Critical roles of glucocorticoid-induced leucine zipper in infectious bursal disease virus (IBDV)-induced suppression of type I Interferon expression and enhancement of IBDV growth in host cells via interaction with VP4.
Li Zhonghua,Wang Yongqiang,Li Xiang,Li Xiaoqi,Cao Hong,Zheng Shijun J
Journal of virology
Infectious bursal disease (IBD) is an acute, highly contagious, and immunosuppressive avian disease caused by IBD virus (IBDV). Although IBDV-induced immunosuppression has been well established, the underlying exact molecular mechanism for such induction is not very clear. We report here the identification of IBDV VP4 as an interferon suppressor by interaction with the glucocorticoid-induced leucine zipper (GILZ) in host cells. We found that VP4 suppressed the expression of type I interferon in HEK293T cells after tumor necrosis factor alpha (TNF-α) treatment or Sendai virus (SeV) infection and in DF-1 cells after poly(I·C) stimulation. In addition, the VP4-induced suppression of type I interferon could be completely abolished by knockdown of GILZ by small interfering RNA (siRNA). Furthermore, knockdown of GILZ significantly inhibited IBDV growth in host cells, and this inhibition could be markedly mitigated by anti-alpha/beta interferon antibodies in the cell cultures (P < 0.001). Thus, VP4-induced suppression of type I interferon is mediated by interaction with GILZ, a protein that appears to inhibit cell responses to viral infection.
10.1128/JVI.02421-12
Infectious bursal disease virus VP5 triggers host shutoff in a transcription-dependent manner.
mBio
Viruses have evolved intricate mechanisms to evade host antiviral responses and exploit cellular resources by manipulating the expression profile of host genes. During infection, viruses encode proteins with shutoff activity to globally inhibit host protein synthesis, which is an effective strategy for immune evasion. In this study, compelling evidence shows that infectious bursal disease virus (IBDV) infection triggers the suppression of host protein synthesis. Furthermore, using both and viral infection models, we have identified that IBDV specifically impedes the transcription of host genes via the shutoff activity of viral VP5, simultaneously conferring advantages to IBDV infection in these circumstances. The proposed mechanism suggests that VP5 competitively binds to RanBP1, disrupting the RanGDP/GTP gradient. This disruption interferes with cellular nucleocytoplasmic transport, impairing the nuclear import of proteins bearing nuclear localization signals. The nuclear transport of pivotal transcriptional regulatory factors, such as p65 and IFN regulatory factor 7, is also compromised, leading to the inhibition of pro-inflammatory cytokines and interferon expression. This newly discovered strategy employed by IBDV enables them to manipulate host gene expression, providing novel insights into how viruses evade host immune responses and establish infections.IMPORTANCEViruses manipulate host processes at various levels to regulate or evade both innate and adaptive immune responses, promoting self-survival and efficient transmission. The "host shutoff," a global suppression of host gene expression mediated by various viruses, is considered a critical mechanism for evading immunity. In this study, we have validated the presence of host shutoff during infectious bursal disease virus (IBDV) infection and additionally uncovered that the viral protein VP5 plays a pivotal role in inhibiting the overall synthesis of host proteins, including cytokines, through a transcription-dependent pathway. VP5 competitively binds with RanBP1, leading to disruption of the Ran protein cycle and consequently interfering with nucleocytoplasmic transport, which ultimately results in the suppression of host gene transcription. These findings unveil a novel strategy employed by IBDV to evade host innate immunity and rapidly establish infection. This study also suggests a novel supplement to understanding the pathway through which viruses inhibit host protein synthesis.
10.1128/mbio.03433-23
Reverse genetics approaches for live-attenuated vaccine development of infectious bursal disease virus.
Yang Hui,Ye Chengjin
Current opinion in virology
Infectious bursal disease (IBD), which is caused by infectious bursal disease virus (IBDV) infection, leads to severe immunosuppression in young chickens and results in significant economic losses in the poultry industry. To date, vaccination with live-attenuated vaccine (LAV) is a convenient method to provide effective protection against IBDV infection. Classical attenuated viruses are usually obtained by either passaging virus in cultured cells or natural isolation. However, these empiric attenuation methods, which are time-consuming and not guaranteed, are not reliable for emergent antigenic variant and very virulent IBDV strains. The reverse genetics (RG) system opens a new avenue for the development of IBDV LAV. In this review, we summarize the current knowledge on the biological characteristics of IBDV structure and genome organization, as well as the established RG systems. We also describe the details for the strategies used to develop IBDV LAV based on the RG systems.
10.1016/j.coviro.2020.08.001
The emerging naturally reassortant strain of IBDV (genotype A2dB3) having segment A from Chinese novel variant strain and segment B from HLJ 0504-like very virulent strain showed enhanced pathogenicity to three-yellow chickens.
Transboundary and emerging diseases
Novel variant infectious bursal disease virus (nvIBDV) is an emerging pathotype that can cause sub-clinical disease with severe, prolonged immunosuppression in young chickens. At present, two major pathotypes, including vvIBDV and nvIBDV, are prevailing in China. In this study, we propose that the nvIBDV is a new genotype (A2dB1b) and also first isolated and characterized a nvIBDV reassortant strain YL160304 (A2dB3) with segments A and B derived, respectively, from the nvIBDV and the HLJ-0504-like vvIBDV from yellow chickens in southern China. The YL160304 causes more extensive cytotropism and can infect specific-pathogen-free chicken embryos with severe subcutaneous hemorrhage. The pathogenicity of YL160304 to 4-week-old three-yellow chickens was determined and compared with those of the nvIBDV QZ191002 and the HLJ-0504-like vvIBDV NN1172. Weight gain was significantly reduced in all the challenged birds. No clinical signs and associated mortality were observed in the birds challenged with QZ191002, while the mortalities in the birds challenged with NN1172 and YL160304 were 30% (3/10) and 10% (1/10), respectively. At 7 days postchallenge, the bursa was severely damaged and the percentage of peripheral blood B lymphocyte (PBBL) decreased significantly in all the challenged birds and the quantity of the viral RNA detected in the bursa was in accordance with the results of the histomorphometry and the depletion of PBBL. This study not only confirmed the emerging epidemic of the novel variant and its reassortant strains, but also discovered that the naturally reassortant nvIBDV strain with the segment B of HLJ 0504-like vvIBDV can significantly enhance the pathogenicity to chickens.
10.1111/tbed.14336
Ex vivo rescue of recombinant very virulent IBDV using a RNA polymerase II driven system and primary chicken bursal cells.
Cubas-Gaona Liliana L,Trombetta Romane,Courtillon Céline,Li Kai,Qi Xiaole,Wang Xiaomei,Lotmani Sofiane,Keita Alassane,Amelot Michel,Eterradossi Nicolas,Soubies Sébastien Mathieu
Scientific reports
Infectious Bursal Disease Virus (IBDV), a member of the Birnaviridae family, causes an immunosuppressive disease in young chickens. Although several reverse genetics systems are available for IBDV, the isolation of most field-derived strains, such as very virulent IBDV (vvIBDV) and their subsequent rescue, has remained challenging due to the lack of replication of those viruses in vitro. Such rescue required either the inoculation of animals, embryonated eggs, or the introduction of mutations in the capsid protein (VP2) hypervariable region (HVR) to adapt the virus to cell culture, the latter option concomitantly altering its virulence in vivo. We describe an improved ex vivo IBDV rescue system based on the transfection of an avian cell line with RNA polymerase II-based expression vectors, combined with replication on primary chicken bursal cells, the main cell type targeted in vivo of IBDV. We validated this system by rescuing to high titers two recombinant IBDV strains: a cell-culture adapted attenuated strain and a vvIBDV. Sequencing of VP2 HVR confirmed the absence of unwanted mutations that may alter the biological properties of the recombinant viruses. Therefore, this approach is efficient, economical, time-saving, reduces animal suffering and can be used to rescue other non-cell culture adapted IBDV strains.
10.1038/s41598-020-70095-x
Critical role for G3BP1 in infectious bursal disease virus (IBDV)-induced stress granule formation and viral replication.
Zhao Dianzheng,Li Jiaxin,Wang Yongqiang,Li Xiaoqi,Gao Li,Cao Hong,Zheng Shijun J
Veterinary microbiology
Stress granules (SGs), complexes for mRNA storage, are formed in host cellular response to stress stimuli and play an important role in innate immune response. GTPase-activating protein (SH3 domain)-binding protein 1 (G3BP1) is a key component of SGs. However, whether IBDV infection induces SG formation in host cells and what role of G3BP1 plays in this process are unclear. We report here that IBDV infection initiated typical stress granule formation and enhanced G3BP1 expression in DF-1 cells. Our data show that knockdown of G3BP1 by RNAi markedly inhibited IBDV-induced SG formation and viral replication in DF-1 cells. Conversely, ectopic expression of G3BP1 enhanced IBDV-induced SG formation and significantly promoted IBDV replication in host cells. Thus, G3BP1 plays a critical role in IBDV-induced SG formation and viral replication, providing an important clue to elucidating how IBDV employs cellular SGs for its own benefits.
10.1016/j.vetmic.2020.108806
Picroside II disrupts IBDV replication via targeting VP1 polymerase.
Veterinary microbiology
Infectious bursal disease virus (IBDV) is a highly contagious virus with a dsRNA genome, predominantly infecting chickens and causing significant economic losses due to high mortality rates. The emergence of recombinant, novel variant, and highly virulent strains that evade current vaccines has led to frequent epidemics and outbreaks in the poultry industry. The lack of targeted antivirals for IBDV underscores the pressing requirement to develop potent therapeutic options. Within this framework, our research investigated the effectiveness of picroside II, a naturally derived iridoid glycoside, against viruses in DF-1 cells. Our findings demonstrate that picroside II significantly inhibits viral replication, with its efficacy increasing proportionally to the dosage administered. Through time-addition and antiviral duration analysis, we determined that picroside II therapeutically blocks IBDV replication, with its effects persisting for over 72 hours. Further investigation revealed that picroside II specifically inhibits the cellular replication stage of IBDV's lifecycle. Additionally, our findings indicate that picroside II impairs VP1 polymerase activity by binding to the active pocket, which significantly disrupts the interaction between VP1 and VP3. Mutations at three critical binding sites on VP1 not only impair virus replication but also hinder polymerase function and disrupt VP1-VP3 interactions. Collectively, these results demonstrate that picroside II, by inhibiting viral polymerase activity, represents a promising antiviral agent against IBDV.
10.1016/j.vetmic.2024.110191