Epithelial-Cell-Derived Phospholipase A2 Group 1B Is an Endogenous Anthelmintic

Lewis J Entwistle,Victoria S Pelly,Stephanie M Coomes,Yashaswini Kannan,Jimena Perez-Lloret,Stephanie Czieso,Mariana Silva Dos Santos,James I Macrae,Lucy Collinson,Abdul Sesay,Nikolay Nikolov,Amina Metidji,Helena Helmby,David Y Hui,Mark S Wilson

doi:10.1016/j.chom.2017.09.006

Abstract

SummaryImmunity to intestinal helminth infections has been well studied, but the mechanism of helminth killing prior to expulsion remains unclear. Here we identify epithelial-cell-derived phospholipase A2 group 1B (PLA2g1B) as a host-derived endogenous anthelmintic. PLA2g1B is elevated in resistant mice and is responsible for killing tissue-embedded larvae. Despite comparable activities of other essential type-2-dependent immune mechanisms, Pla2g1b−/− mice failed to expel the intestinal helminths Heligmosomoides polygyrus or Nippostrongylus brasiliensis. Expression of Pla2g1b by epithelial cells was dependent upon intestinal microbiota, adaptive immunity, and common-gamma chain-dependent signaling. Notably, Pla2g1b was downregulated in susceptible mice and inhibited by IL-4R-signaling in vitro, uncoupling parasite killing from expulsion mechanisms. Resistance was restored in Pla2g1b−/− mice by treating infective H. polygyrus L3 larvae with PLA2g1B, which reduced larval phospholipid abundance. These findings uncover epithelial-cell-derived Pla2g1b as an essential mediator of helminth killing, highlighting a previously overlooked mechanism of anti-helminth immunity.

Highlights

Intestinal helminth infections are highly prevalent in developing countries, with chronic infections causing significant host morbidity (Hotez et al, 2008)
Upon infection, activated epithelial cells secrete a suite of alarmins, including interleukin (IL)-25, thymic stromal lymphopoietin (TSLP), and IL-33, which promote activation and differentiation of innate and adaptive immune cells, leading to type 2 inflammation (Anthony et al, 2006; Katona et al, 1991; McCoy et al, 2008; Urban et al, 1991a)
Resistance to H.p. 2 infection correlated with substantial inflammation and tissue remodeling (Figure 1B), and significantly more transcriptional activity in duodenal tissue than in 1 infection (H.p. 1), with 665 genes differentially expressed in 2 infection compared to 145 genes in 1 infection and 116 common genes (Figure S1A)

Summary

Introduction

Intestinal helminth infections are highly prevalent in developing countries, with chronic infections causing significant host morbidity (Hotez et al, 2008). Upon infection, activated epithelial cells secrete a suite of alarmins, including interleukin (IL)-25, thymic stromal lymphopoietin (TSLP), and IL-33, which promote activation and differentiation of innate and adaptive immune cells, leading to type 2 inflammation (Anthony et al, 2006; Katona et al, 1991; McCoy et al, 2008; Urban et al, 1991a). IL-4-driven CD4+ T helper (Th)-2 cell differentiation, in combination with group 2 innate lymphoid cell (ILC2) activation, leads to the secretion of a suite of cytokines including IL-4, IL-5, IL-9, and IL-13, which propagate type 2 inflammation and activate the local stroma (Grencis et al, 1991; Hashimoto et al, 2009). The precise mechanism of parasite damage and killing, whether in tissue or lumen, has remained unclear

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Conclusion