Figure 1.

Antiviral pathways in silkworm. (A) The siRNAi pathway is activated by viral dsRNA, which is cleaved into siRNAs by Dicer2. Ago2 is associated with one strand of siRNA to form RISC that can target and cleave the viral RNA to inhibit viral replication. (B) The NF-kB-mediated, Imd, and STING pathways. BmCPV induces the extracellular BmPGRP-S2 to active Imd and the downstream NF-kB ortholog Relish; BmNPV infection triggers the production of cGAMP to activate BmSTING for processing Relish. Activated Relish is translocated to the nucleus to initiate the transcription of AMP. Whether AMPs have antiviral function in silkworms needs further study. (C) The JAK/STAT pathway. The extracellular ligands bind to JAK associated receptors upon stimulation, leading to the activation of JAKs, and then cytosolic STATs are phosphorylated, forming the STAT dimers, which are translocated to the nucleus to regulate the expression of antiviral genes. (D) The PPO pathway is initiated by recognizing invading microbes, and then the extracellular cSP cascade is activated to convert the zymogen PPO to active PO. PO catalyzes the formation of melanin, resulting in melanization that kill the microbes. This pathway is negatively regulated by serpins, and baculovirus can induce serpins to suppress the melanization response of host insects for survival. (E) The PI3K/Akt pathway. Activated PI3K converts PIP2 into PIP3 to cause Akt phosphorylation (p-Akt). PTEN is a negative regulator of the PI3K/AKT pathway. BmNPV induces BmPGRP2-2 to suppress PTEN, resulting in increased p-Akt that inhibits cell apoptosis. Upregulated p-Akt also causes the inhibitory phosphorylation of the transcription factor FOXO, decreasing the expression of BmPEPCK-2 and resulting in reduced autophagy genes (ATGs) expression, thereby blocking host autophagy. The inhibited apoptosis and autophagy are beneficial for viral replication. The PI3K inhibitor AZD8835 can decrease the mortality of silkworms infected with BmNPV. (F) The ERK pathway. Upon viral infection, the extracellular ligands activate EGFR (a receptor tyrosine kinase) to promote ERK phosphorylation (p-ERK) through the activation of Ras to the Raf/MEK/ERK phosphorylation cascade. p-ERK can regulate the transcription of viral genes and inhibit apoptosis. The Spry protein is a negative regulator of EGFR/ERK pathway that inhibits Ras or Raf, and both DNA and RNA viruses can downregulate Spry to increase p-ERK to ensure viral reproduction. AG1478 is a specific inhibitor of EGFR and U0126 binds to MEK to prevent p-ERK. The EGER also participates in the activation of PI3K by BmNPV. These pathways are integrated and are responsive to one another, which are complex and merit further investigation.