
Published in: BMC Immunology 1/2015

Open Access 01-12-2015 | Research article

Impairment of dendritic cell function and induction of CD4+CD25+Foxp3+ T cells by excretory-secretory products: a potential mechanism of immune evasion adopted by Echinococcus granulosus

Authors: Ying Wang, Hejun Zhou, Yujuan Shen, Yanjuan Wang, Weiping Wu, Haipeng Liu, Zhongying Yuan, Yuxin Xu, Yuan Hu, Jianping Cao

Published in: BMC Immunology | Issue 1/2015

Login to get access

Abstract

Background

Cystic echinococcosis, caused by infection with Echinococcus granulosus, is one of the most widespread zoonotic helminth diseases. Modulation of host responses is an important strategy used by helminth parasites to promote infection. To better understand the mechanisms adopted by E. granulosus to escape host immune responses, we investigated the effects of excretory–secretory products (ES) and adult worm antigen (AWA) derived from adult E. granulosus on murine bone marrow-derived dendritic cells (BMDC).

Results

Compared with lipopolysaccharide (LPS), AWA, but not ES, induced BMDC maturation or stimulated BMDC cytokine production and co-stimulatory molecule expression (CD40, CD80 and MHC class II). Furthermore, ES-treated BMDCs pulsed with ovalbumin exhibited reduced co-stimulatory molecule expression in comparison with untreated BMDC, even in the presence of the strong Th1 inducer, CpG. Moreover, we detected the effects of ES-treated DC on T cell activation by an in vitro T cell priming assay. We observed that ES-treated BMDC co-cultured with DO11.10 transgenic CD4+ T cells induced the generation of CD4+CD25+Foxp3+ T cells. In addition, in contrast to AWA-treated BMDCs, which had markedly induced IFN-γ secretion and reduced of IL-4 levels in co-cultured T cells, ES-treated BMDCs did not modify their capacity to stimulate IFN-γ or IL-4 production by T cells.

Conclusions

We conclude that ES of adult E. granulosus inhibited DC function, impaired the development of Th1 cells induced by CpG, and induced CD4+CD25+Foxp3+ regulatory T cells in an IL-10-independent manner.
Literature
1.
go back to reference Moro P, Schantz PM. Echinococcosis: a review. Int J Infect Dis. 2009;3:125–33.CrossRef Moro P, Schantz PM. Echinococcosis: a review. Int J Infect Dis. 2009;3:125–33.CrossRef
2.
go back to reference Siracusano A, Rigano R, Ortona E, Profumo E, Margutti P, Buttari B, et al. Immunomodulatory mechanisms during Echinococcus granulosus infection. Exp Parasitol. 2008;119:483–9.CrossRefPubMed Siracusano A, Rigano R, Ortona E, Profumo E, Margutti P, Buttari B, et al. Immunomodulatory mechanisms during Echinococcus granulosus infection. Exp Parasitol. 2008;119:483–9.CrossRefPubMed
3.
go back to reference Hewitson JP, Grainger JR, Maizels RM. Helminth immunoregulation: the role of parasite secreted proteins in modulating host immunity. Mol Biochem Parasitol. 2009;167:1–11.PubMedCentralCrossRefPubMed Hewitson JP, Grainger JR, Maizels RM. Helminth immunoregulation: the role of parasite secreted proteins in modulating host immunity. Mol Biochem Parasitol. 2009;167:1–11.PubMedCentralCrossRefPubMed
4.
go back to reference Johnston MJ, MacDonald JA, McKay DM. Parasitic helminths: a pharmacopeia of anti-inflammatory molecules. Parasitology. 2009;136:125–47.CrossRefPubMed Johnston MJ, MacDonald JA, McKay DM. Parasitic helminths: a pharmacopeia of anti-inflammatory molecules. Parasitology. 2009;136:125–47.CrossRefPubMed
5.
go back to reference Van Hellemond JJ, Retra K, Brouwers JF, van Balkom BW, Yazdanbakhsh M, Shoemaker CB, et al. Functions of the tegument of schistosomes: clues from the proteome and lipidome. Int J Parasitol. 2006;36:691–9.CrossRefPubMed Van Hellemond JJ, Retra K, Brouwers JF, van Balkom BW, Yazdanbakhsh M, Shoemaker CB, et al. Functions of the tegument of schistosomes: clues from the proteome and lipidome. Int J Parasitol. 2006;36:691–9.CrossRefPubMed
6.
7.
go back to reference Steinman RM. Dendritic cells. In: Paul WE, editor. Fundamental Immunolog. 4th ed. Philadelphia, PA: Lippincott-Raven Publishers; 1991. p. 547–73. Steinman RM. Dendritic cells. In: Paul WE, editor. Fundamental Immunolog. 4th ed. Philadelphia, PA: Lippincott-Raven Publishers; 1991. p. 547–73.
8.
go back to reference Kanan JHC, Chain BM. Modulation of dendritic cell differentiation and cytokine secretion by the hydatid cyst fluid of Echinococcus granulosus. Immunology. 2006;118:271–8.PubMedCentralCrossRefPubMed Kanan JHC, Chain BM. Modulation of dendritic cell differentiation and cytokine secretion by the hydatid cyst fluid of Echinococcus granulosus. Immunology. 2006;118:271–8.PubMedCentralCrossRefPubMed
9.
go back to reference Rigano R, Buttari B, Profumo E, Ortona E, Delunardo F, Margutti P, et al. Echinococcus granulosus antigen B impairs human dendritic cell differentiation and polarizes immature dendritic cell maturation towards a Th2 cell response. Infect Immun. 2007;75:1667–78.PubMedCentralCrossRefPubMed Rigano R, Buttari B, Profumo E, Ortona E, Delunardo F, Margutti P, et al. Echinococcus granulosus antigen B impairs human dendritic cell differentiation and polarizes immature dendritic cell maturation towards a Th2 cell response. Infect Immun. 2007;75:1667–78.PubMedCentralCrossRefPubMed
10.
go back to reference Casaravilla C, Pittini A, Ruickerl D, Seoane PI, Jenkins SJ, MacDonald AS, et al. Unconventional maturation of dendritic cells induced by particles from the laminated layer of larval Echinococcus granulosus. Infect Immun. 2014;82:3164–76.PubMedCentralCrossRefPubMed Casaravilla C, Pittini A, Ruickerl D, Seoane PI, Jenkins SJ, MacDonald AS, et al. Unconventional maturation of dendritic cells induced by particles from the laminated layer of larval Echinococcus granulosus. Infect Immun. 2014;82:3164–76.PubMedCentralCrossRefPubMed
11.
go back to reference Nono JK, Pletinckx K, Lutz MB, Brehm K. Excretory/secretory-products of Echinococcus multilocularis larvae induce apoptosis and tolerogenic properties in dendritic cells in vitro. PLoS Negl Trop Dis. 2012;6:e1516.PubMedCentralCrossRefPubMed Nono JK, Pletinckx K, Lutz MB, Brehm K. Excretory/secretory-products of Echinococcus multilocularis larvae induce apoptosis and tolerogenic properties in dendritic cells in vitro. PLoS Negl Trop Dis. 2012;6:e1516.PubMedCentralCrossRefPubMed
12.
go back to reference Pan W, Zhou HJ, Shen YJ, Wang Y, Xu YX, Hu Y, et al. Surveillance on the status of immune cells after Echinococcus granulosus protoscoleces infection in Balb/c mice. PLoS ONE. 2013;8:e59746.PubMedCentralCrossRefPubMed Pan W, Zhou HJ, Shen YJ, Wang Y, Xu YX, Hu Y, et al. Surveillance on the status of immune cells after Echinococcus granulosus protoscoleces infection in Balb/c mice. PLoS ONE. 2013;8:e59746.PubMedCentralCrossRefPubMed
13.
go back to reference Inaba KM, Inaba N, Romani H, Aya H, Dequchi M, Ikehara S, et al. Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/ macrophage colony stimulating factor. J Exp Med. 1992;176:1693–702.CrossRefPubMed Inaba KM, Inaba N, Romani H, Aya H, Dequchi M, Ikehara S, et al. Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/ macrophage colony stimulating factor. J Exp Med. 1992;176:1693–702.CrossRefPubMed
14.
go back to reference Lutz MB, Kukutsch N, Ogilvie AL, Rossner S, Koch F, Romani N, et al. An advanced culture method for generating large quantities of highly pure dendritic cells from mouse bone marrow. J Immunol Methods. 1999;223:77–92.CrossRefPubMed Lutz MB, Kukutsch N, Ogilvie AL, Rossner S, Koch F, Romani N, et al. An advanced culture method for generating large quantities of highly pure dendritic cells from mouse bone marrow. J Immunol Methods. 1999;223:77–92.CrossRefPubMed
15.
go back to reference Chemale G, van Rossum AJ, Jefferies JR, Barrett J, Brophy PM, Ferreira HB, et al. Proteomic analysis of the larval stage of the parasite Echinococcus granulosus: Causative agent of cystic hydatid disease. Proteomics. 2003;3:1633–6.CrossRefPubMed Chemale G, van Rossum AJ, Jefferies JR, Barrett J, Brophy PM, Ferreira HB, et al. Proteomic analysis of the larval stage of the parasite Echinococcus granulosus: Causative agent of cystic hydatid disease. Proteomics. 2003;3:1633–6.CrossRefPubMed
16.
go back to reference Monteiro KM, de Carvalho MO, Zaha A, Ferreira HB. Proteomic analysis of the Echinococcus granulosus metacestode during infection of its intermediate host. Proteomics. 2010;10:1985–99.CrossRefPubMed Monteiro KM, de Carvalho MO, Zaha A, Ferreira HB. Proteomic analysis of the Echinococcus granulosus metacestode during infection of its intermediate host. Proteomics. 2010;10:1985–99.CrossRefPubMed
17.
go back to reference Aziz A, Zhang W, Li J, Loukas A, McManus DP, Mulvenna J. Proteomic characterization of Echinococcus granulosus hydatid cyst fluid from sheep, cattle and humans. J Proteomics. 2011;74:1560–72.CrossRefPubMed Aziz A, Zhang W, Li J, Loukas A, McManus DP, Mulvenna J. Proteomic characterization of Echinococcus granulosus hydatid cyst fluid from sheep, cattle and humans. J Proteomics. 2011;74:1560–72.CrossRefPubMed
18.
go back to reference Virginio VG, Monteiro KM, Drumond F, de Carvalho MO, Vargas DM, Zaha A, et al. Excretory/secretory products from in vitro-cultured Echinococcus granulosus protoscoleces. Mol Biochem Parasitol. 2012;183:15–22.CrossRefPubMed Virginio VG, Monteiro KM, Drumond F, de Carvalho MO, Vargas DM, Zaha A, et al. Excretory/secretory products from in vitro-cultured Echinococcus granulosus protoscoleces. Mol Biochem Parasitol. 2012;183:15–22.CrossRefPubMed
19.
go back to reference Siracusano A, Margutti P, Delunardo F, Profumo E, Rigano R, Buttari B, et al. Molecular cross-talk in host-parasite relationships: the intriguing immunomodulatory role of Echinococcus antigen B in cystic echinococcosis. Inter J Parasitol. 2008;38:1371–6.CrossRef Siracusano A, Margutti P, Delunardo F, Profumo E, Rigano R, Buttari B, et al. Molecular cross-talk in host-parasite relationships: the intriguing immunomodulatory role of Echinococcus antigen B in cystic echinococcosis. Inter J Parasitol. 2008;38:1371–6.CrossRef
20.
go back to reference Shepherd CS, Kitken A, McManus DP. A protein secreted in vivo by Echinococcus granulosus inhibits elastase activity and neutrophil chemotaxis. Mol Biochem Parasitol. 1991;44:81–90.CrossRefPubMed Shepherd CS, Kitken A, McManus DP. A protein secreted in vivo by Echinococcus granulosus inhibits elastase activity and neutrophil chemotaxis. Mol Biochem Parasitol. 1991;44:81–90.CrossRefPubMed
21.
go back to reference Rigano R, Profumo E, Bruschi F, Carulli G, Azzara A, Ioppolo S, et al. Modulation of human immune response by Echinococus granulosus antigen B and its possible role in evading host defenses. Infect Immun. 2001;69:288–96.PubMedCentralCrossRefPubMed Rigano R, Profumo E, Bruschi F, Carulli G, Azzara A, Ioppolo S, et al. Modulation of human immune response by Echinococus granulosus antigen B and its possible role in evading host defenses. Infect Immun. 2001;69:288–96.PubMedCentralCrossRefPubMed
22.
go back to reference Margutti P, Ortona E, Vaccari S, Barca S, Rigano R, Teggi A, et al. Cloning and expression of a cDNA encoding an elongation factor 1β/δ protein from Echinococcus granulosus with immunogenic activity. Parasite Immunol. 1999;21:485–92.CrossRefPubMed Margutti P, Ortona E, Vaccari S, Barca S, Rigano R, Teggi A, et al. Cloning and expression of a cDNA encoding an elongation factor 1β/δ protein from Echinococcus granulosus with immunogenic activity. Parasite Immunol. 1999;21:485–92.CrossRefPubMed
23.
go back to reference Ortona E, Margutti P, Vaccari S, Rigano R, Profumo E, Buttari B, et al. Elongation factor 1β/δ of Echinococcus granulosus and allergic manifestations in human cystic echinococcosis. Clin Exp Immunol. 2001;125:110–6.PubMedCentralCrossRefPubMed Ortona E, Margutti P, Vaccari S, Rigano R, Profumo E, Buttari B, et al. Elongation factor 1β/δ of Echinococcus granulosus and allergic manifestations in human cystic echinococcosis. Clin Exp Immunol. 2001;125:110–6.PubMedCentralCrossRefPubMed
24.
go back to reference Ortona E, Vaccari S, Margutti P, Delunardo F, Rigano R, Profumo E, et al. Immunological characterization of Echinococcus granulosus cyclophilin, an allergen reactive with IgE and IgG4 from patient with cystic echinococcosis. Clin Exp Immunol. 2002;128:124–30.PubMedCentralCrossRefPubMed Ortona E, Vaccari S, Margutti P, Delunardo F, Rigano R, Profumo E, et al. Immunological characterization of Echinococcus granulosus cyclophilin, an allergen reactive with IgE and IgG4 from patient with cystic echinococcosis. Clin Exp Immunol. 2002;128:124–30.PubMedCentralCrossRefPubMed
25.
go back to reference Ortona E, Marguitti P, Delunardo F, Vaccari S, Rigano R, Profumo E, et al. Molecular and immunological characterization of the C-terminal region of a new Echinococcus granulosus Heat Shock Protein 70. Parasite Immunol. 2003;25:119–26.CrossRefPubMed Ortona E, Marguitti P, Delunardo F, Vaccari S, Rigano R, Profumo E, et al. Molecular and immunological characterization of the C-terminal region of a new Echinococcus granulosus Heat Shock Protein 70. Parasite Immunol. 2003;25:119–26.CrossRefPubMed
26.
go back to reference Ortona E, Margutti P, Delunardo F, Nobili V, Profumo E, Rigano R, et al. Screening of an Echinococcus granulosus cDNA library with IgG4 from patient with cystic echinococcosis identifies a new tegumental protein involved in the immune escape. Clin Exp Immunol. 2005;142:528–38.PubMedCentralPubMed Ortona E, Margutti P, Delunardo F, Nobili V, Profumo E, Rigano R, et al. Screening of an Echinococcus granulosus cDNA library with IgG4 from patient with cystic echinococcosis identifies a new tegumental protein involved in the immune escape. Clin Exp Immunol. 2005;142:528–38.PubMedCentralPubMed
27.
go back to reference Delunardo F, Ortona E, Margutti P, Perdicchio M, Vacirca D, Teggi A, et al. Identification of a novel 19 kDa Echinococcus granulosus antigen. Acta Trop. 2010;113:42–7.CrossRefPubMed Delunardo F, Ortona E, Margutti P, Perdicchio M, Vacirca D, Teggi A, et al. Identification of a novel 19 kDa Echinococcus granulosus antigen. Acta Trop. 2010;113:42–7.CrossRefPubMed
28.
go back to reference Gottstein B, Hemphill A. Echinococcus multilocularis: the parasite-host interplay. Exp Parasitol. 2008;119:447–52.CrossRefPubMed Gottstein B, Hemphill A. Echinococcus multilocularis: the parasite-host interplay. Exp Parasitol. 2008;119:447–52.CrossRefPubMed
29.
go back to reference Balic A, Harcus Y, Holland MJ, Maizels RM. Selective maturation of dendritic cells by Nippostrongylus brasiliensis-secreted proteins drives Th2 immune responses. Eur J Immunol. 2004;34:3047–59.CrossRefPubMed Balic A, Harcus Y, Holland MJ, Maizels RM. Selective maturation of dendritic cells by Nippostrongylus brasiliensis-secreted proteins drives Th2 immune responses. Eur J Immunol. 2004;34:3047–59.CrossRefPubMed
30.
go back to reference Thomas PG, Varter MR, Atochina O, Da’Dara AA, Piskorska D, McGuire E, et al. Maturation of dendritic cell 2 phenotype by a helminth glycan uses a Toll-like receptor 4-depandent mechanism. J Immunol. 2003;171:5837–41.CrossRefPubMed Thomas PG, Varter MR, Atochina O, Da’Dara AA, Piskorska D, McGuire E, et al. Maturation of dendritic cell 2 phenotype by a helminth glycan uses a Toll-like receptor 4-depandent mechanism. J Immunol. 2003;171:5837–41.CrossRefPubMed
31.
go back to reference Van der Kleij D, Latz E, Brouwers JF, Kruize YC, Schmitz M, Kurt-Jones EA, et al. Schistosomal lyso-phosphatidylserine activates Toll-like receptor 2 and affects immune polarization. J Biol Chem. 2002;277:48122–9.CrossRefPubMed Van der Kleij D, Latz E, Brouwers JF, Kruize YC, Schmitz M, Kurt-Jones EA, et al. Schistosomal lyso-phosphatidylserine activates Toll-like receptor 2 and affects immune polarization. J Biol Chem. 2002;277:48122–9.CrossRefPubMed
32.
go back to reference MacDonald AS, Straw AD, Bauman B, Pearce EJ. CD8- dendritic cell activation status plays an integral role in influencing Th2 response development. J Immunol. 2001;167:1982–8.CrossRefPubMed MacDonald AS, Straw AD, Bauman B, Pearce EJ. CD8- dendritic cell activation status plays an integral role in influencing Th2 response development. J Immunol. 2001;167:1982–8.CrossRefPubMed
33.
go back to reference Whelan M, Harnett MM, Houston KM, Patel V, Harnett W, Rigley KP. A filarial nematode-secreted product signals dendritic cells to acquire a phenotype that drives development of Th2 cells. J Immunol. 2000;164:6453–60.CrossRefPubMed Whelan M, Harnett MM, Houston KM, Patel V, Harnett W, Rigley KP. A filarial nematode-secreted product signals dendritic cells to acquire a phenotype that drives development of Th2 cells. J Immunol. 2000;164:6453–60.CrossRefPubMed
34.
go back to reference Elliott DE, Setiawan T, Metwali A, Blum A, Urban Jr JF, Weinstock JV. Heligmosomoides polygyrus inhibits established colitis in IL-10-deficient mice. Eur J Immunol. 2004;34:2690–8.CrossRefPubMed Elliott DE, Setiawan T, Metwali A, Blum A, Urban Jr JF, Weinstock JV. Heligmosomoides polygyrus inhibits established colitis in IL-10-deficient mice. Eur J Immunol. 2004;34:2690–8.CrossRefPubMed
35.
go back to reference Zhou H, Sun X, Lv Z, Shen Y, Peng H, Yang L, et al. The secretions products from invading cercatiae of S. japonicum (0-3hRP) restrain mouse dendritic cells to mature. Parasitol Res. 2012;110:119–26.CrossRefPubMed Zhou H, Sun X, Lv Z, Shen Y, Peng H, Yang L, et al. The secretions products from invading cercatiae of S. japonicum (0-3hRP) restrain mouse dendritic cells to mature. Parasitol Res. 2012;110:119–26.CrossRefPubMed
36.
go back to reference Chen CC, Louie S, McCormick BA, Walker WA, Shi HN. Helminth-primed dendritic cells alter the host response to enteric bacterial infection. J Immunol. 2006;176:472–83.PubMedCentralCrossRefPubMed Chen CC, Louie S, McCormick BA, Walker WA, Shi HN. Helminth-primed dendritic cells alter the host response to enteric bacterial infection. J Immunol. 2006;176:472–83.PubMedCentralCrossRefPubMed
37.
go back to reference Smits HH, de Jong EC, Wierenga EA, Kapsenberg ML. Different faces of regulatory DCs in homeostasis and immunity. Trends Immunol. 2005;26:123–9.CrossRefPubMed Smits HH, de Jong EC, Wierenga EA, Kapsenberg ML. Different faces of regulatory DCs in homeostasis and immunity. Trends Immunol. 2005;26:123–9.CrossRefPubMed
38.
go back to reference Mills KH. Regulatory T cells: friend or foe in immunity to infection? Nat Rev Immunol. 2004;4:841–55.CrossRefPubMed Mills KH. Regulatory T cells: friend or foe in immunity to infection? Nat Rev Immunol. 2004;4:841–55.CrossRefPubMed
39.
go back to reference Hoerauf A, Brattig N. Resistance and susceptibility in human onchocerciasis – beyond Th1 vs Th2. Trends Parasitol. 2002;18:25–31.CrossRefPubMed Hoerauf A, Brattig N. Resistance and susceptibility in human onchocerciasis – beyond Th1 vs Th2. Trends Parasitol. 2002;18:25–31.CrossRefPubMed
40.
go back to reference Vieira PL, Christensen JR, Minaee S, O’Neill E, Barrat FJ, Boonstra A, et al. IL-10-secreting regulatory T cells do not express Foxp3 but have comparable regulatory function to naturally occurring CD4+CD25+ regulatory T cells. J Immunol. 2004;172:5986–93.CrossRefPubMed Vieira PL, Christensen JR, Minaee S, O’Neill E, Barrat FJ, Boonstra A, et al. IL-10-secreting regulatory T cells do not express Foxp3 but have comparable regulatory function to naturally occurring CD4+CD25+ regulatory T cells. J Immunol. 2004;172:5986–93.CrossRefPubMed
41.
go back to reference Segura M, Su Z, Piccirillo C, Stevenson MM. Impairment of dendritic cell function by excretory-secretory products: a potential mechanism for nematode-induced immunosuppression. Eur J Immunol. 2007;37:1887–904.CrossRefPubMed Segura M, Su Z, Piccirillo C, Stevenson MM. Impairment of dendritic cell function by excretory-secretory products: a potential mechanism for nematode-induced immunosuppression. Eur J Immunol. 2007;37:1887–904.CrossRefPubMed
42.
go back to reference Barrat FJ, Cua DJ, Boostra A, Richards DF, Crain C, Savelkoul HF, et al. In vitro generation of interleukin 10-producing regulatory CD4+ T cells is induced by immunosuppressive drugs and inhibited by T helper type 1 (Th1)-and Th2-inducing cytokines. J Exp Med. 2002;195:603–16.PubMedCentralCrossRefPubMed Barrat FJ, Cua DJ, Boostra A, Richards DF, Crain C, Savelkoul HF, et al. In vitro generation of interleukin 10-producing regulatory CD4+ T cells is induced by immunosuppressive drugs and inhibited by T helper type 1 (Th1)-and Th2-inducing cytokines. J Exp Med. 2002;195:603–16.PubMedCentralCrossRefPubMed
43.
go back to reference Sundstedt A, O’Neill EJ, Nicolson KS, Wraith DC. Role for IL-10 in suppression mediated by peptide-induced regulatory T cells in vivo. J Immunol. 2003;170:1240–8.CrossRefPubMed Sundstedt A, O’Neill EJ, Nicolson KS, Wraith DC. Role for IL-10 in suppression mediated by peptide-induced regulatory T cells in vivo. J Immunol. 2003;170:1240–8.CrossRefPubMed
Metadata
Title
Impairment of dendritic cell function and induction of CD4+CD25+Foxp3+ T cells by excretory-secretory products: a potential mechanism of immune evasion adopted by Echinococcus granulosus
Authors
Ying Wang
Hejun Zhou
Yujuan Shen
Yanjuan Wang
Weiping Wu
Haipeng Liu
Zhongying Yuan
Yuxin Xu
Yuan Hu
Jianping Cao
Publication date
01-12-2015
Publisher
BioMed Central
Published in
BMC Immunology / Issue 1/2015
Electronic ISSN: 1471-2172
DOI
https://doi.org/10.1186/s12865-015-0110-3

Other articles of this Issue 1/2015

BMC Immunology 1/2015 Go to the issue