MyD88 signaling inhibits protective immunity to the gastrointestinal helminth parasite heligmosomoides polygyrus

Lisa A. Reynolds, Yvonne Harcus, Katherine A. Smith, Lauren M. Webb, James P. Hewitson, Ewan A. Ross, Sheila Brown, Satoshi Uematsu, Shizuo Akira, David Gray, Mohini Gray, Andrew S. MacDonald, Adam F. Cunningham, Rick M. Maizels*

*Corresponding author for this work

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)2984-2993
Number of pages10
JournalJournal of Immunology
Volume193
Issue number6
Early online date5 Sep 2014
DOIs
Publication statusE-pub ahead of print - 5 Sep 2014

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Nematospiroides dubius
Helminths
Immunity
Parasites
Granuloma
Inbred C57BL Mouse
Infection
Myeloid Differentiation Factor 88
Interleukin-17
Interleukin-1
Interleukin-4
Proteins
Lymph Nodes
Genotype

Bibliographical note

Copyright © 2014 The Authors
This is an open-access article distributed under the terms of the CC-BY 3.0 Unported license.

Cite this

Reynolds, Lisa A. ; Harcus, Yvonne ; Smith, Katherine A. ; Webb, Lauren M. ; Hewitson, James P. ; Ross, Ewan A. ; Brown, Sheila ; Uematsu, Satoshi ; Akira, Shizuo ; Gray, David ; Gray, Mohini ; MacDonald, Andrew S. ; Cunningham, Adam F. ; Maizels, Rick M. / MyD88 signaling inhibits protective immunity to the gastrointestinal helminth parasite heligmosomoides polygyrus. In: Journal of Immunology. 2014 ; Vol. 193, No. 6. pp. 2984-2993.
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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.",
author = "Reynolds, {Lisa A.} and Yvonne Harcus and Smith, {Katherine A.} and Webb, {Lauren M.} and Hewitson, {James P.} and Ross, {Ewan A.} and Sheila Brown and Satoshi Uematsu and Shizuo Akira and David Gray and Mohini Gray and MacDonald, {Andrew S.} and Cunningham, {Adam F.} and Maizels, {Rick M.}",
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Reynolds, LA, Harcus, Y, Smith, KA, Webb, LM, Hewitson, JP, Ross, EA, Brown, S, Uematsu, S, Akira, S, Gray, D, Gray, M, MacDonald, AS, Cunningham, AF & Maizels, RM 2014, 'MyD88 signaling inhibits protective immunity to the gastrointestinal helminth parasite heligmosomoides polygyrus', Journal of Immunology, vol. 193, no. 6, pp. 2984-2993. https://doi.org/10.4049/jimmunol.1401056

MyD88 signaling inhibits protective immunity to the gastrointestinal helminth parasite heligmosomoides polygyrus. / Reynolds, Lisa A.; Harcus, Yvonne; Smith, Katherine A.; Webb, Lauren M.; Hewitson, James P.; Ross, Ewan A.; Brown, Sheila; Uematsu, Satoshi; Akira, Shizuo; Gray, David; Gray, Mohini; MacDonald, Andrew S.; Cunningham, Adam F.; Maizels, Rick M.

In: Journal of Immunology, Vol. 193, No. 6, 05.09.2014, p. 2984-2993.

Research output: Contribution to journalArticle

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T1 - MyD88 signaling inhibits protective immunity to the gastrointestinal helminth parasite heligmosomoides polygyrus

AU - Reynolds, Lisa A.

AU - Harcus, Yvonne

AU - Smith, Katherine A.

AU - Webb, Lauren M.

AU - Hewitson, James P.

AU - Ross, Ewan A.

AU - Brown, Sheila

AU - Uematsu, Satoshi

AU - Akira, Shizuo

AU - Gray, David

AU - Gray, Mohini

AU - MacDonald, Andrew S.

AU - Cunningham, Adam F.

AU - Maizels, Rick M.

N1 - Copyright © 2014 The Authors This is an open-access article distributed under the terms of the CC-BY 3.0 Unported license.

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N2 - 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.

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