Authors

G Mulcahy³; Y Fu³; A Garcia-Campos³; L Garza-Cuartero³; M Sekiya³; S N O'Neill²; J P Dalton¹; T Geurden⁴;  ¹ Queen's University Belfast, UK;  ² School of Biotechnology, Dublin City University, UK;  ³ School of Veterinary Medicine and Conway Institute, University College Dublin, UK;  ⁴ Veterinary Medicine Research and Development, Zoetis Inc, Belgium, UK

Discussion

Liver fluke infection - fasciolosis - is one of the problematic conditions where the search for a commercially-viable vaccine still continues. In spite of intensive work over many years by several laboratories, and repeated demonstration as "proof of principal" that partial protection is achievable, significant hurdles remain to be overcome.

These include consistency in achieving protection in repeated trials, as well as variations in fluke burden stemming from both parasite strain differences and host factors. In addition, the "extreme immunoregulation" induced by infection with Fasciola hepatica makes achieving vaccine-mediated protection an even tougher target.

Our laboratory has recently therefore "taken a step back", in an attempt to better understand both parasite-mediated immunoregulation and the nature of protective and non-protective immune responses to the parasite in ruminants.

Our approaches have included looking at the host immune transcriptome at acute and chronic stages of infection, examining the differences between vaccine-induced responses and responses to infection, as well as seeking to understand the role of glycans in host-parasite interaction.

Examination of the transciptome of ovine peripheral blood mononuclear cells (PBMC) reveals a large number of differentially-expressed genes at both acute and chronic stages of infection. Pathway analysis of the response sheds light on the suppression of IFN-γ and parasite-specific IgG2 during infection, as well as alteration of macrophage metabolic pathways and activation of death receptors. In contrast, initial analysis of the bovine transcriptome indicates a more muted response during the acute stage of infection, and reflecting the different disease phenotype in sheep vs cattle.

In comparing responses of ruminants to infection (non-protective) and vaccination (partially protective), we have known for some time that high-titre, high-affinity antibody to specific antigens is required for protection, and that a mixed, rather than a skewed Th2/Treg response is required. Extending these studies to the fine-specificity of the response to a target antigen, FhCL1, we have observed areas of this ES protein that may be serving as decoy antigens, and others which are associated with protective responses.

An effective liver fluke vaccine would further animal health and welfare as well as public health. Despite the difficulties inherent in pursuing this goal, we are encouraged that the Back to the Drawing Board approach we have adopted will pave the way for smart vaccines capable of inducing protective responses while neutralizing non-protective elements.