Transcriptomic Analysis and Functional Characterization Reveal the Duck Interferon Regulatory Factor 1 as an Important Restriction Factor in the Replication of Tembusu Virus

Xiang, Chengwei; Huang, Mei; Xiong, Tingting; Fang, Rong; Li, Linyu; Liu, Ding Xiang; Chen, Rui Ai

doi:10.3389/fmicb.2020.02069

Cited by 14 publications

(18 citation statements)

References 60 publications

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“…In the present study, MDA5 and IFN-β were found to be involved in the production of chCMPK2 upon virus infection. Our results were consistent with preliminary hypothesis on duck that CMPK2 may be induced through the IFNα/β signaling pathway ( Xiang et al, 2020 ). MDA5 and RIG-I, as members of the evolutionarily conserved RIG-like helicase family, play critical roles in the host antiviral defense against pathogens.…”

Section: Discussionsupporting

confidence: 93%

“…In the current report, we first demonstrated that chCMPK2 inhibited the propagation of AIV H9N2 in a dose-dependent way, and chCMPK2 may also be an antiviral molecule against NDV. CMPK2 has been reported to be able to inhibit viral and bacterial infection, including SVCV, Dengue virus (DENV), Duck Tembusu virus (DTMUV), HIV-1 and Aeromonas hydrophila CCL1 ( El-Diwany et al, 2018 ; Liu et al, 2019 ; Xiang et al, 2020 ; Feng et al, 2021 ; Lai et al, 2021 ). Our analysis indicated that overexpression of chCMPK2 in DF-1 cells significantly inhibited H9N2 NP expression at the mRNA and protein levels, and knockdown of chCMPK2 had the opposite effects, which suggested that chCMPK2 was an important antiviral factor against AIV.…”

Section: Discussionmentioning

confidence: 99%

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A Role for the Chicken Interferon-Stimulated Gene CMPK2 in the Host Response Against Virus Infection

Feng

Liu

et al. 2022

Front. Microbiol.

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Virus infection can lead to the production of interferon, which activates the JAK/STAT pathway and induces the expression of multiple downstream interferon-stimulated genes (ISGs) to achieve their antiviral function. Cytidine/uridine monophosphate kinase 2 (CMPK2) gene has been identified as an ISG in human and fish, and is also known as a rate-limiting enzyme in mitochondria to maintain intracellular UTP/CTP levels, which is necessary for de novo mitochondrial DNA synthesis. By mining previous microarray data, it was found that both Avian Influenza Virus (AIV) and Newcastle Disease Virus (NDV) infection can lead to the significant upregulation of chicken CMPK2 gene. However, little is known about the function of CMPK2 gene in chickens. In the present study, the open reading frame (ORF) of chicken CMPK2 (chCMPK2) was cloned from DF-1, a chicken embryo fibroblasts cell line, and subjected to further analysis. Sequence analysis showed that chCMPK2 shared high similarity in amino acid with CMPK2 sequences from all the other species, especially reptiles. A thymidylate kinase (TMK) domain was identified in the C-terminus of chCMPK2, which is highly conserved among all species. In vitro, AIV infection induced significant increases in chCMPK2 expression in DF-1, HD11, and the chicken embryonic fibroblasts (CEF), while obvious increase only detected in DF-1 cells and CEF cells after NDV infection. In vivo, the expression levels of chCMPK2 were up-regulated in several tissues from AIV infected chickens, especially the brain, spleen, bursa, kidney, intestine, heart and thymus, and notable increase of chCMPK2 was detected in the bursa, kidney, duodenum, lung, heart, and thymus during NDV infection. Here, using MDA5 and IFN-β knockdown cells, we demonstrated that as a novel ISG, chCMPK2 could be regulated by the MDA5/IFN-β pathway. The high expression level of exogenous chCMPK2 displayed inhibitory effects on AIV and NDV as well as reduced viral RNA in infected cells. We further demonstrated that Asp135, a key site on the TMK catalytic domain, was identified as critical for the antiviral activities of chCMPK2. Taken together, these data demonstrated that chCMPK2 is involved in the chicken immune system and may play important roles in host anti-viral responses.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

A Role for the Chicken Interferon-Stimulated Gene CMPK2 in the Host Response Against Virus Infection

Feng

Liu

et al. 2022

Front. Microbiol.

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“…According to the previous exploration, CMPK2 was upregulated in response to the LPS in macrophages [ 48 ] and various types of viruses [ 40 , 43 , 57 ]. Our RNA seq analysis in THP-1 and expression study in THP-1 cells and BMDMs showed LPS and Poly (I:C) dependent CMPK2 expression.…”

Section: Discussionmentioning

confidence: 99%

UMP-CMP kinase 2 gene expression in macrophages is dependent on the IRF3-IFNAR signaling axis

et al. 2021

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Toll-like receptors (TLRs) are highly-conserved pattern recognition receptors that mediate innate immune responses to invading pathogens and endogenous danger signals released from damaged and dying cells. Activation of TLRs trigger downstream signaling cascades, that culminate in the activation of interferon regulatory factors (IRFs), which subsequently leads to type I interferon (IFN) response. In the current study, we sought to expand the scope of gene expression changes in THP1-derived macrophages upon TLR4 activation and to identify interferon-stimulated genes. RNA-seq analysis led to the identification of several known and novel differentially expressed genes, including CMPK2, particularly in association with type I IFN signaling. We performed an in-depth characterization of CMPK2 expression, a nucleoside monophosphate kinase that supplies intracellular UTP/CTP for nucleic acid synthesis in response to type I IFN signaling in macrophages. CMPK2 was significantly induced at both RNA and protein levels upon stimulation with TLR4 ligand—LPS and TLR3 ligand—Poly (I:C). Confocal microscopy and subcellular fractionation indicated CMPK2 localization in both cytoplasm and mitochondria of THP-1 macrophages. Furthermore, neutralizing antibody-based inhibition of IFNAR receptor in THP-1 cells and BMDMs derived from IFNAR KO and IRF3 KO knockout mice further revealed that CMPK2 expression is dependent on LPS/Poly (I:C) mediated IRF3- type I interferon signaling. In summary, our findings suggest that CMPK2 is a potential interferon-stimulated gene in THP-1 macrophages and that CMPK2 may facilitate IRF3- type I IFN-dependent anti-bacterial and anti-viral roles.

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“…Duck OASL activates the OAS/RNaseL pathway (58). Similarly, overexpression of duck Viperin reduces viral replication (59).…”

Section: Discussionmentioning

confidence: 99%

Tissue Specific Transcriptome Changes Upon Influenza A Virus Replication in the Duck

et al. 2021

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Ducks are the natural host and reservoir of influenza A virus (IAV), and as such are permissive to viral replication while being unharmed by most strains. It is not known which mechanisms of viral control are globally regulated during infection, and which are specific to tissues during infection. Here we compare transcript expression from tissues from Pekin ducks infected with a recombinant H5N1 strain A/Vietnam 1203/04 (VN1203) or an H5N2 strain A/British Columbia 500/05 using RNA-sequencing analysis and aligning reads to the NCBI assembly ZJU1.0 of the domestic duck (Anas platyrhynchos) genome. Highly pathogenic VN1203 replicated in lungs and showed systemic dissemination, while BC500, like most low pathogenic strains, replicated in the intestines. VN1203 infection induced robust differential expression of genes all three days post infection, while BC500 induced the greatest number of differentially expressed genes on day 2 post infection. While there were many genes globally upregulated in response to either VN1203 or BC500, tissue specific gene expression differences were observed. Lungs of ducks infected with VN1203 and intestines of birds infected with BC500, tissues important in influenza replication, showed highest upregulation of pattern recognition receptors and interferon stimulated genes early in the response. These tissues also appear to have specific downregulation of inflammatory components, with downregulation of distinct sets of proinflammatory cytokines in lung, and downregulation of key components of leukocyte recruitment and complement pathways in intestine. Our results suggest that global and tissue specific regulation patterns help the duck control viral replication as well as limit some inflammatory responses in tissues involved in replication to avoid damage.

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Transcriptomic Analysis and Functional Characterization Reveal the Duck Interferon Regulatory Factor 1 as an Important Restriction Factor in the Replication of Tembusu Virus

Cited by 14 publications

References 60 publications

A Role for the Chicken Interferon-Stimulated Gene CMPK2 in the Host Response Against Virus Infection

A Role for the Chicken Interferon-Stimulated Gene CMPK2 in the Host Response Against Virus Infection

UMP-CMP kinase 2 gene expression in macrophages is dependent on the IRF3-IFNAR signaling axis

Tissue Specific Transcriptome Changes Upon Influenza A Virus Replication in the Duck

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