Metabolomic Profiling Reveals New Insight of Fowl Adenovirus Serotype 4 Infection

Highly pathogenic fowl adenovirus serotype 4 (FAdV-4) is the causative agent of hydropericardium syndrome (HPS), which is characterized by pericardial effusion and hepatitis, and is one of the foremost causes of economic losses to the poultry industry over the last 30 years. However, the metabolic changes in cells in response to FAdV-4 infection remain unclear. In order to understand the metabolic interactions between the host cell and virus, we utilized ultra-high-performance liquid chromatography/quadrupole time-of-flight tandem mass spectrometry to analyze the metabolic profiles with hepatocellular carcinoma cell line (LMH) infected with FAdV-4. The results showed that FAdV-4 could restore metabolic networks in LMH cells and tricarboxylic acid cycle, glycolysis, and metabolism of purines, pyrimidines, alanine, aspartate, glutamate, and amino sugar and nucleotide sugar moieties. Moreover, FAdV-4 production was significantly reduced in LMH cells cultured in glucose or glutamine-deficient medium. These observations highlighted the importance of host cell metabolism in virus replication. Therefore, similarities and disparities in FAdV-4-regulation of the metabolism of host cells could help improve targeted drug and reduce infection.

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Transcriptome Analysis Reveals the Potential Role of Long Noncoding RNAs in Regulating Fowl Adenovirus Serotype 4-Induced Apoptosis in Leghorn Male Hepatocellular Cells

Viruses ◽

10.3390/v13081623 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1623

Author(s):

Bo Wen ◽

Xueping Wang ◽

Lulu Yang ◽

Ting Wang ◽

Xiaolan Hou ◽

...

Keyword(s):

Signaling Pathway ◽

Noncoding Rnas ◽

Long Noncoding Rnas ◽

Host Cells ◽

Economic Losses ◽

Adenovirus Serotype ◽

Fowl Adenovirus ◽

Induced Apoptosis ◽

Lmh Cells ◽

Fowl Adenovirus Serotype 4

Hepatitis-hydropericardium syndrome (HHS) is caused by fowl adenovirus serotype 4 (FAdV-4) and has resulted in considerable economic losses to the poultry industry globally. FAdV-4 elicits apoptosis in host cells. Long noncoding RNAs (lncRNAs) have emerged as important regulatory RNAs with profound effects on various biological processes, including apoptosis. However, it remains unknown whether lncRNAs participate in FAdV-4-induced apoptosis. In this study, RNA sequencing was applied to determine the transcription of cellular lncRNA in leghorn male hepatocellular (LMH) cells infected with FAdV-4. Cellular RNA transcription analysis demonstrated that FAdV-4 infection elicited 1798 significantly differentially expressed (DE) lncRNAs in infected LMH cells at 24 h post-infection (hpi) compared to mock control infection. In addition, 2873 DE mRNAs were also found. Target prediction and analyses revealed that 775 DE lncRNAs whose 671 target mRNAs were among the DE mRNAs were involved in several signaling pathways, including the AMPK signaling pathway, p53 signaling pathway and insulin signaling pathway. From these 775 DE lncRNAs, we identified 71 DE lncRNAs related to apoptosis based on their target gene functions. Subsequently, lncRNA 54128 was selected from the 71 identified DE lncRNAs, and its role in FAdV-4-induced apoptosis was verified. LncRNA 54128 interference significantly suppressed the rate of apoptosis, which was accompanied by reduced BMP4 transcription levels. To the best of our knowledge, this is the first study to analyze host lncRNA transcription during FAdV-4 infection. Our findings provide a better understanding of host responses to FAdV-4 infection and provide new directions for understanding the potential association between lncRNAs and FAdV-4 pathogenesis.

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Requirement of Cellular Protein CCT7 for the Replication of Fowl Adenovirus Serotype 4 (FAdV-4) in Leghorn Male Hepatocellular Cells Via Interaction with the Viral Hexon Protein

Viruses ◽

10.3390/v11020107 ◽

2019 ◽

Vol 11 (2) ◽

pp. 107 ◽

Cited By ~ 2

Author(s):

Junfeng Gao ◽

Mingliang Zhao ◽

Xueyan Duan ◽

Yongqiang Wang ◽

Hong Cao ◽

...

Keyword(s):

Molecular Mechanisms ◽

Ectopic Expression ◽

Cellular Protein ◽

Economic Losses ◽

Adenovirus Serotype ◽

Hydropericardium Syndrome ◽

Fowl Adenovirus ◽

Infected Cells ◽

Lmh Cells ◽

Fowl Adenovirus Serotype 4

Fowl adenovirus serotype 4 (FAdV-4) causes hepatitis-hydropericardium syndrome (HHS), leading to severe economic losses in the poultry industry. Although the pathogenesis of FAdV-4 infection has caused much attention, the underlying molecular mechanisms remain poorly understood. Here, we identified chaperonin containing TCP-1 subunit eta (CCT7) as an interacting partner of the FAdV-4 capsid protein hexon. We found that ectopic expression of CCT7 in leghorn male hepatocellular (LMH) cells enhanced hexon expression in pRK5-flag-hexon transfected cells. On the contrary, knockdown of cellular CCT7 by RNAi markedly reduced hexon expression in FAdV-4-infected cells and suppressed viral replication. These data suggest that CCT7 is required for FAdV-4 replication and may serve as a potential target for controlling FAdV-4 infection.

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A tandem mass tag-based quantitative proteomic analysis of fowl adenovirus serotype 4-infected LMH cells

Veterinary Microbiology ◽

10.1016/j.vetmic.2021.109026 ◽

2021 ◽

Vol 255 ◽

pp. 109026

Author(s):

Lidan Hou ◽

Xiaochun Chen ◽

Jia Wang ◽

Junping Li ◽

Hanchun Yang

Keyword(s):

Proteomic Analysis ◽

Tandem Mass ◽

Adenovirus Serotype ◽

Quantitative Proteomic Analysis ◽

Fowl Adenovirus ◽

Tandem Mass Tag ◽

Lmh Cells ◽

Fowl Adenovirus Serotype 4 ◽

Mass Tag

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Identification, Pathogenicity of Novel Fowl Adenovirus Serotype 4 SDJN0105 in Shandong, China and Immunoprotective Evaluation of the Newly Developed Inactivated Oil-emulsion FAdV-4 Vaccine

Viruses ◽

10.3390/v11070627 ◽

2019 ◽

Vol 11 (7) ◽

pp. 627 ◽

Cited By ~ 5

Author(s):

Kai Meng ◽

Xiaoyuan Yuan ◽

Jiang Yu ◽

Yuxia Zhang ◽

Wu Ai ◽

...

Keyword(s):

Clinical Symptoms ◽

Histopathological Examination ◽

Lethal Dose ◽

Economic Losses ◽

Effective Vaccine ◽

Drug Candidate ◽

Adenovirus Serotype ◽

Oil Emulsion ◽

Fowl Adenovirus ◽

Fowl Adenovirus Serotype 4

Since mid-2015, numerous outbreaks of hydropericardium-hepatitis syndrome (HHS), which is caused by a novel fowl adenovirus serotype 4 (FAdV-4), have been reported in chickens in parts of China, thereby causing huge economic losses to the poultry industry. Thus, an effective vaccine to control the further spread of infections with this hyper-virulent FAdV-4 is imperative. In this study, we isolated a novel FAdV-4 strain SDJN0105 from a broiler farm with HHS disease in Shandong Province. Pathogenicity was evaluated by the observation of clinical symptoms, necropsy changes, and pathological tissue sections after oral and intramuscular (IM) infection of Specific pathogen free (SPF) chickens. The chickens infected by IM injection all died within three days, and chickens infected via the oculonasal route died within five days post-infection (dpi). Histopathological examination revealed that the pathology was confined to heart, liver, spleen, lung, kidney, and particularly the liver. Irrespective of the inoculation route, the highest viral DNA copy numbers were detected in the livers of infected chickens. The mRNA expression levels of IL-1β, IL-6, IL-8, IFNs, TNF-α, Mx, and OASL were significantly upregulated during the viral infection. In addition, an inactivated oil-emulsion FAdV-4 vaccine was developed. The vaccine could provide full protection for SPF chickens against a lethal dose of the FAdV-4 strain SDJN0105 and a high level of antibodies. These results improve our understanding of the innate immune responses in chickens infected with FAdV-4 and the pathogenesis of FAdV-4 caused by host factors, and the developed FAdV-4 vaccine is promising as a drug candidate for the prevention and reduction of the spread of HHS in poultry in China.

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A Novel Role for PX, a Structural Protein of Fowl Adenovirus Serotype 4 (FAdV4), as an Apoptosis-Inducer in Leghorn Male Hepatocellular Cell

Viruses ◽

10.3390/v12020228 ◽

2020 ◽

Vol 12 (2) ◽

pp. 228

Author(s):

Mingliang Zhao ◽

Xueyan Duan ◽

Yongqiang Wang ◽

Li Gao ◽

Hong Cao ◽

...

Keyword(s):

Nuclear Localization ◽

Structural Protein ◽

Adenovirus Serotype ◽

Fowl Adenovirus ◽

Apoptosis Inhibition ◽

Apoptosis Inducer ◽

Viral Factor ◽

Induced Apoptosis ◽

Lmh Cells ◽

Fowl Adenovirus Serotype 4

Hydropericardium-Hepatitis Syndrome (HHS) caused by Fowl Adenovirus Serotype 4 (FAdV4) infection is a severe threat to the poultry industry worldwide, especially in China since 2015. Recent studies show that FAdV4 induces liver injury through apoptosis. However, the underlying molecular mechanism is still unclear. We report here that FAdV4 infection caused apoptosis in Leghorn male hepatocellular (LMH) cells and that PX, a structural protein of FAdV4, acted as a major viral factor inducing apoptosis. Furthermore, the nuclear localization of PX is determined by the R/K regions of PX and required for PX-induced apoptosis. Moreover, alanines 11 and 129 of PX are crucial to PX-induced apoptosis. Inhibition of FAdV4-induced apoptosis by caspase inhibitors retarded viral replication, suggesting that PX serves as a virulence factor for FAdV4 infection, which may further our understandings of the pathogenesis of FAdV4 infection.

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

Viruses ◽

10.3390/v11060517 ◽

2019 ◽

Vol 11 (6) ◽

pp. 517 ◽

Cited By ~ 2

Author(s):

Guanliu Yu ◽

Yun Lin ◽

Yanguo Dou ◽

Yi Tang ◽

Youxiang Diao

Keyword(s):

Shandong Province ◽

Economic Losses ◽

Infection Status ◽

Adenovirus Serotype ◽

Fowl Adenovirus ◽

Chicken Infectious Anemia Virus ◽

Bursal Disease ◽

Chicken Infectious Anemia ◽

Anemia Virus ◽

Fowl Adenovirus Serotype 4

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.

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