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Highlights • Novel variant IBDVs were first identified in China.. • The Chinese novel variant IBDVs were obviously different from the American variant IBDV.. • The serious threat of the variant IBDV to chicken was further confirmed by animal experiments. Abstract Infectious bursal disease (IBD) is one of the most important immunosuppressive diseases that seriously threaten poultry farming and food safety worldwide. The variant strain of infectious bursal disease virus (IBDV) has been greatly neglected for more than 30 years. Recently, the subclinical infection of suspected IBD, causing considerable economic losses, occurred in the main chicken-farming regions of China. Through RT-PCR, sequencing, and phylogenic analyses, novel variant IBDVs were first identified in six provinces of eastern China. Immunological detection further confirmed the antigenic variation of the Chinese variant IBDVs. The Chinese IBDV variants were obviously different from the American IBDV variants, with less than a 97.7% (VP1) or 98.7% (VP2) amino acid sequence identity. Animal experiments further confirmed the serious threat of the variant IBDVs to chickens, demonstrating irreversible damage to the central immune organ, obvious immunosuppression, and growth retardation. This study not only identified the pandemic nature of the novel variant IBDVs for the first time but also discovered the distinct molecular epidemiological characteristics of these viruses, which will contribute more to the control of the disease. [ABSTRACT FROM AUTHOR]

• The vaccine candidate strain (rGtVarVP2) of novel variant IBDV was developed. • The rGtVarVP2 induced a good immune response. • The rGtVarVP2 was safe and effective. Infectious bursal disease (IBD), caused by infectious bursal disease virus (IBDV), is the most important immunosuppressive disease threatening the poultry industry worldwide. Recently, the novel variant IBDV has been emerging in large-scale in Asia including China and is becoming a new threat to the healthy development of the poultry industry, but no ideal vaccine is available. Therefore, it is necessary and urgent to develop a new vaccine against the novel variant IBDV. In this study, based on the skeleton of an attenuated vaccine strain Gt, a reassortment virus strain rGtVarVP2 was constructed for the first time, which could express the main protective antigen VP2 of the novel variant IBDV and replicate well in cell culture. Subsequently, the safety and effectiveness of rGtVarVP2 were further evaluated using animal experiments. The rGtVarVP2 is nonpathogenic to specific-pathogen-free (SPF) chicken. The immunization of rGtVarVP2 could induce the specific neutralizing antibodies against the novel variant IBDV. The challenge protection tests further confirmed the effectiveness of the IBDV reassortment virus rGtVarVP2. No atrophy and obvious lesions were observed in the immunization group while the bursae of non-immunization control group were severely destroyed after challenge, which showed that rGtVarVP2 could provide complete protection against the novel variant IBDV. These data indicate that the vaccine candidate (rGtVarVP2 strain) is safe and effective, which is of great significance for comprehensive control of IBD and healthy breeding. [ABSTRACT FROM AUTHOR]

• A naturally occurring cell-adapted classic strain of IBDV named IBD17JL01 was first identified. • IBD17JL01 with peculiar molecular characteristics can adapt to cell culture in vitro. • IBD17JL01 could induce serious pathological injury in vivo. Infectious bursal disease virus (IBDV), the etiological agent of infectious bursal disease (IBD), is a variable RNA virus of Avibirnavirus. Some artificially attenuated vaccine strains of IBDV can adapt to cell culture of chicken embryo fibroblast (CEF) cell or its immortalized cell line DF1 in vitro while wild-type IBDV cannot. In this study, for the first time, a naturally occurring cell-adapted classic strain (genogroup 1) of IBDV named IBD17JL01 was identified in China. Animal experiments showed that IBD17JL01 could severely damage the central immune organ of infected chickens. Sequence analysis of the full-length genome revealed the peculiar molecular characteristics of IBD17JL01 with a few amino acid substitutions that might be involved in cell-tropism, antigenicity, and virulence of IBDV. Identification of this novel strain is beneficial to our understanding of the complexity of the epidemiology of IBDV. And the expansion of viral cell-tropism might increase the potential risk of the reassortment of different IBDVs including the live vaccines. [ABSTRACT FROM AUTHOR]

• Novel variant IBDV induced severe bursa lesions in chickens immunized with vvIBDV vaccines. • The antigenic mismatch between novel variant IBDV and vvIBDV was confirmed. • Key aa residues might be involved in antigenicity and virulence differences were analyzed. • Unique novel variant IBDV pathogenicity allows for the prevalence of atypical IBD. In recent years, atypical infectious bursal disease (IBD) with severe immunosuppression has brought new threats to the poultry industry and has caused considerable economic losses. Novel variant infectious bursal disease virus (IBDV) has been identified as the etiological pathogen and for unknown reasons is widespread in poultry on many chicken farms in China that have been immunized with vaccines against very virulent IBDV (vvIBDV). Using immunoprotection experiments in specific-pathogen-free chickens, we first verified that novel variant IBDV could severely damage the bursa of Fabricius of the important immune organ of immunized chicken in the presence of antibodies induced by three types of vvIBDV vaccines, which is a primary reason for the current epidemic of atypical IBD. Monoclonal antibody reactivity patterns and cross-neutralization assays further confirmed the obvious antigenic mismatch between novel variant IBDV and vvIBDV. Sequence analysis of the genome of novel variant IBDV (SHG19 strain) was performed and the key amino acid residues that might be involved in antigenicity and virulence differences of novel variant IBDV compared to vvIBDV were further analyzed. This study not only determined the primary reason for the atypical IBD epidemic, but also remind us of the urgency for developing new vaccines against novel variant IBDV. [ABSTRACT FROM AUTHOR]

Infectious bursal disease virus (IBDV) is a non-enveloped, bi-segmented double-stranded RNA virus and the causative agent of a poultry immunosuppressive disease known as infectious bursal disease (IBD). The novel variant IBDV (nVarIBDV) recently posed a great threat to the development of the poultry industry. In this study, we identified a novel segment-reassortant IBDV strain, IBDV-JS19-14701 (Genotype A2dB3). Phylogenic analysis showed that Segments A and B of IBDV-JS19-14701 were derived from emerging nVarIBDV (Genotype A2dB1) and long-prevalent HLJ0504-like strains (Genotype A3B3) in China, respectively. The pathogenicity of IBDV-JS19-14701 was further evaluated via animal experiments. IBDV-JS19-14701 exhibited a similar virulence to chickens with the nVarIBDV. The identification of this reassortment event is beneficial for understanding the epidemiology of nVarIBDV and will contribute to the efficient prevention and control of IBD. [ABSTRACT FROM AUTHOR]

Infectious bursal disease virus (IBDV), a double-stranded RNA virus, causes immunosuppression and high mortality in 3–6-week-old chickens. Innate immune defense is a physical barrier to restrict viral replication. After viral infection, the host shows crucial defense responses, such as stimulation of antiviral effectors to restrict viral replication. Here, we conducted RNA-seq in avian cells infected by IBDV and identified TRIM25 as a host restriction factor. Specifically, TRIM25 deficiency dramatically increased viral yields, whereas overexpression of TRIM25 significantly inhibited IBDV replication. Immunoprecipitation assays indicated that TRIM25 only interacted with VP3 among all viral proteins, mediating its K27-linked polyubiquitination and subsequent proteasomal degradation. Moreover, the Lys854 residue of VP3 was identified as the key target site for the ubiquitination catalyzed by TRIM25. The ubiquitination site destroyed enhanced the replication ability of IBDV in vitro and in vivo. These findings demonstrated that TRIM25 inhibited IBDV replication by specifically ubiquitinating and degrading the structural protein VP3. Author summary: Owing to the immunosuppression and high mortality caused by infectious bursal disease virus (IBDV) in chickens, hosts urgently boost their antiviral immune responses to resist IBDV infection. Here, we identified the host antiviral factor TRIM25, which defended against IBDV infection by direct targeting the viral protein VP3 for subsequent ubiquitination and degradation. To our knowledge, this is the first report of host TRIM25 restricting IBDV replication. Additionally, we found that Lys854 of VP3 was the target site ubiquitinated by TRIM25. Mutation in the ubiquitination site of VP3 abrogated the degradation of VP3 and further enhanced IBDV replication, but did not influence its virulence. Our work not only uncovers an all-important molecular mechanism of chicken TRIM25 against IBDV but also provides new insights for developing high-titer live IBDV vaccines. [ABSTRACT FROM AUTHOR]

• A recombinant IBDV between the novel variant and the intermediate vaccine strains was identified and named IBD16HeN01. • The homologous recombination resulted in increased pathogenicity of the novel variant IBDV strain to chick embryos. • IBD16HeN01 could induce severe bursal lesions in vivo. Infectious bursal disease virus (IBDV) is the causative agent of infectious bursal disease (IBD), an important immunosuppressive disease seriously threatening poultry farming worldwide. Since the identification of the classic strain in 1957, variant IBDV, very virulent IBDV, and novel variant IBDV have successively emerged brought severe challenges. Over the years, attenuated, intermediate, and intermediate-plus live vaccines have been developed to control the disease. The coexistence of various strains in flocks increases the probability of homologous recombination, and in this study, a naturally occurring homologous recombination between a novel variant strain and an intermediate vaccine strain of IBDV was first identified. Sequence analyses demonstrated that the IBD16HeN01 strain was a recombinant IBDV incorporating the skeleton of the novel variant IBDV (SHG19-like strain), where the 3′ region of segment A (nt 1539–3260) was replaced by an intermediate vaccine strain (W2512-like strain). Pathogenicity experiments indicated that IBD16HeN01 could cause severe bursal lesions and the recombination increased viral pathogenicity to chick embryos compared with the novel variant IBDV. Homologous recombination in IBDV has increased the complexity of disease prevention and control and reminds us that we should use live vaccines more scientifically and cautiously. [ABSTRACT FROM AUTHOR]