The parasitic helminth Fasciola hepatica (liver fluke) causes economic loss to the livestock industry globally and also causes zoonotic disease. New control strategies such as vaccines are urgently needed, due to the rise of drug resistance in parasite populations. Vaccine development requires a comprehensive understanding of the immunological events during infection. Previous in vivo studies by our group have investigated global differentially expressed genes (DEGs) in ovine peripheral blood mononuclear cells (PBMC) in response to both acute and chronic F. hepatica infection. This work demonstrated that pathways involved in the pathogenesis of ovine fasciolosis included fibrosis, inhibition of macrophage nitric oxide production, and antibody isotype switching, among others. Transcriptomic changes in PBMC populations following F. hepatica infection in cattle, in which the disease phenotype is quite different, have not yet been examined. Using RNA sequencing we investigated gene expression changes in PBMC isolated from 9 non-infected and 11 F. hepatica-experimentally-infected calves immediately before infection, at 1 and at 14 weeks post-infection. Longitudinal time-course comparisons between groups revealed 21 and 1,624 DEGs driven exclusively by F. hepatica infection in cattle at acute and chronic stages, respectively. These results show that fewer DEGs at the acute stage of infection can be identified in cattle, as compared with sheep. In addition, the log 2 fold-changes of these DEGs were relatively low (−1 to 3) reflecting the different clinical presentation of F. hepatica infection in cattle. Gene pathways for hepatic fibrosis and hepatic cholestasis along with apoptosis of antigen-presenting cells were enriched at chronic stages. Our results reflect the major differences in the disease phenotype between cattle and sheep and may indicate pathways to target in vaccine development.

SUMMARYBovine tuberculosis (BTB), caused by Mycobacterium bovis, has an annual incidence in cattle of 0.5% in the Republic of Ireland and 4.7% in the UK, despite long-standing eradication programmes being in place. Failure to achieve complete eradication is multifactorial, but the limitations of diagnostic tests are significant complicating factors. Previously, we have demonstrated that Fasciola hepatica infection, highly prevalent in these areas, induced reduced sensitivity of the standard diagnostic tests for BTB in animals co-infected with F. hepatica and M. bovis. This was accompanied by a reduced M. bovis-specific Th1 immune response. We hypothesized that these changes in co-infected animals would be accompanied by enhanced growth of M. bovis. However, we show here that mycobacterial burden in cattle is reduced in animals co-infected with F. hepatica. Furthermore, we demonstrate a lower mycobacterial recovery and uptake in blood monocyte-derived macrophages (MDM) from F. hepatica-infected cattle which is associated with suppression of pro-inflammatory cytokines and a switch to alternative activation of macrophages. However, the cell surface expression of TLR2 and CD14 in MDM from F. hepatica-infected cattle is increased. These findings reflecting the bystander effect of helminth-induced downregulation of pro-inflammatory responses provide insights to understand host-pathogen interactions in co-infection.

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Background Fasciolosis is one of the most important parasitic diseases of livestock. The need for better control strategies gave rise to the identification of various vaccine candidates. The recombinant form of a member of the cysteine protease family, cathepsin L1 of Fasciola hepatica (FhCL1) has been a vaccine target for the past few decades since it has been shown to behave as an immunodominant antigen. However, when FhCL1 was used as vaccine, it has been observed to elicit significant protection in some trials, whereas no protection was provided in others. Methods In order to improve vaccine development strategy, we conducted a linear B-cell epitope mapping of FhCL1 in sheep vaccinated with FhCL1, FhHDM, FhLAP and FhPrx plus Montanide and with significant reduction of the fluke burden, sheep vaccinated with FhCL1, FhHDM, FhLAP and FhPrx plus aluminium hydroxide and with non-significant reduction of the fluke burden, and in unvaccinated-infected sheep. Results Our study showed that the pattern and dynamic of peptide recognition varied noticeably between both vaccinated groups, and that the regions 55–63 and 77–84, which are within the propeptide, and regions 102–114 and 265–273 of FhCL1 were specifically recognised only by vaccinated sheep with significant reduction of the fluke burden. In addition, these animals also showed significant production of specific IgG2, whereas none was observed in vaccinated-Aluminium hydroxide and in infected control animals. Conclusions We have identified 42 residues of FhCL1 that contributed to protective immunity against infection with F. hepatica in sheep. Our results provide indications in relation to key aspects of the immune response. Given the variable outcomes of vaccination trials conducted in ruminants to date, this study adds new insights to improve strategies of vaccine development.

A reductionist approach to the study of infection does not lend itself to an appraisal of the interactions that occur between 2 or more organisms that infect a host simultaneously. In reality, hosts are subject to multiple simultaneous influences from multiple pathogens along the spectrum from symbiotic microflora to virulent pathogen. In this review, we draw from our own work on Fasciola hepatica and that of others studying helminth co-infection to give examples of how such interactions can influence not only the outcome of infection but also its diagnosis and control. The new tools of systems biology, including both the ''omics'' approaches and mathematical biology, have significant promise in unraveling the as yet largely unexplored complexities of co-infection.

Johne’s disease (JD) is a chronic granulomatous enteritis caused by Mycobacterium avium subsp. paratuberculosis (MAP). While it is generally accepted that MAP employs immune subversion mechanisms, aspects of the host-pathogen relationship are not fully understood. We sampled 3 ileal tissue sections from 17 naturally infected cattle ( n = 51 sections) to analyze differences in cell types, apoptosis, and phagocytic cells. Diffuse multibacillary (DM) was the most common lesion type ( n = 17) followed by diffuse intermediate (DI; n = 15). DM lesions had significantly greater proportion of Treg cells (CD3+ FoxP3+) relative to all CD3+ T cells as compared to DI forms ( P < .05). CD68+ individual cell size was significantly smaller in DM than in diffuse lymphocytic (DL) forms ( P < .05). Area of caspase-3 positivity (apoptosis) was greater in DM lesions than DL ( P < .05) and DI ( P < .0001), and was linked to higher numbers of MAP within the macrophage.

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Like many parasites, Fasciola hepatica produces immunoregulatory changes in its host. Cattle co-infected with F. hepatica and Mycobacterium bovis display reduced responsiveness to skin and interferon gamma (IFN-γ) tests, reduced bovine tuberculosis (BTB) lesion scores and decreased bacterial recovery compared to cattle infected with M. bovis only. 1-3 Studies of co-infection with other