title: MyD88 signaling inhibits protective immunity to the gastrointestinal helminth parasite Heligmosomoides polygyrus.
abstract: Helminth parasites remain one of the most common causes of infections worldwide, yet little is still known about the immune signaling pathways that control their expulsion. C57BL/6 mice are chronically susceptible to infection with the gastrointestinal helminth parasite Heligmosomoides polygyrus. In this article, we report that C57BL/6 mice lacking the adapter protein MyD88, which mediates signaling by TLRs and IL-1 family members, showed enhanced immunity to H. polygyrus infection. Alongside increased parasite expulsion, MyD88-deficient mice showed heightened IL-4 and IL-17A production from mesenteric lymph node CD4(+) cells. In addition, MyD88(-/-) mice developed substantial numbers of intestinal granulomas around the site of infection, which were not seen in MyD88-sufficient C57BL/6 mice, nor when signaling through the adapter protein TRIF (TIR domain-containing adapter-inducing IFN-β adapter protein) was also ablated. Mice deficient solely in TLR2, TLR4, TLR5, or TLR9 did not show enhanced parasite expulsion, suggesting that these TLRs signal redundantly to maintain H. polygyrus susceptibility in wild-type mice. To further investigate signaling pathways that are MyD88 dependent, we infected IL-1R1(-/-) mice with H. polygyrus. This genotype displayed heightened granuloma numbers compared with wild-type mice, but without increased parasite expulsion. Thus, the IL-1R-MyD88 pathway is implicated in inhibiting granuloma formation; however, protective immunity in MyD88-deficient mice appears to be granuloma independent. Like IL-1R1(-/-) and MyD88(-/-) mice, animals lacking signaling through the type 1 IFN receptor (i.e., IFNAR1(-/-)) also developed intestinal granulomas. Hence, IL-1R1, MyD88, and type 1 IFN receptor signaling may provide pathways to impede granuloma formation in vivo, but additional MyD88-mediated signals are associated with inhibition of protective immunity in susceptible C57BL/6 mice.
authors.affiliation: Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, EH9 3JT, United Kingdom; Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh, EH9 3JT, United Kingdom;
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Reynolds
authors.affiliation: Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, EH9 3JT, United Kingdom; Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh, EH9 3JT, United Kingdom;
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Harcus
authors.affiliation: Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, EH9 3JT, United Kingdom; Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh, EH9 3JT, United Kingdom;
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Smith
authors.affiliation: Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, EH9 3JT, United Kingdom; Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh, EH9 3JT, United Kingdom;
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Webb
authors.affiliation: Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, EH9 3JT, United Kingdom; Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh, EH9 3JT, United Kingdom;
authors.forename: James P
authors.initials: JP
authors.lastname: Hewitson
authors.affiliation: Medical Research Council Centre for Immune Regulation, Institute of Microbiology and Infection, School of Immunity and Infection, University of Birmingham, Birmingham, B15 2TT, United Kingdom;
authors.forename: Ewan A
authors.initials: EA
authors.lastname: Ross
authors.affiliation: Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, EH9 3JT, United Kingdom; Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh, EH9 3JT, United Kingdom;
authors.forename: Sheila
authors.initials: S
authors.lastname: Brown
authors.affiliation: Division of Innate Immune Regulation, International Research and Development Center for Mucosal Vaccines, Institute of Medical Science, The University of Tokyo, Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan;
authors.forename: Satoshi
authors.initials: S
authors.lastname: Uematsu
authors.affiliation: Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan; and Laboratory of Host Defense, World Premier Institute Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.affiliation: Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, EH9 3JT, United Kingdom; Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh, EH9 3JT, United Kingdom;
authors.forename: David
authors.initials: D
authors.lastname: Gray
authors.affiliation: Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, EH9 3JT, United Kingdom; Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh, EH9 3JT, United Kingdom;
authors.forename: Mohini
authors.initials: M
authors.lastname: Gray
authors.affiliation: Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, EH9 3JT, United Kingdom; Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh, EH9 3JT, United Kingdom;
authors.forename: Andrew S
authors.initials: AS
authors.lastname: MacDonald
authors.affiliation: Medical Research Council Centre for Immune Regulation, Institute of Microbiology and Infection, School of Immunity and Infection, University of Birmingham, Birmingham, B15 2TT, United Kingdom;
authors.forename: Adam F
authors.initials: AF
authors.lastname: Cunningham
authors.affiliation: Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, EH9 3JT, United Kingdom; Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh, EH9 3JT, United Kingdom; r.maizels@ed.ac.uk.
authors.forename: Rick M
authors.initials: RM
authors.lastname: Maizels
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D006099:Granuloma / Q000235:genetics / Q000276:immunology; D020381:Interleukin-17 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics* / Q000276:immunology*; D009351:Nematospiroides dubius / Q000276:immunology*; D053633:Receptor, Interferon alpha-beta / Q000235:genetics; D053573:Receptors, Interleukin-1 Type I / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D017206:Strongylida Infections / Q000276:immunology* / Q000469:parasitology; D051195:Toll-Like Receptor 2 / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000235:genetics; D051198:Toll-Like Receptor 5 / Q000235:genetics; D051217:Toll-Like Receptor 9 / Q000235:genetics
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D020381:Interleukin-17; D015847:Interleukin-4; D053594:Myeloid Differentiation Factor 88; D053633:Receptor, Interferon alpha-beta; D053573:Receptors, Interleukin-1 Type I; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051198:Toll-Like Receptor 5; D051217:Toll-Like Receptor 9; C583355:IL1R1 protein, mouse; C508032:Ifnar1 protein, mouse; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; C495370:Tlr9 protein, mouse
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