Myc-induced nuclear antigen constrains a latent intestinal epithelial cell-intrinsic anthelmintic pathway.

Meenu R Pillai,Mathew L Coleman,Toshinori Nakayama,Mark Bix,Tokiyoshi Ayabe,Kiminori Nakamura,Belgacem Mihi,Naoya Sakuragi,David B Finkelstein,Kenji Ishiwata,Maureen A Mcgargill

doi:10.1371/journal.pone.0211244

Abstract

Expulsion of parasitic gastrointestinal nematodes requires diverse effector mechanisms coordinated by a Th2-type response. The evolutionarily conserved JmjC protein; Myc Induced Nuclear Antigen (Mina) has been shown to repress IL4, a key Th2 cytokine, suggesting Mina may negatively regulate nematode expulsion. Here we report that expulsion of the parasitic nematode Trichuris muris was indeed accelerated in Mina deficient mice. Unexpectedly, this was associated not with an elevated Th2- but rather an impaired Th1-type response. Further reciprocal bone marrow chimera and conditional KO experiments demonstrated that retarded parasite expulsion and a normal Th1-type response both required Mina in intestinal epithelial cells (IECs). Transcriptional profiling experiments in IECs revealed anti-microbial α-defensin peptides to be the major target of Mina-dependent retention of worms in infected mice. In vitro exposure to recombinant α-defensin peptides caused cytotoxic damage to whipworms. These results identify a latent IEC-intrinsic anthelmintic pathway actively constrained by Mina and point to α-defensins as important effectors that together with Mina may be attractive therapeutic targets for the control of nematode infection.

Highlights

Over 2 billion people are chronically infected with parasitic gastrointestinal (GI) nematodes, extracting a massive global toll in morbidity and mortality [1]; in addition, the rapid spread of drug resistance in livestock GI nematodes has created a global economic crisis that portends a further humanitarian one [2,3,4,5,6,7,8,9,10]
We have shown that the JmjC protein Myc Induced Nuclear Antigen (Mina) can repress transcription of IL4, a key T helper 2 (Th2) cytokine, suggesting a possible negative regulatory role in GI nematode expulsion [12]
We did note that Mina KO mice exhibited a slight but significant decrease in mesenteric lymph nodes (MLN) B cells and a significant increase in MLN CD8+ DCs

Summary

Introduction

Over 2 billion people are chronically infected with parasitic gastrointestinal (GI) nematodes, extracting a massive global toll in morbidity and mortality [1]; in addition, the rapid spread of drug resistance in livestock GI nematodes has created a global economic crisis that portends a further humanitarian one [2,3,4,5,6,7,8,9,10]. Expulsion of GI nematodes requires the host T helper 2 (Th2)-type response to mobilize multiple GI effector mechanisms including goblet cell. Role of Myc-induced nuclear antigen in parasite expulsion. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Methods

Results

Conclusion