Dataset Information

Goose Mx and OASL Play Vital Roles in the Antiviral Effects of Type I, II, and III Interferon against Newly Emerging Avian Flavivirus.

ABSTRACT: Duck Tembusu virus (TMUV), an emerging avian flavivirus, is highly pathogenic to birds and has the potential to become a zoonotic pathogen. Here, the molecular antiviral mechanism of goose type I, II, and III interferon (goIFN?, goIFN?, and goIFN?), the key components of the innate immune pathway, against TMUV was studied. We found that the transcription of goIFNs was obviously driven by TMUV infection in vivo and in vitro, and the titers and copies of TMUV were significantly reduced following treatment with goIFNs. The results of RNA sequencing (RNA-seq) revealed that goIFN stimulation triggered a set of differentially expressed genes at different levels and a positive regulatory feedback loop of IFN release against infection. Two important interferon-stimulated genes, goMx and goOASL, were identified as workhorse IFNs in the inhibition of TMUV replication. The antiviral effects of goMx and goOASL were confirmed by transient overexpression and knockdown assay in vitro. Overall, our findings defined that goose Mx and OASL play key roles in the antiviral effects of type I, II, and III interferon against the TMUV. These results extend our understanding of the transcriptional profile of the goose IFN-mediated signaling pathway and provide insight into the antiviral mechanism of goIFNs against flavivirus infection.

SUBMITTER: Chen S

PROVIDER: S-EPMC5572330 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Goose Mx and OASL Play Vital Roles in the Antiviral Effects of Type I, II, and III Interferon against Newly Emerging Avian Flavivirus.

Chen Shun S Zhang Wei W Wu Zhen Z Zhang Jinyue J Wang Mingshu M Jia Renyong R Zhu Dekang D Liu Mafeng M Sun Kunfeng K Yang Qiao Q Wu Ying Y Chen Xiaoyue X Cheng Anchun A

Frontiers in immunology 20170823

Duck Tembusu virus (TMUV), an emerging avian flavivirus, is highly pathogenic to birds and has the potential to become a zoonotic pathogen. Here, the molecular antiviral mechanism of goose type I, II, and III interferon (goIFNα, goIFNγ, and goIFNλ), the key components of the innate immune pathway, against TMUV was studied. We found that the transcription of goIFNs was obviously driven by TMUV infection <i>in vivo</i> and <i>in vitro</i>, and the titers and copies of TMUV were significantly reduc ...[more]

PMID: 28878774

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Project description:Purpose：Next-generation sequencing (NGS) has revolutionized systems-based analysis of cellular pathways. PBMCs are important immune cells and effectively respond to IFN treatment. Therefore, the goals of this study are to compare the transcriptional profile of the goose IFN (goIFNα, goIFNγ and goIFNλ)-mediated immune response in PBMCs. Methods：Peripheral blood mononuclear cells (PBMCs) were stimulated with recombinant goIFN-α, γ and λ for 3 h, and those treated with cell lysates from pcDNA3.1 (+)-transfected BHK-21 cells were considered as control group. Cells were harvested with 1 mL RNAiso Plus reagent for RNA extraction. Obtained RNA quantity and quality were evaluated using NanoDrop, Qubit and Agilent 2100 Bioanalyzer. After qualification and quantification using an Agilent 2100 Bioanalyzer and ABI Step One Plus Real Time PCR System, the libraries were sequenced with Illumina HiSeqTM 2000. Results：Comparisons between IFN treatment groups and the control group were performed, and DEGs were analysed using the DESeq R package, a model based on the negative binomial distribution. For the statistical analysis, all read counts were normalized by calculating the FPKM value, and further, the FPKM + 1 values were log2 transformed and the means of expression (in log2 FPKMs) were used for further analysis. An P value < 0.05, which was adjusted by the false discovery rate (FDR), was defined as the threshold of DEGs, and log2-fold change ＞ 0 (or < 0) was defined as up-regulated (down-regulated genes). According to the results of DEG analysis, we selected 17 IFN‑responsive genes from the RNA-seq data for validation by RT-qPCR. Conclusion：Our study represents the first detailed analysis of the transcriptional profile of the goose IFN (goIFNα, goIFNγ and goIFNλ) immune response in PBMCs. The stimulation of goIFNs initiated a series of signalling cascades at early stages, leading to the transcriptional regulation of hundreds of DEGs, and each IFN induced a unique and partially overlapping set of ISGs. Most importantly, we identified approximately 101 immune-related genes, which were mainly involved in the toll-like receptor signalling pathway, JAK-STAT signalling pathway and antiviral pathway. Moreover, these results were verified by RT-qPCR, and the correlation analysis of RNA-Seq data and qRT-PCR results showed that some relevant relationships between candidate genes may be related to the balance of the host immune response, which remains to be further studied in the future.

Project description:Bats serve as a reservoir for various, often zoonotic viruses, including significant human pathogens such as Ebola and influenza viruses. However, for unknown reasons, viral infections rarely cause clinical symptoms in bats. A tight control of viral replication by the host innate immune defense might contribute to this phenomenon. Transcriptomic studies revealed the presence of the interferon-induced antiviral myxovirus resistance (Mx) proteins in bats, but detailed functional aspects have not been assessed. To provide evidence that bat Mx proteins might act as key factors to control viral replication we cloned Mx1 cDNAs from three bat families, Pteropodidae, Phyllostomidae, and Vespertilionidae. Phylogenetically these bat Mx1 genes cluster closely with their human ortholog MxA. Using transfected cell cultures, minireplicon systems, virus-like particles, and virus infections, we determined the antiviral potential of the bat Mx1 proteins. Bat Mx1 significantly reduced the polymerase activity of viruses circulating in bats, including Ebola and influenza A-like viruses. The related Thogoto virus, however, which is not known to infect bats, was not inhibited by bat Mx1. Further, we provide evidence for positive selection in bat Mx1 genes that might explain species-specific antiviral activities of these proteins. Together, our data suggest a role for Mx1 in controlling these viruses in their bat hosts.IMPORTANCE Bats are a natural reservoir for various viruses that rarely cause clinical symptoms in bats but are dangerous zoonotic pathogens, like Ebola or rabies virus. It has been hypothesized that the interferon system might play a key role in controlling viral replication in bats. We speculate that the interferon-induced Mx proteins might be key antiviral factors of bats and have coevolved with bat-borne viruses. This study evaluated for the first time a large set of bat Mx1 proteins spanning three major bat families for their antiviral potential, including activity against Ebola virus and bat influenza A-like virus, and we describe here their phylogenetic relationship, revealing patterns of positive selection that suggest a coevolution with viral pathogens. By understanding the molecular mechanisms of the innate resistance of bats against viral diseases, we might gain important insights into how to prevent and fight human zoonotic infections caused by bat-borne viruses.

Project description:Avian Tembusu virus (TMUV) is a newly emerging avian pathogenic flavivirus in China and Southeast Asia with features of rapid spread, an expanding host range, and cross-species transmission. The mechanisms of its infection and pathogenesis remain largely unclear. Here, we investigated the tropism of this arbovirus in peripheral blood mononuclear cells of specific-pathogen-free (SPF) ducks and SPF chickens and identified monocytes/macrophages as the key targets of TMUV infection. In vivo studies in SPF ducks and SPF chickens with monocyte/macrophage clearance demonstrated that the infection of monocytes/macrophages was crucial for viral replication, transmission, and pathogenesis. Further genome-wide transcriptome analyses of TMUV-infected chicken macrophages revealed that host antiviral innate immune barriers were the major targets of TMUV in macrophages. Despite the activation of major pattern recognition receptor signaling, the inductions of alpha interferon (IFN-?) and IFN-? were blocked by TMUV infection on transcription and translation levels, respectively. Meanwhile, TMUV inhibited host redox responses by repressing the transcription of genes encoding NADPH oxidase subunits and promoting Nrf2-mediated antioxidant responses. The recovery of either of the above-mentioned innate immune barriers was sufficient to suppress TMUV infection. Collectively, we identify an essential step of TMUV infection and reveal extensive subversion of host antiviral innate immune responses.IMPORTANCE Mosquito-borne flaviviruses include a group of pathogenic viruses that cause serious diseases in humans and animals, including dengue, West Nile, and Japanese encephalitis viruses. These flaviviruses are zoonotic and use animals, including birds, as amplifying and reservoir hosts. Avian Tembusu virus (TMUV) is an emerging mosquito-borne flavivirus that is pathogenic for many avian species and can infect cells derived from mammals and humans in vitro Although not currently pathogenic for primates, the infection of duck industry workers and the potential risk of TMUV infection in immunocompromised individuals have been highlighted. Thus, the prevention of TMUV in flocks is important for both avian and mammalian health. Our study reveals the escape of TMUV from the first line of the host defense system in the arthropod-borne transmission route of arboviruses, possibly helping to extend our understanding of flavivirus infection in birds and refine the design of anti-TMUV therapeutics.

Dataset Information

Goose Mx and OASL Play Vital Roles in the Antiviral Effects of Type I, II, and III Interferon against Newly Emerging Avian Flavivirus.

Publications

Goose Mx and OASL Play Vital Roles in the Antiviral Effects of Type I, II, and III Interferon against Newly Emerging Avian Flavivirus.

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