Numerous Fasciola plasminogen-binding proteins may underlie blood-brain barrier leakage and explain neurological disorder complexity and heterogeneity in the acute and chronic phases of human fascioliasis.

J González-Miguel,C Mas-Bargues,M A Valero,F Simón,M Reguera-Gomez,S Mas-Coma,M D Bargues

doi:10.1017/s0031182018001464

Abstract

Human fascioliasis is a worldwide, pathogenic food-borne trematodiasis. Impressive clinical pictures comprising puzzling polymorphisms, manifestation multifocality, disease evolution changes, sequelae and mortality, have been reported in patients presenting with neurological, meningeal, neuropsychic and ocular disorders caused at distance by flukes infecting the liver. Proteomic and mass spectrometry analyses of the Fasciola hepatica excretome/secretome identified numerous, several new, plasminogen-binding proteins enhancing plasmin generation. This may underlie blood-brain barrier leakage whether by many simultaneously migrating, small-sized juvenile flukes in the acute phase, or by breakage of encapsulating formations triggered by single worm tracks in the chronic phase. Blood-brain barrier leakages may subsequently occur due to a fibrinolytic system-dependent mechanism involving plasmin-dependent generation of the proinflammatory peptide bradykinin and activation of bradykinin B2 receptors, after different plasminogen-binding protein agglomeration waves. Interactions between diverse parasitic situations and non-imbalancing fibrinolysis system alterations are for the first time proposed that explain the complexity, heterogeneity and timely variations of neurological disorders. Additionally, inflammation and dilation of blood vessels may be due to contact system-dependent generation bradykinin. This baseline allows for search of indicators to detect neurological risk in fascioliasis patients and experimental work on antifibrinolytic treatments or B2 receptor antagonists for preventing blood-brain barrier leakage.

Highlights

Fascioliasis is a worldwide food-borne trematodiasis caused by two Fasciola species transmitted by freshwater lymnaeid snails: Fasciola hepatica in Europe, Africa, Asia, the Americas and Oceania, and Fasciola gigantica in parts of Africa and Asia (Mas-Coma et al, 2009)
Analyses showed that proteins of F. hepatica adults (FhES) extract bind plasminogen and that this binding is directly proportional to the amount of plasminogen
Our results suggest that tissue plasminogen activator (tPA) overexpression due to the numerous plasminogen-binding proteins of the Fasciola excretome/secretome increases the permeability of the intact blood-brain barrier by a plasminogen-dependent mechanism

Summary

Introduction

Fascioliasis is a worldwide food-borne trematodiasis caused by two Fasciola species transmitted by freshwater lymnaeid snails: Fasciola hepatica in Europe, Africa, Asia, the Americas and Oceania, and Fasciola gigantica in parts of Africa and Asia (Mas-Coma et al, 2009) This disease is well known in the veterinary field due to the economic losses it causes in animal husbandry including livestock morbidity and mortality (Torgerson and Claxton, 1999). A new serious public health scenario progressively appeared from the 1990s (Chen and Mott, 1990), with the description of many human endemic areas and non-stop increasing number of case reports (Mas-Coma et al, 2014a) This led to demonstrate that it is the vector-borne parasitic disease with the widest latitudinal, longitudinal and altitudinal distribution known and to reach a global estimation of 17 million people infected (Mas-Coma, 2005). Efforts to go deep in the advanced chronic phase demonstrated its implications in pathogenicity (Valero et al, 2003, 2006, 2008, 2016), immunogenicity (Girones et al, 2007) and in the reinfections during this chronic period (Valero et al, 2017)

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