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Abstract
The spontaneously immortalised DF-1 cell line is rapidly replacing its progenitor primary chicken embryo fibroblasts (CEFs) for studies on avian viruses such as avian influenza but no comprehensive study has as yet been reported comparing their innate immunity phenotypes. We conducted microarray analyses of DF-1 and CEFs, under both normal and stimulated conditions using chicken interferon-α (chIFN-α) and the attenuated infectious bursal disease virus vaccine strain PBG98. We found that DF-1 have an attenuated innate response compared to CEFs. Basal expression levels of Suppressor of Cytokine Signalling 1 (chSOCS1), a negative regulator of cytokine signalling in mammals, are 16-fold higher in DF-1 than in CEFs. The chSOCS1 “SOCS box” domain (which in mammals, interacts with an E3 ubiquitin ligase complex) is not essential for the inhibition of cytokine-induced JAK/STAT signalling activation in DF-1. Overexpression of SOCS1 in chIFN-α-stimulated DF-1 led to a relative decrease in expression of interferon-stimulated genes (ISGs; MX1 and IFIT5) and increased viral yield in response to PBG98 infection. Conversely, knockdown of SOCS1 enhanced induction of ISGs and reduced viral yield in chIFN-α-stimulated DF-1. Consequently, SOCS1 reduces induction of the IFN signalling pathway in chicken cells and can potentiate virus replication.
Highlights
The increasing occurrence of zoonotic infections attributable to avian viruses such as avian influenza viruses H5N1 and H7N9, West Nile virus, Japanese encephalitis virus, eastern equine encephalitis viruses, as well as avian Salmonella and Campylobacter bacterial species, has highlighted the need for well-established avian experimental models of infection and immunity
Transcripts that were overexpressed in chicken embryo fibroblasts (CEFs) relative to DF-1 cells (Table 2) were associated with extracellular matrix (ECM) and cytoskeleton remodelling involved in embryonic development (MMP-9, MMP-13, TIMP3, PLAU, Keratin-5, −7, −14, −19), cell adhesion (E-cadherin, VE-cadherin) and signalling cascades (FGF, plasmin, TGF-β)
Infection studies in chicken cell lines are compromised by a lack of definitive understanding of the chicken innate response and in particular the type I IFN response, which is the first line of defence, upon virus infection
Summary
The increasing occurrence of zoonotic infections attributable to avian viruses such as avian influenza viruses H5N1 and H7N9, West Nile virus, Japanese encephalitis virus, eastern (and western) equine encephalitis viruses, as well as avian Salmonella and Campylobacter bacterial species, has highlighted the need for well-established avian experimental models of infection and immunity. DF-1 cells are characterized by a suppression of cell death pathways (consistent with their immortal hyperproliferative phenotype18), dysfunctional cell proliferation-related genes p53 and E2F-1, as well as defective antioxidant gene expression[11,19,20] Compared with their progenitor CEFs, DF-1 have enhanced growth potential[18], smaller morphology[21] and can support comparable or even higher replication of IBDV, ASLV, avian influenza and some other viruses[12,13,16]. High viral replication in DF-1 implies that viruses (even attenuated vaccine strains) are not efficiently restricted by the cells’ antiviral innate immunity This is despite reports that DF-1 readily express known interferon-stimulated genes (ISGs), potentially with antiviral activity, following stimulation with recombinant chIFN-α or, to lesser extent, with recombinant chIFN-β22. The constitutive gene expression profile of DF-1 relative to CEF has been compared[18], their induced innate responses have not been compared directly
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