Transcriptional analysis identifies key genes involved in metabolism, fibrosis/tissue repair and the immune response against Fasciola hepatica in sheep liver

Abstract

BackgroundAlthough fascioliasis has been relatively well studied, little is known about the molecular basis of this disease. This is particularly relevant, considering the very different response that sheep have to Fasciola hepatica relative to cattle. The acute phase of this disease is severe in sheep, whereas chronic fascioliasis is more common in cattle.MethodsTo begin to explore the host-response to Fasciola in sheep and improve the understanding of the host-pathogen interactions during the parasite’s migration through liver parenchyma to the bile duct, we used RNA sequencing (RNA-seq) to investigate livers from sheep infected for eight weeks compared with those from uninfected controls.ResultsThis study identified 572 and 42 genes that were up- and down-regulated, respectively, in infected livers relative to uninfected controls. Our molecular findings provide significant new insights into the mechanisms linked to metabolism, fibrosis and tissue-repair in sheep, and highlight the relative importance of specific components of immune response pathways, which appear to be driven toward a suppression of inflammation.ConclusionsThis study is, to our knowledge, the first detailed investigation of the transcriptomic responses in the liver tissue of any host to F. hepatica infection. It defines the involvement of specific genes associated with the host’s metabolism, immune response and tissue repair/regeneration, and highlights an apparent overlapping function of many genes involved in these processes.Electronic supplementary materialThe online version of this article (doi:10.1186/s13071-015-0715-7) contains supplementary material, which is available to authorized users.

Gene expression response to a nematode parasite in novel and native eel hosts

“…Differential regulation of processes associated with both the innate and the adaptive immune system in immune organs and at the site of infection is a common feature in natural and experimental infections in vertebrates (e.g., Alvarez Rojas et al, ; Babayan et al, ; Huang et al, ) and the gradual shift from the regulation of innate to adaptive immune processes can be observed in gene expression studies (Ehret, Spork, Dieterich, Lucius, & Heitlinger, ). Additionally, parasite infections cause differential expression of genes not directly related to an immune response, such as those involved in metabolic processes, tissue repair, or organ function and development (Alvarez Rojas et al, ; Babayan et al, ; Ronza et al, ; Zhang et al, ) and this has also been observed in the European eel (Bracamonte et al, ; Schneebauer et al, ). How A. crassus affects gene expression in the Japanese eel and what processes are modified upon infection have not yet been determined for any parasitic stage.…”

“…RNA‐seq studies of infection experiments on a range of species indicate that the number of affected processes, the magnitude of change, and the specific genes involved differ considerably among host species‐parasite species systems (e.g., Alvarez Rojas et al, ; Haase et al, ; Kumar, Abd‐Elfattah, & El‐Matbouli, ; Zhang et al, ). Infections with invasive parasites have consistently induced a more pronounced response in susceptible hosts compared with resistant hosts.…”

“…Studies of the European eel using RNA-seq to examine gene expression have found that genes involved in an immune response were differentially expressed in the swim bladder (the site of infection) of naturally infected eels (i.e., containing parasites of all stages) (Schneebauer, Dirks, & Pelster, 2017), as well as in the spleen and the head kidney (immune organs) very soon after experimental infection F I G U R E 1 The Japanese eel (Anguilla japonica) is the native host of Anguillicola crassus, a parasitic swim bladder nematode invasive in the European eel (Anguilla anguilla) (3 dpi, i.e., containing only larvae) . Differential regulation of processes associated with both the innate and the adaptive immune system in immune organs and at the site of infection is a common feature in natural and experimental infections in vertebrates (e.g., Alvarez Rojas et al, 2015;Babayan et al, 2018;Huang et al, 2016) and the gradual shift from the regulation of innate to adaptive immune processes can be observed in gene expression studies (Ehret, Spork, Dieterich, Lucius, & Heitlinger, 2017). Additionally, parasite infections cause differential expression of genes not directly related to an immune response, such as those involved in metabolic processes, tissue repair, or organ function and development (Alvarez Rojas et al, 2015;Babayan et al, 2018;Ronza et al, 2016;Zhang et al, 2017) and this has also been observed in the European eel Schneebauer et al, 2017).…”

A prospective view of animal and human Fasciolosis

“…While signalling via FXR also represses NFκB‐dependent transcription resulting in an anti‐inflammatory response , activation of this receptor also increases the expression of several genes associated with antibacterial actions such as IL‐18 . Notably, infection with F. hepatica results in significant increases in the production of bile acids and IL‐18 was recently identified as the most significantly up‐regulated interleukin in the liver of infected sheep . Such preliminary observations encourage further characterization of the composition of bile acid during acute and chronic infection with F. hepatica in animals and humans and an assessment of the ability of these to regulate the functions of innate and adaptive immune cells as well as influence the microbiome of the gut into which they are passed.…”

“…During the later chronic stages, Treg cells release cytokines that inhibit inflammatory Th1/Th2 cytokines; PBMCs isolated from F. hepatica ‐infected cattle produced enhanced levels of IL‐4 and IFN‐γ cytokines when cultured in vitro in the presence of TGF‐β and IL‐10 neutralizing antibodies . This immune profile is similar in sheep infected with F. hepatica as they also present a mixed Th1/Th2 cytokine profile in the spleen at week 3 after infection and as infection progresses enhanced gene expression of Th2 but not Th1 cytokines is observed . Interestingly, although an overall systemic Th2 immune response dominates, different cytokines are expressed at different anatomical locations; in sheep, IL‐5 can be detected in the hepatic lymph nodes, while IL‐10 is primarily observed in the spleen , whereas in goats, IFN‐γ and high levels of IL‐4 can be detected in both the hepatic lymph node and liver .…”