Dataset Information

Proteomics analyses of immature (21 day post infection) Fasciola hepatica

ABSTRACT: The major pathogenesis associated with Fasciola hepatica infection results from the extensive tissue damage caused by the tunnelling and feeding activity of immature flukes during their migration, growth and development in the liver. This is compounded by the pathology caused by host innate and adaptive immune responses that struggle to repair this damage. Complementary transcriptomic and proteomic approaches defined the F. hepatica factors associated with their migration in the liver, and the resulting immune-pathogenesis. The liver-stage parasites display different secretome profiles, reflecting their distinct niche within the host, and supports the view that cathepsin peptidases, cathepsin peptidase inhibitors, saposins and leucine aminopeptidases play a central role in the parasite’s destructive migration, digest of host tissue and blood. Immature flukes are also primed for countering immune attack by secreting immunomodulating fatty acid binding proteins (FABP) and helminth defense molecules (FhHDM). The migration of immature F. hepatica parasites within the liver is associated with an increase in protein production, expression of signalling pathways and neoblast proliferation that drive their rapid growth and development. The secretion of a defined set of molecules, particularly cathepsin L peptidases, peptidase-inhibitors, saponins, immune-regulators and anti-oxidants allow the parasite to negotiate the liver micro-environment, immune attack and increasing levels of oxidative stress. This data contributes to the growing F. hepatica -omics information that can be exploited to understand parasite development more fully and for the design of novel control strategies to prevent host liver tissue destruction and pathology.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Fasciola Hepatica (liver Fluke)

SUBMITTER: Krystyna Cwiklinski

LAB HEAD: John P Dalton

PROVIDER: PXD021221 | Pride | 2021-09-09

REPOSITORIES: Pride

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Publications

Complementary transcriptomic and proteomic analyses reveal the cellular and molecular processes that drive growth and development of Fasciola hepatica in the host liver.

Cwiklinski Krystyna K Robinson Mark W MW Donnelly Sheila S Dalton John P JP

BMC genomics 20210111 1

<h4>Background</h4>The major pathogenesis associated with Fasciola hepatica infection results from the extensive tissue damage caused by the tunnelling and feeding activity of immature flukes during their migration, growth and development in the liver. This is compounded by the pathology caused by host innate and adaptive immune responses that struggle to simultaneously counter infection and repair tissue damage.<h4>Results</h4>Complementary transcriptomic and proteomic approaches defined the F. ...[more]

PMID: 33430759

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Project description:The liver fluke Fasciola hepatica is an economically important pathogen of livestock. Fasciolosis in humans is an important re-emerging zoonosis, with 180 million people at risk. Development of novel control strategies requires an understanding of parasite virulence and tissue invasion, and of how the parasite evades and modulates the immune response during early infection. A combination of immunological and proteomic analyses was employed to investigate the peritoneal fluid of sheep infected with F. hepatica to characterise early tissue invasion and liver pathogenesis. At 18 days post-infection (dpi), histopathology of sheep liver showed white necrotic foci/tracts indicative of F. hepatica migration. Within the peritoneal fluid of infected animals, specific F. hepatica antigen FhCL1 antibodies coincided with an intense innate and adaptive cellular immune response, with increasing numbers of total leukocytes and a marked eosinophilia (49%). Cytokine qPCR analysis revealed IL-10, IL-12, IL-13, IL-23 and TGFβ were elevated but not statistically significant at 18 dpi compared to uninfected sheep indicating that whilst the immune response is developing it has not polarised to the Th2 type associated with chronic fasciolosis. Proteomic analysis of the peritoneal fluid identified 178 proteins, with 25 proteins more highly expressed in the infected animals, based on fold changes in protein concentration compared to the uninfected animals. Components of the liver extracellular matrix, including collagen, periostin and the adhesion protein, VCAM-1, exhibited increased expression associated with early fasciolosis, which may be important in signalling host immune responses to tissue damage. In early F. hepatica infection cellular infiltration with marked eosinophilia, adaptive immune responses and products of liver pathology are evident in the peritoneum. Although cytokine responses are developing they are mixed and not yet polarised to a Th2-type. We have characterised biomarkers of parasite-induced liver damage which could be exploited for diagnosis, and vaccine development aimed at reducing/preventing liver pathology.

Project description:Background: Fasciola hepatica infection still remains one of the helminthic neglected tropical diseases (NTDs). It has a huge worldwide distribution, affecting mainly cattle and, sometimes, human beings. In addition to data reported about the immunological response induced by helminthic infections and that induced by Fasciola hepatica, little is known about the gene expression profile in its organ target, the liver, which is where adult worms are established and live for long periods of time, causing its characteristic pathology. In the present work, we study both the early and late gene expression profiles in the livers of mice infected with Fasciola hepatica metacercariae using a microarray-based methodology. Methodology: A total of 9 female-6-week-old BALB/c mice (Charles River Laboratories, Barcelona, Spain) weighing 20 to 35 g were used for the experiments. Two groups of BALB/c mice were orally infected with seven F. hepatica metacercariae, and the other group remained untreated and served as a control. Mice were humanely euthanized and necropsied for liver recovery, histological assessment of hepatic damage, RNA isolation, microarray design and gene expression analysis on the day of infection (t0), seven days post-infection (t7) and twenty-one days post-infection (t21). Results: We found that Fasciola hepatica infection induces the differential expression of 128 genes in the liver in the early stage of infection and 308 genes in the late stage, and most of them are up-regulated. The Ingenuity Pathway Analysis revealed significant changes in the pathways related to metabolism, biosynthesis and signaling as well as genes implicated in inducing liver-toxicity, injury and death. Conclusion: The present study provides us insights at the molecular level about the underlying mechanisms used by Fasciola hepatica, leading to liver damage and its subsequent pathophysiology. The expression pattern obtained here could also be used to explain the lack of association between infection with F. hepatica and cholangiocarcinoma. However, more studies should be performed to confirm this hypothesis. We used three experimental groups each containing 3 mice. Group 1 remains untreated and served as control. Group 2 was infected with Fasciola hepatica metacercariae on day 0 and humanely necropsied at 7 days post-infection. Group 3 was infected with Fasciola hepatica metacercariae on day 0 and humanely necropsied at 21 days post- infection. At the time of necropsy, liver of each mice were removed and the RNA was isolated. We compared the gene expression profile in the liver of mice infected with Fasciola hepatica.

Dataset Information

Proteomics analyses of immature (21 day post infection) Fasciola hepatica

Publications

Complementary transcriptomic and proteomic analyses reveal the cellular and molecular processes that drive growth and development of Fasciola hepatica in the host liver.

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