Abstract
In response to viral infection, host cells activate various antiviral responses to inhibit virus replication. While feline herpesvirus 1 (FHV-1) manipulates the host early innate immune response in many different ways, the host could activate the antiviral response to counteract it through some unknown mechanisms. MicroRNAs (miRNAs) which serve as a class of regulatory factors in the host, participate in the regulation of the host innate immune response against virus infection. In this study, we found that the expression levels of miR-26a were significantly upregulated upon FHV-1 infection. Furthermore, FHV-1 infection induced the expression of miR-26a via a cGAS-dependent pathway, and knockdown of cellular cGAS significantly blocked the expression of miR-26a induced by poly (dA:dT) or FHV-1 infection. Next, we investigated the biological function of miR-26a during viral infection. miR-26a was able to increase the phosphorylation of STAT1 and promote type I IFN signaling, thus inhibiting viral replication. The mechanism study showed that miR-26a directly targeted host SOCS5. Knockdown of SOCS5 increased the phosphorylation of STAT1 and enhanced the type I IFN-mediated antiviral response, and overexpression of suppressor of the cytokine signalling 5 (SOCS5) decreased the phosphorylation of STAT1 and inhibited the type I IFN-mediated antiviral response. Meanwhile, with the knockdown of SOCS5, the upregulated expression of phosphorylated STAT1 and the anti-virus effect induced by miR-26a were significantly inhibited. Taken together, our data demonstrated a new strategy of host miRNAs against FHV-1 infection by enhancing IFN antiviral signaling.
Highlights
feline herpesvirus 1 (FHV-1) is a member of the Varicellovirus genus of the subfamily Alphaherpesvirinae [1,2], which mainly infects domestic cats as well as other members of Felidae [3,4,5,6,7,8], and leads to feline viral rhinotracheitis
We demonstrated that miR-26a could suppress FHV-1 replication by enhancing type I IFN-induced antiviral signalling by directly targeting a negative regulator of this pathway, suppressor of the cytokine signalling 5 (SOCS5)
To further verify that miR-26a regulated IFN antiviral signalling pathway by the SOCS5-STAT1 axis, we examined the level of phosphorylation of STAT1 (p-STAT1) induced by miR-26a upon FHV-1 infection together with knockdown of SOCS5. miR-26a mimics were co-transfected into F81 cells together with siSOCS5#1 for
Summary
FHV-1 is a member of the Varicellovirus genus of the subfamily Alphaherpesvirinae [1,2], which mainly infects domestic cats as well as other members of Felidae [3,4,5,6,7,8], and leads to feline viral rhinotracheitis. Previous studies indicated that α-herpesviruses usually encoded 65–80 open reading frames (ORFs) [11], and FHV-1 encoded 74 viral proteins [12]. These viral proteins contribute to manipulating the host innate immune response. Our previous studies found that a total of 11 viral proteins (UL30, ICP0, UL11, UL55, UL1, UL45, UL27, UL3.5, UL48, UL4 and US3) could inhibit the IFN-β promoter activity [13]. Activated type I IFN signalling is suppressed within 12 h after FHV-1 infection [13], but it is unclear how and what ways the host would use to counteract viral immune evasion
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