Since 2015, severe outbreaks of hepatitis-hydropericardium syndrome (HHS), caused by hypervirulent fowl adenovirus serotype 4 (FAdV-4), have emerged in several provinces in China, posing a great threat to poultry industry. So far, factors contributing to the pathogenesis of hypervirulent FAdV-4 have not been fully uncovered. Elucidation of the pathogenesis of FAdV-4 will facilitate the development of effective FAdV-4 vaccine candidates for the control of HHS and vaccine vector. The interaction between pathogen and host defense system determines the pathogenicity of the pathogen. Therefore, the present review highlights the knowledge of both viral and host factors contributing to the pathogenesis of hypervirulent FAdV-4 strains to facilitate the related further studies.

Pathogenesis of Hypervirulent Fowl Adenovirus Serotype 4: The Contributions of Viral and Host Factors.

Since 2015, severe hydropericardium-hepatitis syndrome (HHS) associated with a novel fowl adenovirus 4 (FAdV-4) has emerged in China, representing a new challenge for the poultry industry. Although various highly pathogenic FAdV-4 strains have been isolated, the virulence factor and the pathogenesis of novel FAdV-4 are unclear. In our previous studies, we reported that a large genomic deletion (1,966 bp) is not related to increased virulence. Here, two recombinant chimeric viruses, rHN20 strain and rFB2 strain, were generated from a highly pathogenic FAdV-4 strain by replacing the hexon or fiber-2 gene of a nonpathogenic FAdV-4, respectively. Both chimeric strains showed similar titers to the wild-type strain in vitro. Notably, rFB2 and the wild-type strain induced 100% mortality, while no mortality or clinical signs appeared in chickens inoculated with rHN20, indicating that hexon, but not fiber-2, determines the novel FAdV-4 virulence. Furthermore, an R188I mutation in the hexon protein identified residue 188 as the key amino acid for the reduced pathogenicity. The rR188I mutant strain was significantly neutralized by chicken serum in vitro and in vivo, whereas the wild-type strain was able to replicate efficiently. Finally, the immunogenicity of the rescued rR188I was investigated. Nonpathogenic rR188I provided full protection against lethal FAdV-4 challenge. Collectively, these findings provide an in-depth understanding of the molecular basis of novel FAdV-4 pathogenicity and present rR188I as a potential live attenuated vaccine candidate or a novel vaccine vector for HHS vaccines. IMPORTANCE HHS associated with a novel FAdV-4 infection in chickens has caused huge economic losses to the poultry industry in China since 2015. The molecular basis for the increased virulence remains largely unknown. Here, we demonstrate that the hexon gene is vital for FAdV-4 pathogenicity. Furthermore, we show that the amino acid residue at position 188 of the hexon protein is responsible for pathogenicity. Importantly, the rR188I mutant strain was neutralized by chicken serum in vitro and in vivo, whereas the wild-type strain was not. Further, the rR188I mutant strain provided complete protection against FAdV-4 challenge. Our results provide a molecular basis of the increased virulence of novel FAdV-4. We propose that the rR188I mutant is a potential live attenuated vaccine against HHS and a new vaccine vector for HHS-combined vaccines.

A Single Amino Acid at Residue 188 of the Hexon Protein Is Responsible for the Pathogenicity of the Emerging Novel Virus Fowl Adenovirus 4.

Infection with fowl adenoviruses (FAdVs) can result in a number of syndromes in the production of chicken, including inclusion body hepatitis (IBH), hepatitis-hydropericardium syndrome (HHS), and others, causing enormous economic losses around the globe. FAdVs are divided into 12 serotypes and five species (A–E; 1–8a and 8b−11). Most avian species are prone to infection due to the widespread distribution of FAdV strains. The genus aviadenovirus, which is a member of the adenoviridae family, is responsible for both IBH and HHS. The most popular types of transmission are mechanical, vertical, and horizontal. Hepatitis with basophilic intranuclear inclusion bodies distinguishes IBH, but the buildup of translucent or straw-colored fluid in the pericardial sac distinguishes HHS. IBH and HHS require a confirmatory diagnosis because their clinical symptoms and postmortem abnormalities are not unique to those conditions. Under a microscope, the presence of particular lesions and inclusion bodies may provide clues. Traditional virus isolation in avian tissue culture is more delicate than in avian embryonated eggs. Additionally, aviadenovirus may now be quickly and precisely detected using molecular diagnostic tools. Preventive techniques should rely on efficient biosecurity controls and immunize breeders prior to production in order to protect progeny. This current review gives a general overview of the current local and global scenario of IBH, and HHS brought on by FAdVs and covers both their issues and preventative vaccination methods.

/pdf/epidemiology-pathology-prevention-and-control-strategies-of-1mr7gfcc.pdf

Epidemiology, pathology, prevention, and control strategies of inclusion body hepatitis and hepatitis-hydropericardium syndrome in poultry: A comprehensive review

Fowl adenovirus serotype 4 (FAdV-4) is the pathogenic agent of hydropericardium hepatitis syndrome (HHS) in chickens and ducks, which has caused huge economic losses for the Chinese poultry industry since 2015. In order to objectively determine the prevalence and co-infection status of the virus in Shandong province in China, we analyzed a total of 679 clinical cases of chickens and ducks from 36 farms in the province. The results showed that the FAdV-4 infection rate was 65.2% (443/679), and the rate in breeder ducks was almost two-fold higher than that in breeder chickens (68.57% vs. 34.30%). Notably, co-infection by H9N2 avian influenza virus, infectious bursal disease virus, and/or chicken infectious anemia virus was very common in the 443 FAdV-4-positive cases. Furthermore, phylogenetic analysis of the hexon genes of four Shandong FAdV-4 isolates revealed that these strains clustered into Indian reference strains, indicating that the Shandong FAdV-4 strains might have originated in India. These findings provide the first data on the prevalence and co-infection status of FAdV-4 in Shandong province, which may serve as a foundation for the prevention of FAdV-4 in the field.

Prevalence of Fowl Adenovirus Serotype 4 and Co-Infection by Immunosuppressive Viruses in Fowl with Hydropericardium Hepatitis Syndrome in Shandong Province, China.

Pathogenicity of fowl adenovirus serotype 4 (FAdV-4) in chickens

Pathogenicity of a fowl adenovirus serotype 4 isolated from chickens associated with hydropericardium-hepatitis syndrome in China

Fowl adenovirus serotype 4 (FAdV-4) is a causative agent of inclusion body hepatitis and hydropericardium–hepatitis syndrome. These diseases cause considerable economic losses in the global poultry industry and are significant stressors for infected chickens. However, the molecular mechanisms of FAdV-4 pathogenesis are poorly understood. In the present study, we identified differentially expressed genes from the livers of FAdV-4-infected chickens using RNA-seq at 7, 14 and 21 days after FAdV-4 infection. We identified 2395 differentially expressed genes at the three time points. These genes were enriched in variety of biological processes and pathways including PPAR and Notch signaling, cytokine–cytokine receptor interactions and Toll-like receptor signaling pathways. The transcriptional data were validated by quantitative real-time PCR. Our results will assist in the understanding of the molecular pathogenesis of FAdV-4 infection and for developing novel antiviral therapies.

/pdf/transcriptome-analysis-of-fowl-adenovirus-serotype-4-1twhqblqa0.pdf

Transcriptome analysis of fowl adenovirus serotype 4 infection in chickens.

The invention discloses a Hexon protein. The Hexon protein is obtained by transforming escherichia coli with a recombinant vector and then conducting induction, and the recombinant vector comprises ahexon gene sequence optimized by escherichia coli preferred codons. The invention also provides a preparation method of the Hexon protein, and a monoclonal antibody and a reagent kit which are obtained from the Hexon protein. The Hexon protein has a high expression level.

Hexon protein, preparation method of Hexon protein, monoclonal antibody and reagent kit

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Pathogenicity of a fowl adenovirus serotype 4 isolated from chickens associated with hydropericardium-hepatitis syndrome in China

Transcriptome analysis of fowl adenovirus serotype 4 infection in chickens.

Hexon protein, preparation method of Hexon protein, monoclonal antibody and reagent kit