Network Analysis of the Systemic Response to Fasciola hepatica Infection in Sheep Reveals Changes in Fibrosis, Apoptosis, Toll-Like Receptors 3/4, and B Cell Function.

Yan Fu,Grace Mulcahy,John A Browne,Kate Killick

doi:10.3389/fimmu.2017.00485

Abstract

The Trematode Fasciola hepatica is an important cause of disease in livestock and in man. Modulation of immunity is a critical strategy used by this parasite to facilitate its long-term survival in the host. Understanding the underlying mechanisms at a system level is important for the development of novel control strategies, such as vaccination, as well as for increasing general understanding of helminth-mediated immunoregulation and its consequences. Our previous RNA sequencing work identified a large number of differentially expressed genes (DEG) from ovine peripheral blood mononuclear cells (PBMCs) at acute and chronic stages of F. hepatica infection, and yielded important information on host–parasite interaction, with particular reference to the immune response. To extend our understanding of the immunoregulatory effects of this parasite, we employed InnateDB to further analyze the DEG dataset and identified 2,458 and 224 molecular interactions in the context of innate immunity from the acute and chronic stages of infection, respectively. Notably, 458 interactions at the acute stage of infection were manually curated from studies involving PBMC-related cell-types, which guaranteed confident hypothesis generation. NetworkAnalyst was subsequently used to construct and visualize molecular networks. Two complementary strategies (function-first and connection-first) were conducted to interpret the networks. The function-first approach highlighted subnetworks implicated in regulation of Toll-like receptor 3/4 signaling in both acute and chronic infections. The connection-first approach highlighted regulation of intrinsic apoptosis and B-cell receptor-signaling during acute and chronic infections, respectively. To the best of our knowledge, this study is the first system level analysis of the regulation of host innate immunity during F. hepatica infection. It provides insights into the profound changes induced by F. hepatica infection that not only favors parasite survival into chronic infection but also impedes the host’s immune response to other pathogens, and render vaccination against fasciolosis a difficult challenge. The information provided will be useful in the design of specific vaccine protocols to overcome parasite-mediated immunoregulation and in furthering general understanding of the interplay between helminth infection and host immune systems.

Highlights

Fasciola hepatica is an important helminth parasite of economically important animals, such as cattle and sheep (1), and a major food-borne zoonosis worldwide (2–4)
We have previously reported the transcriptomic changes of peripheral blood mononuclear cells (PBMCs) from eight lambs in response to F. hepatica infection using RNA sequencing (RNA-seq) (NCBI GEO accession number: GSE71431) (15)
Since the interactome is very much dependent on the context of a particular cell type under investigation (21), we focused on the interactions from studies involving PBMC-related cell types including B cells, T cells, NK cells, and monocytes

Summary

Introduction

Fasciola hepatica is an important helminth parasite of economically important animals, such as cattle and sheep (1), and a major food-borne zoonosis worldwide (2–4). A better understanding of host–parasite interactions is expected to further refine development of vaccines and may lead to novel therapeutic approaches against F. hepatica infection. F. hepatica interacts with various host innate immune cells [e.g., dendritic cells (DC), macrophages, and mast cells] as soon as infection commences with excystation of the juvenile flukes which cross the gut wall within hours (10). Innate effector mechanisms, such as alternative activation of macrophages, play an important role in early host responses against F. hepatica infection as well as in regulating and shaping the Th2-biased adaptive immune response (11). Previous studies have suggested that F. hepatica infection can modify the maturation and function of host DC through a number of different mechanisms, which could further mediate the stimulation of naïve T cells (12–14)

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