Research Article: Myc-induced nuclear antigen constrains a latent intestinal epithelial cell-intrinsic anthelmintic pathway

Date Published: February 26, 2019

Publisher: Public Library of Science

Author(s): Meenu R. Pillai, Belgacem Mihi, Kenji Ishiwata, Kiminori Nakamura, Naoya Sakuragi, David B. Finkelstein, Maureen A. McGargill, Toshinori Nakayama, Tokiyoshi Ayabe, Mathew L. Coleman, Mark Bix, Richard Karl Grencis.

http://doi.org/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.

Partial Text

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 [2–10]. Expulsion of GI nematodes requires the host T helper 2 (Th2)-type response to mobilize multiple GI effector mechanisms including goblet cell hyperplasia and increased epithelial cell turnover [11]. However, the full panoply of effector mechanisms remains still to be elucidated. We have shown that the JmjC protein Mina can repress transcription of IL4, a key Th2 cytokine, suggesting a possible negative regulatory role in GI nematode expulsion [12]. To gain further insight, we explored genetic models of Mina deficiency during infection with the parasitic whipworm Trichuris muris (TM) that models human infection with the soil transmitted helminth Trichuris trichiura [13]. Unexpectedly, we discovered Mina acts in intestinal epithelial cells (IECs) rather than CD4 T cells to constrain parasite expulsion by a novel mechanism associated with mobilization of anti-microbial α-defensins that can directly inflict damage upon parasites and with repression of the Th1 response that antagonizes worm expulsion. Thus, therapeutic inhibition of Mina in intestinal epithelial cells could unleash a latent host-protective anthelmintic response.

Our previous work had led us to hypothesize that Mina, acting as an Il4 repressor [12], would act to retard the highly Th2-dependent expulsion of parasitic helminths. Surprisingly however, analysis of in vitro Th2 differentiation in Mina KO cells revealed Mina not to be an essential regulator of Th2 development, perhaps due to functional redundancy with its close structural and evolutionary homolog NO66 [23]. Nevertheless, germline Mina deficiency did accelerate TM expulsion. Consistent with our in vitro data, accelerated expulsion was associated with a normal rather than an enhanced Th2 response. Providing a potential explanation for the accelerated expulsion phenotype, we discovered that Mina KO mice exhibited an impaired Th1 response to TM. As Th1 responses are well documented to promote chronic GI nematode infection [11], our results, point to a role for Mina in repressing worm expulsion by promoting the Th1 response.

 

Source:

http://doi.org/10.1371/journal.pone.0211244

 

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