DHAV-1 Blocks the Signaling Pathway Upstream of Type I Interferon by Inhibiting the Interferon Regulatory Factor 7 Protein

Abstract

Duck hepatitis A virus (DHAV), which mainly infects 1- to 4-week-old ducklings, has a fatality rate of 95% and poses a huge economic threat to the duck industry. However, the mechanism by which DHAV-1 regulates the immune response of host cells is rarely reported. This study examined whether DHAV-1 contains a viral protein that can regulate the innate immunity of host cells and its specific regulatory mechanism, further exploring the mechanism by which DHAV-1 resists the host immune response. In the study, the dual-luciferase reporter gene system was used to screen the viral protein that regulates the host innate immunity and the target of this viral protein. The results indicate that the DHAV-1 3C protein inhibits the pathway upstream of interferon (IFN)-β by targeting the interferon regulatory factor 7 (IRF7) protein. In addition, we found that the 3C protein inhibits the nuclear translocation of the IRF7 protein. Further experiments showed that the 3C protein interacts with the IRF7 protein through its N-terminus and that the 3C protein degrades the IRF7 protein in a caspase 3-dependent manner, thereby inhibiting the IFN-β-mediated antiviral response to promote the replication of DHAV-1. The results of this study are expected to serve as a reference for elucidating the mechanisms of DHAV-1 infection and pathogenicity.

DHAV 3CD targets IRF7 and RIG-I proteins to block the type I interferon upstream signaling pathway

“…Previous studies have shown that the DHAV-1 3C protein can inhibit the IFNβ upstream signaling pathway by targeting the IRF7 protein [ 26 ]. The presence of 3CD protein as a precursor to 3C protease and 3D polymerase is unclear as to whether it also has the immune evasion function of 3C protein.…”

“…In eukaryotic cells, protein degradation pathways are mainly divided into the autophagy-lysosomal pathway, proteasome pathway, and caspase-dependent pathway [ 27 ]. To determine whether these protein degradation pathways play a role in the DHAV-1 3CD-induced reduction of RIG-I, the proteasome inhibitor MG132, the autophagy inhibitor 3-MA, the lysosomal inhibitor NH 4 Cl, and the broad-spectrum caspase inhibitor Z-VAD-FMK were used to assess the inhibitory effect and it has been shown that these inhibitors did not affect cellular activity [ 26 ]. Cells were transfected with 3CD-HA and RIG-I(N-terminal)-Flag and maintained in the presence or absence of the inhibitors.…”

“…DHAV-1 is a member of the Picornaviridae family and also can evade the type I IFN signaling pathway. The DHAV-1 3 C protein inhibits nuclear translocation of the IRF7 protein and interacts with the IRF7 protein through its N-terminus, and degrades the IRF7 protein through the caspase 3-dependent protein degradation pathway, thereby inhibiting IFNβ-mediated antiviral innate immunity to promote the replication of DHAV-1 [ 26 ] (Figure 9 ). In this study, we demonstrate for the first time the antagonistic role of the DHAV-1 3CD protein in the host innate immune response.…”

The role of turmeric and black pepper oil nanoemulsion in attenuating cytokine storm triggered by duck hepatitis A virus type I (DHAV-I)-induced infection in ducklings

“…Picornaviruses, including DHAV-1 have evolved immune evasion mechanisms to suppress the host cell's innate immune response ( Zhang et al, 2020 ). They can inhibit the expression of critical receptors involved in the immune response, including TLR3, TLR7, MDA5, RIG-I, and NLRP3 ( Xie et al, 2018 ; Lai et al, 2021 ). It is well established that TLR-7 is a crucial PRR that recognizes single-stranded RNA viruses and is primarily involved in initiating the innate defense against DHAV-1 infection, thereby generating proinflammatory cytokines and IFNs ( Mao et al, 2017 ).…”

“…DHAV-1 employs an immune evasion strategy in host cells by inhibiting PRRs ( Xia et al, 2023 ). This evasion tactic hinders the natural IFN-mediated antiviral immunity and facilitates DHAV-1 replication ( Lai et al, 2021 ). In the current study, we revealed a significant ( P < 0.05) finding of a pronounced downregulation of IFN-α and IFN-β expression levels in the positive control group (G2) at 48 hpi, accompanied by an increase in DHAV-1 copies.…”