transforming-growth-factor-beta and Fascioliasis

Helminths parasites undergo developmental changes and migration within their definitive host, in addition to establishing chronic infection. Essential to this is the evasion of host immune responses; the canonical Th2 response is effective at removing parasites resident in the intestine. Conversely, helminths also promote the development of antigen-specific anergy and regulation. This often limits pathology but allows parasite survival, parasite effectors mediating this are the subject of intense study. They may be useful as future vaccine targets or xenogenic therapeutics. Fasciola hepatica possesses a family of TGF-like molecules of which one member, FhTLM, is capable of promoting intrinsic and extrinsic effects. Here we review the extrinsic effects of FhTLM on the host macrophage and its consequences for protective immunity. This review also discusses the specificities of FhTLM in light a very recent description of a nematode TGF-β mimic and the effects of endogenous TGF-β.

Topics: Animals; Fasciola hepatica; Fascioliasis; Helminth Proteins; Host-Parasite Interactions; Humans; Transforming Growth Factor beta

Parasitic helminths reside in immunologically-exposed extracellular locations within their hosts, yet they are capable of surviving for extended periods. To enable this survival, these parasites have developed complex and multifaceted mechanisms to subvert or suppress host immunity. This review summarises current knowledge of immune modulation by helminth parasites of ruminants and the parasite-derived molecules involved in driving this modulation. Such immunomodulatory molecules have considerable promise as vaccine targets, as neutralisation of their function is predicted to enhance anti-parasite immunity and, as such, current knowledge in this area is presented herein. Furthermore, we summarise current evidence that, as well as affecting parasite-specific immunity, immune modulation by these parasites may also affect the ability of ruminant hosts to control concurrent diseases or mount effective responses to vaccination.

Topics: Animals; Apyrase; Cathepsin L; Fasciola hepatica; Fascioliasis; Galectins; Helminth Proteins; Helminthiasis, Animal; Host-Parasite Interactions; Immunocompetence; Intestinal Diseases, Parasitic; Macrophage Migration-Inhibitory Factors; Peroxiredoxins; Rumen; Ruminants; Stomach Diseases; Transforming Growth Factor beta; Vaccination; Vaccines

Liver flukes, Fasciola spp., are veterinary and medically important parasites infecting numerous species of economically important animals in addition to humans on a global scale. The components of transforming growth factor beta (TGF-β) signalling are widely distributed throughout the animal kingdom and are considerably conserved. Through shared common signal transduction mechanisms, crosstalk of TGF-β signalling between a host and the parasite during infection is possible. Herein, we have identified and undertaken the molecular characterisation of a putative TGF-β homologue from the tropical liver fluke F. gigantica (FgTLM). A FgTLM cDNA was 3557 bp in length, it encoded for 620 amino acid polypeptide which consisted of 494 amino acids of prodomain and 126 amino acids comprising the mature protein. FgTLM displayed characteristic structures of mammalian TGF-β ligands that were unique to the inhibin-β chain, monomer of activin. A phylogenetic analysis revealed the high degree of conservation with TGF-β molecules from trematode species. Interestingly, the sequence of amino acid in the active domain of FgTLM was completely identical to FhTLM from F. hepatica. FgTLM expressed throughout the lifecycle of F. gigantica but was highly expressed in developmental active stages. The dynamics of expression of FgTLM during the developmental stages of F. gigantica was comparable to the pattern of TGF-β expression in F. hepatica. Our findings demonstrated that FgTLM exhibits a high level of similarity to FhTLM in the context of both amino acid sequence and the life stage expression patterns. These similarities underline the possibility that the FgTLM molecule might have the same properties and functions as FhTLM in biological processes of the immature parasites and host immune evasion. Consequently, the specific biological functions of FgTLM on either parasite or relevant hosts need to be defined experimentally.

Topics: Amino Acids; Animals; Fasciola; Fasciola hepatica; Fascioliasis; Humans; Mammals; Phylogeny; Transforming Growth Factor beta

The helminth Fasciola hepatica causes fasciolosis throughout the world, a major disease of livestock and an emerging zoonotic disease in humans. Sustainable control mechanisms such as vaccination are urgently required. To discover potential vaccine targets we undertook a genome screen to identify members of the transforming growth factor (TGF) family of proteins. Herein we describe the discovery of three ligands belonging to this superfamily and the cloning and characterisation of an activin/TGF like molecule we term FhTLM. FhTLM has a limited expression pattern both temporally across the parasite stages but also spatially within the worm. Furthermore, a recombinant form of this protein is able to enhance the rate (or magnitude) of multiple developmental processes of the parasite indicating a conserved role for this protein superfamily in the developmental biology of a major trematode parasite. Our study demonstrates for the first time the existence of this protein superfamily within F. hepatica and assigns a function to one of the three identified ligands. Moreover further exploration of this superfamily may yield future targets for diagnostic or vaccination purposes due to its stage restricted expression and functional role.

Topics: Animals; Fasciola hepatica; Fascioliasis; Helminth Proteins; Ligands; Phylogeny; Proteome; Transforming Growth Factor beta; Vaccines

The effects of the lipopolysaccharide (LPS) from Ochrobactrum intermedium in sheep with fasciolosis was reported previously, resulting in lower fecal egg counts and fluke burden. In the current study, we analyzed its immunological effects in two groups of sheep, treated (T) and controls (C). Fasciolosis induces a T helper (Th) type-2 response, characterized by IL-4 and IL-10 production; however, at the beginning of the infection, the IFN-γ production predominates (Th type-1 response). Although we did not find differences in IL-4 production or in the expression level of this gene in the hepatic lymph nodes, the expression level of IL-10 was higher (P < 0.05) in the T group at 4 wpi. The IFN-γ production was higher (P < 0.01) at 12 wpi as well as its level of expression at 4 wpi (P < 0.05) in the T group. We found a higher expression level of TGF-β at 4 wpi in the T group (P < 0.05), associated with the previous report of thicker fibrous tracks in a treated group. Immunoglobulin G1, related with a Th type-2 response, was higher (P < 0.01) in the T group at 4 and 12 wpi. In conclusion, the effects of LPS from O. intermedium could have resulted from a predominant Th type-2 immune response.

Topics: Animals; Fasciola hepatica; Fascioliasis; Feces; Immunoglobulin G; Interferon-gamma; Interleukin-10; Interleukin-4; Lipopolysaccharides; Ochrobactrum; Sheep; Sheep Diseases; Th2 Cells; Transforming Growth Factor beta

In fascioliasis, T-helper 2 (Th2) responses predominate, while little is known regarding early immune phenomenon. We herein analyzed early immunophenotype changes of BALB/c, C57BL/6, and C3H/He mice experimentally infected with 5 Fasciola hepatica metacercariae. A remarkable expansion of CD19(+) B cells was observed as early as week 1 post-infection while CD4(+)/CD8(+) T cells were down-regulated. Accumulation of Mac1(+) cells with time after infection correlated well with splenomegaly of all mice strains tested. The expression of tumor necrosis factor (TNF)-α mRNA in splenocytes significantly decreased while that of IL-4 up-regulated. IL-1β expression was down-modulated in BALB/c and C57BL/6 mice, but not in C3H/He. Serum levels of transforming growth factor (TGF)-β were considerably elevated in all mice during 3 weeks of infection period. These collective results suggest that experimental murine fascioliasis might derive immune suppression with elevated levels of TGF-β and IL-4 during the early stages of infection.

Topics: Animals; B-Lymphocytes; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Down-Regulation; Fasciola hepatica; Fascioliasis; Immunophenotyping; Immunosuppression Therapy; Interleukin-4; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Spleen; Transforming Growth Factor beta

The lower incidence of allergy and autoimmune diseases in developing countries has been associated with a high prevalence of parasitic infections. Here we provide direct experimental evidence that parasites can exert bystander immunosuppression of pathogenic T cells that mediate autoimmune diseases. Infection of mice with Fasciola hepatica resulted in recruitment of dendritic cells, macrophages, eosinophils, neutrophils, and CD4(+) T cells into the peritoneal cavity. The dendritic cells and macrophages in infected mice expressed IL-10 and latency-associated peptide, and they had low surface expression of costimulatory molecules and/or MHC class II. Furthermore, most CD4(+) T cells in the peritoneal cavity of infected mice secreted IL-10, but not IFN-gamma or IL-4. There was a less significant expansion of CD4(+)Foxp3(+) T cells. F. hepatica-specific Tr1-type clones generated from infected mice suppressed proliferation and IFN-gamma production by Th1 cells. Infection was associated with suppression of parasite-specific Th1 and Th2 responses, which was reversed in IL-10-defective mice. Infection with F. hepatica also exerted bystander suppression of immune responses to autoantigens and attenuated the clinical signs of experimental autoimmune encephalomyelitis. Protection was associated with suppression of autoantigen-specific IFN-gamma and IL-17 production. The suppression of Th1 and Th17 responses and attenuation of experimental autoimmune encephalomyelitis by F. hepatica was maintained in IL-10(-/-) mice but was reversed by neutralization of TGF-beta in vivo. Our study provides evidence that F. hepatica-induced IL-10 subverts parasite-specific Th1 and Th2 responses, but that F. hepatica-induced TGF-beta plays a critical role in bystander suppression of autoantigen-specific Th1 and Th17 responses that mediate autoimmune diseases.

Topics: Animals; Autoantigens; Autoimmunity; Fasciola hepatica; Fascioliasis; Interleukin-10; Interleukin-17; Mice; Peritoneum; Th1 Cells; Th2 Cells; Transforming Growth Factor beta

Hosts infected with Fasciola hepatica experience immunosuppression during the acute and chronic phases of the disease. This immunosuppression may allow parasite survival in the face of an ongoing immune response. In bovine hosts early IL-4 and continued IgG1 production is one of the few remaining features of the characteristic type 0/2 helper (Th0/2) response present in the chronic stage of disease. Here we demonstrate elevated levels of parasite-specific, in vitro peripheral blood mononuclear cell (PBMC)-derived transforming growth factor (TGF)-beta1 from the early phases of infection and increasing levels of IL-10 as the infection becomes chronic. In vitro neutralisation of these cytokines during culture of PBMCs from experimentally-infected cattle increased IL-4 and IFN-gamma production in response to parasite-specific and non-specific stimulation. At 4 weeks p.i. neutralisation of TGF-beta results in an increase in parasite driven IL-4, while also having a greater role, compared with IL-10, in influencing specific and non-specific IFN-gamma. At 12 weeks p.i. ex vivo parasite driven IL-4 was not restored by inhibiting either IL-10 or TGF-beta. However IL-10 influenced both parasite-specific and non-specific IFN-gamma production at this time. This highlights the roles of IL-10 and TGF-beta in fasciolosis, however the cellular sources of these have yet to be defined. This suggests that suppression of IFN-gamma production by parasite molecules occurs during infection and it is possible that the suppression of IFN-gamma production may mediate parasite survival in this disease.

Topics: Acute Disease; Animals; Cattle; Cytokines; Enzyme-Linked Immunosorbent Assay; Fasciola hepatica; Fascioliasis; Interferon-gamma; Interleukin-10; Interleukin-4; Lymphocytes; Transforming Growth Factor beta