Abstract
BackgroundFasciola gigantica-induced immunomodulation is a major hurdle faced by the host for controlling infection. Here, we elucidated the role of F. gigantica Ras-related protein Rab10 (FgRab10) in the modulation of key functions of peripheral blood mononuclear cells (PBMCs) of goats.MethodsWe cloned and expressed recombinant FgRab10 (rFgRab10) protein and examined its effects on several functions of goat PBMCs. Protein interactors of rFgRab10 were predicted in silico by querying the databases Intact, String, BioPlex and BioGrid. In addition, a total energy analysis of each of the identified interactions was also conducted. Gene Ontology (GO) enrichment analysis was carried out using FuncAssociate 3.0.ResultsThe FgRab10 gene (618 bp), encodes 205-amino-acid residues with a molecular mass of ~23 kDa, had complete nucleotide sequence homology with F. hepatica Ras family protein gene (PIS87503.1). The rFgRab10 protein specifically cross-reacted with anti-Fasciola antibodies as shown by Western blot and immunofluorescence analysis. This protein exhibited multiple effects on goat PBMCs, including increased production of cytokines [interleukin-2 (IL-2), IL-4, IL-10, transforming growth factor beta (TGF-β) and interferon gamma (IFN-γ)] and total nitric oxide (NO), enhancing apoptosis and migration of PBMCs, and promoting the phagocytic ability of monocytes. However, it significantly inhibited cell proliferation. Homology modelling revealed 63% identity between rFgRab10 and human Rab10 protein (Uniprot ID: P61026). Protein interaction network analysis revealed more stabilizing interactions between Rab proteins geranylgeranyltransferase component A 1 (CHM) and Rab proteins geranylgeranyltransferase component A 2 (CHML) and rFgRab10 protein. Gene Ontology analysis identified RabGTPase mediated signaling as the most represented pathway.ConclusionsrFgRab10 protein exerts profound influences on various functions of goat PBMCs. This finding may help explain why F. gigantica is capable of provoking recognition by host immune cells, less capable of destroying this successful parasite.
Highlights
Fasciola gigantica-induced immunomodulation is a major hurdle faced by the host for controlling infection
Our results indicate that rFgRab10 protein can significantly influence key functions of goat peripheral blood mononuclear cells (PBMCs), all are critical facets of the immunopathogenesis of F. gigantica infection
The specificity of rFgRab10 protein was confirmed by Western blot analysis, wherein rFgRab10 protein reacted with serum from Fasciola-infected sheep as indicated by the presence of a single ~39 kDa band
Summary
Fasciola gigantica-induced immunomodulation is a major hurdle faced by the host for controlling infection. At least 2.4 million people have been infected with fascioliasis, with a further 180 million people at risk of being infected [3]. Despite this high impact and investigations for decades using clinical studies as well as animal models, knowledge about host defense mechanisms against F. gigantica is limited. This challenge is partly due to the fact that Fasciola spp. are very efficient modulators of the host immune response [4]. The immunomodulatory capacity of F. gigantica, mediated by parasite-derived effector molecules, is believed to play important roles in the establishment of long-lasting infection in the host
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