MyD88 signaling inhibits protective immunity to the gastrointestinal helminth parasite Heligmosomoides polygyrus.

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

doi:10.4049/jimmunol.1401056

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.

Highlights

Wild-type C57BL/6 mice are chronically susceptible to this parasite, a lack of MyD88 signaling was found to render mice markedly more resistant to infection, with a lower H. polygyrus egg output seen at days 14 and 27 post infection (Fig. 1A, 1B), an indication of lower worm fitness, which correlates with stronger immune responsiveness [10]
A striking phenotype in MyD882/2 mice was the increased number of granulomas that formed along the small intestinal tract following H. polygyrus infection, which were rarely observed at this time point in wild-type C57BL/6 mice (Fig. 1D)
We investigated the outcome of a primary H. polygyrus infection in mice deficient in MyD88 signaling, and found that they were more resistant to infection than wild-type C57BL/6 mice and had a higher frequency of IL-4–producing CD4+ T cells following infection

Summary

Introduction

We set out to investigate how immunity to H. polygyrus was affected when C57BL/6 mice, which typically are chronically susceptible to infection with this parasite, lacked the adapter protein MyD88, a major mediator of signaling through TLRs [27] and IL-1 family members [28]. This resistance was associated with a heightened Th2 response, as well as a dramatic increase in the number of granulomas being produced following H. polygyrus infection, which rarely formed in C57BL/6 wild-type control mice.

Results

Conclusion