IL-33 facilitates rapid expulsion of the parasitic nematode Strongyloides ratti from the intestine via ILC2- and IL-9-driven mast cell activation.

Jana Meiners,Lennart Heepmann,Martina Reitz,Lena Rudolf,Henry J Mcsorley,Nikolas Rüdiger,Jan-Eric Turner,Minka Breloer,Wiebke Hartmann,Meera Goh Nair

doi:10.1371/journal.ppat.1009121

Abstract

Parasitic helminths are sensed by the immune system via tissue-derived alarmins that promote the initiation of the appropriate type 2 immune responses. Here we establish the nuclear alarmin cytokine IL-33 as a non-redundant trigger of specifically IL-9-driven and mast cell-mediated immunity to the intestinal parasite Strongyloides ratti. Blockade of endogenous IL-33 using a helminth-derived IL-33 inhibitor elevated intestinal parasite burdens in the context of reduced mast cell activation while stabilization of endogenous IL-33 or application of recombinant IL-33 reciprocally reduced intestinal parasite burdens and increased mast cell activation. Using gene-deficient mice, we show that application of IL-33 triggered rapid mast cell-mediated expulsion of parasites directly in the intestine, independent of the adaptive immune system, basophils, eosinophils or Gr-1+ cells but dependent on functional IL-9 receptor and innate lymphoid cells (ILC). Thereby we connect the described axis of IL-33-mediated ILC2 expansion to the rapid initiation of IL-9-mediated and mast cell-driven intestinal anti-helminth immunity.

Highlights

Helminths are large multicellular pathogens that affect one quarter of the human population [1]
Parasitic worms leave a trail of destruction while migrating through their host’s tissue. Thereby they trigger the release of tissue-derived alarmin cytokines such as IL-33 that promote the initiation of efficient anti-helminth immune responses
We use mice infected with the parasitic nematode Strongyloides ratti to unravel the chain of events leading from parasite sensing to parasite expulsion

Summary

Introduction

Helminths are large multicellular pathogens that affect one quarter of the human population [1] They are controlled and eradicated in the context of a canonical type 2 immune response [2]. Infective third stage larvae (L3) penetrate the skin of their hosts and over the following 2 days migrate via skin, head and lung to the mouth. Eradication of migrating Strongyloides L3 during the first 2 days of infection is mediated predominantly by eosinophilic and neutrophilic granulocytes [5,6,7,8,9], whereas efficient expulsion from the intestine is executed by basophils [10] and mast cells [11,12]. The factors regulating initiation of this anti-helminth response, are still not fully understood

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Conclusion