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  • A previous study reported that it is unlikely that


    A previous study reported that it is unlikely that silkworm mounts a general type of immune response to all viruses (Liu et al., 2015). It is not clear whether there is a common pattern of host regulation for silkworm viruses. Spry is a general inhibitor of receptor tyrosine kinases (RTKs), which is first identified as an antagonist of fibroblast growth factor (FGF) signaling that patterns apical branching in Drosophila (Hacohen et al., 1998). Many studies have reported that the mode of action of Spry is multifaceted and subject to complex regulation, and the suppressive function of Spry targets several RTKs dependent signaling steps including ERK (Kim and Bar-Sagi, 2004). The ligand binding to RTKs activates the ERK/MAPK cascade, which induces the upregulated transcription of Spry. As a negative feedback regulator, the inhibitory activity of Spry is upstream of ERK (Kim and Bar-Sagi, 2004). Spry is a single copy gene in silkworm and Drosophila (Jin et al., 2014). BmSpry is similar to Spry of Galleria mellonella, Heliothis virescens, Trichoplusia ni, and Ostrinia furnacalis. Overexpression of BmSpry decreased ERK phosphorylation (p-ERK) and inhibited BmNPV in BmE phalloidin (Jin et al., 2014). In this study, we tested the role of BmSpry in silkworm after infection with BmNPV, BmBDV, and BmCPV, and observed that BmSpry is downregulated by the three viruses to elevate p-ERK and viral proliferation. This is the first report on a host cellular pathway being regulated by three viruses in silkworm.
    Materials and methods
    Discussion BmSpry was cloned in our previous study (Jin et al., 2014). In this study, we detected the role of BmSpry in silkworm larvae after infection with BmNPV, BmBDV, and BmCPV. We found that BmSpry was downregulated by the three silkworm viruses to promote their proliferation. Spry is a negative regulator upstream of ERK (Kim and Bar-Sagi, 2004). BmSpry was decreased (Fig. 1) and p-ERK was increased (Fig. 6A) in silkworms after infection with each silkworm virus. The expression level of BmSpry was reduced in the transgenic RNAi silkworms Spry-I compared with that in the non-transgenic silkworms (Fig. 2). Lower levels of BmSpry resulted in higher p-ERK (Fig. 6B), virus content, and mortality (Fig. 3, Fig. 4, Fig. 5) in Spry-I after infection with each silkworm virus. BmNPV activated the ERK signaling pathway and an inhibitor of ERK inhibited p-ERK as well as BmNPV multiplication in BmN cells (Katsuma et al., 2007). Overexpression of BmSpry decreased the p-ERK levels and viral content after infection with BmNPV in BmE cells (Jin et al., 2014). Combined with previous reports (Jin et al., 2014; Katsuma et al., 2007), the current study suggested that three silkworm viruses downregulated BmSpry to activate p-ERK and thus elevate their multiplication. The interaction of host and virus includes immune responses of the host against the virus, virus regulation of host to ensure viral reproduction, and enhancement of host resistance (Jiang and Xia, 2014). Viruses and hosts are co-evolving in confrontation. ERK is widely expressed and involved in the regulation of cellular processes such as proliferation, differentiation, and apoptosis, which is a conserved signal pathway among different species (Katsuma et al., 2007; Zaremba et al., 2011). Considering the vital role played by ERK pathway in controlling diverse host physiological processes, it is not surprising that viruses usurp this pathway to their own benefit (Bonjardim, 2017). Many DNA viruses (including Adenovirus, KSHV, HCMV, RRV, HSV-1, HPV, HBV, and HBx) and RNA viruses (including Influenza virus, Ebola virus, and HCV) activate ERK pathway to enhance viral replication (Bonjardim, 2017). This study revealed that ERK is regulated by three different classes of silkworm viruses (dsDNA virus BmNPV, dsRNA virus BmCPV, and ssDNA virus BmBDV). However, further experiments are needed to determine whether other host cellular pathways are also targeted by the three viruses in silkworms. Adenoviral oncoproteins E1A targets Spry to regulate the ERK pathway in mouse embryo (Zaremba et al., 2011). The mechanisms underlying the downregulation of BmSpry by silkworm viruses need to be explored in future studies. Spry is downregulated in a number of cancers (Fong et al., 2006; Kwabi-Addo et al., 2004; Sutterluty et al., 2007), and aberrant activation of ERK pathway is associated with more than 30% of human cancers, this pathway has been considered a potential target for drug therapy in the clinic (Akinleye et al., 2013; Bonjardim, 2017). It is presumed that overexpression of BmSpry could enhance the antiviral capacity of transgenic silkworms to the three viruses, which will be examined in the next study.