Abstract
Flaviviruses are constantly evolving diverse immune evasion strategies, and the exploitation of the functions of suppressors of cytokine signalling (SOCS) and protein inhibitors of activated STATs (PIAS) to favour virus replication has been described for Dengue and Japanese encephalitis viruses but not for yellow fever virus (YFV), which is still of global importance despite the existence of an effective vaccine. Some mechanisms that YFV employs to evade host immune defence has been reported, but the expression patterns of SOCS and PIAS in infected cells is yet to be determined. Here, we show that SOCS1 is down-regulated early in YFV-infected HeLa and HEK 293T cells, while SOCS3 and SOCS5 are not significantly altered, and PIAS mRNA expression appears to follow a rise-dip pattern akin to circadian-controlled genes. We also demonstrate that YFV evades interferon-β application to produce comparable viral titres. This report provides initial insight into the in vitro expression dynamics of SOCS and PIAS upon YFV infection and a basis for further investigation into SOCS/PIAS expression and how these modulate the immune response in animal models.
Highlights
Upon flavivirus infection, viral RNA sensing in cells via pathogen recognition receptors (PRR)triggers the release of type I interferons (IFNs), which bind to their cognate receptors to activate the janus kinase/signal transducer and activator of the transcription (JAK/STAT) signalling pathway [1].JAK/STAT activation leads to a signalling cascade that eventually results in the transcription of several interferon stimulated genes (ISGs) to establish antiviral status that limits the rate of replication and spread of viruses to neighbouring cells [2]
While the pre-treatment of hepatoma cells with IFN-β inhibited Dengue virus (DENV) replication [21] and the inhibition of Understanding how flaviviruses interact with the host innate immune system has improved our current knowledge of disease pathogenesis and spurred the development of efficient vaccines and antiviral countermeasures
We obtained comparable viral titres in IFN-β treated and untreated cells in the early time points but the titres were decreased by two-fold in the IFN-β stimulated cells compared to the un-stimulated cells in the later time point of infection (48 hpi), as shown in Figure 1, and are suggestive that yellow fever virus (YFV) evaded interferon activity during the early phase of infection
Summary
Triggers the release of type I interferons (IFNs), which bind to their cognate receptors to activate the janus kinase/signal transducer and activator of the transcription (JAK/STAT) signalling pathway [1]. JAK/STAT activation leads to a signalling cascade that eventually results in the transcription of several interferon stimulated genes (ISGs) to establish antiviral status that limits the rate of replication and spread of viruses to neighbouring cells [2]. The JAK/STAT pathway is, tightly regulated by suppressors of cytokine signalling (SOCS) [3] and protein inhibitors of the activated STATs (PIAS) [4]. Viruses have adopted many strategies, including the exploitation of the regulatory functions of SOCS and PIAS proteins as a means of evading host innate immune response, which has been SOCS and PIAS proteins down-regulate JAK/STAT signalling via negative feedback inhibition among other mechanisms, either by binding to JAKs and channelling them to proteasomal degradation, or by binding to STATs to cause a conformational change that prevents STAT binding to DNA recognition elements [5,6].
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