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African Swine Fever Virus MGF360-12L Inhibits Type I Interferon Production by Blocking the Interaction of Importin α and NF-κB Signaling Pathway.

ABSTRACT: African swine fever (ASF) is an infectious transboundary disease of domestic pigs and wild boar and spreading throughout Eurasia. There is no vaccine and treatment available. Complex immune escape strategies of African swine fever virus (ASFV) are crucial factors affecting immune prevention and vaccine development. MGF360 genes have been implicated in the modulation of the IFN-I response. The molecular mechanisms contributing to innate immunity are poorly understood. In this study, we demonstrated that ASFV MGF360-12L (MGF360 families 12L protein) significantly inhibited the mRNA transcription and promoter activity of IFN-β and NF-κB, accompanied by decreases of IRF3, STING, TBK1, ISG54, ISG56 and AP-1 mRNA transcription. Also, MGF360-12L might suppress the nuclear localization of p50 and p65 mediated by classical nuclear localization signal (NLS). Additionally, MGF360-12L could interact with KPNA2, KPNA3, and KPNA4, which interrupted the interaction between p65 and KPNA2, KPNA3, KPNA4. We further found that MGF360-12L could interfere with the NF-κB nuclear translocation by competitively inhibiting the interaction between NF-κB and nuclear transport proteins. These findings suggested that MGF360-12L could inhibit the IFN-I production by blocking the interaction of importin α and NF-κB signaling pathway, which might reveal a novel strategy for ASFV to escape the host innate immune response.

SUBMITTER: Zhuo Y

PROVIDER: S-EPMC7606853 | biostudies-literature |

REPOSITORIES: biostudies-literature

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African Swine Fever Virus MGF360-14L Negatively Regulates Type I Interferon Signaling by Targeting IRF3.

Project description:African swine fever (ASF) is a devastating infectious disease caused by African swine fever virus (ASFV). The ASFV genome encodes multiple structural and non-structural proteins that contribute to evasion of host immunity. In this study, we determined that the viral non-structural protein MGF360-14L inhibits interferon-β (IFN-β) promoter activity induced by cGAS-STING signaling. MGF360-14L was also found to downregulate expression of the IRF3 protein and promote its degradation through ubiquitin-meditated proteolysis. Moreover, MGF360-14L was shown to interact with and destabilize IRF3 by facilitating E3 ligase TRIM21-mediated K63-linked ubiquitination of IRF3. Overall, our study revealed that MGF360-14L promotes degradation of IRF3 through TRIM21, thereby inhibiting type I interferon production. These findings provide new insights into the mechanisms underlying ASFV immune evasion.

| S-EPMC8790226 | biostudies-literature

African swine fever virus MGF360-11L negatively regulates cGAS-STING-mediated inhibition of type I interferon production.

Project description:The type I interferon (IFN-I) signaling pathway is an important part of the innate immune response and plays a vital role in controlling and eliminating pathogens. African swine fever virus (ASFV) encodes various proteins to evade the host's natural immunity. However, the molecular mechanism by which the ASFV-encoded proteins inhibit interferon production remains poorly understood. In the present study, ASFV MGF360-11L inhibited cGAS, STING, TBK1, IKKε, IRF7 and IRF3-5D mediated activation of the IFN-β and ISRE promoters, accompanied by decreases in IFN-β, ISG15 and ISG56 mRNA expression. ASFV MGF360-11L interacted with TBK1 and IRF7, degrading TBK1 and IRF7 through the cysteine, ubiquitin-proteasome and autophagy pathways. Moreover, ASFV MGF360-11L also inhibited the phosphorylation of TBK1 and IRF3 stimulated by cGAS-STING overexpression. Truncation mutation analysis revealed that aa 167-353 of ASFV MGF360-11L could inhibit cGAS-STING-mediated activation of the IFN-β and ISRE promoters. Finally, the results indicated that ASFV MGF360-11L plays a significant role in inhibiting IL-1β, IL-6 and IFN-β production in PAM cells (PAMs) infected with ASFV. In short, these results demonstrated that ASFV MGF360-11L was involved in regulating IFN-I expression by negatively regulating the cGAS signaling pathway. In summary, this study preliminarily clarified the molecular mechanism by which the ASFV MGF360-11L protein antagonizes IFN-I-mediated antiviral activity, which will help to provide new strategies for the treatment and prevention of ASF.

| S-EPMC8785597 | biostudies-literature

Aloe-emodin inhibits African swine fever virus replication by promoting apoptosis via regulating NF-κB signaling pathway.

Project description:African swine fever (ASF) is an acute infectious haemorrhagic fever of pigs caused by African swine fever virus (ASFV). Aloe-emodin (Ae) is an active ingredient of Chinese herbs with antiviral, anticancer, and anti-inflammatory effects. We investigated the antiviral activity and mechanism of action of Ae against ASFV using Real-time quantitative PCR (qPCR), western blotting, and indirect immunofluorescence assays. Ae significantly inhibited ASFV replication. Furthermore, transcriptomic analysis revealed that ASFV infection activated the NF-κB signaling pathway in the early stage and the apoptosis pathway in the late stage. Ae significantly downregulated the expression levels of MyD88, phosphor-NF-κB p65, and pIκB proteins as well as the mRNA levels of IL-1β and IL-8 in porcine alveolar macrophages (PAMs) infected with ASFV, thereby inhibiting the activation of the NF-κB signaling pathway induced by ASFV. Flow cytometry and western blot analysis revealed that Ae significantly increased the percentage of ASFV-induced apoptotic cells. Additionally, Ae promoted apoptosis by upregulating the expression levels of cleaved-caspase3 and Bax proteins and downregulating the expression levels of Bcl-2 proteins. This suggests that Ae promotes apoptosis by inhibiting the NF-κB pathway, resulting in inhibition of ASFV replication. These findings have further improved therapeutic reserves for the prevention and treatment of ASF.

| S-EPMC10357809 | biostudies-literature

The African Swine Fever Virus with MGF360 and MGF505 Deleted Reduces the Apoptosis of Porcine Alveolar Macrophages by Inhibiting the NF-κB Signaling Pathway and Interleukin-1β.

Project description:African swine fever virus (ASFV) poses serious threats to the swine industry. The mortality rate of African swine fever (ASF) is 100%, and there is no effective vaccine currently available. Complex immune escape strategies of ASFV are crucial factors affecting immune prevention and vaccine development. CD2v and MGF360-505R genes have been implicated in the modulation of the immune response. The molecular mechanisms contributing to innate immunity are poorly understood. In this study, we discover the cytopathic effect and apoptosis of ΔCD2v/ΔMGF360-505R-ASFV after infection in porcine alveolar macrophages (PAMs) was significantly less than wild-type ASFV. We demonstrated that CD2v- and MGF360-505R-deficient ASFV decrease the level of apoptosis by inhibiting the NF-κB signaling pathway and IL-1β mRNA transcription. Compared with wild-type ASFV infection, the levels of phospho-NF-κB p65 and p-IκB protein decreased in CD2v- and MGF360-505R-deficient ASFV. Moreover, CD2v- and MGF360-505R-deficient ASFV induced less IL-1β production than wild-type ASFV and was attenuated in replication compared with wild-type ASFV. We further found that MGF360-12L, MGF360-13L, and MGF-505-2R suppress the promoter activity of NF-κB by reporter assays, and CD2v activates the NF-κB signaling pathway. These findings suggested that CD2v- and MGF360-505R-deficient ASFV could reduce the level of ASFV p30 and the apoptosis of PAMs by inhibiting the NF-κB signaling pathway and IL-1β mRNA transcription, which might reveal a novel strategy for ASFV to maintain the replication of the virus in the host.

| S-EPMC8622997 | biostudies-literature

African Swine Fever Virus Ubiquitin-Conjugating Enzyme Is an Immunomodulator Targeting NF-κB Activation.

Project description:African swine fever virus (ASFV) is an acute and persistent swine virus with a high economic burden that encodes multiple genes to evade host immune response. In this work, we have revealed that early viral protein UBCv1, the only known conjugating enzyme encoded by a virus, modulates innate immune and inflammatory signaling. Transient overexpression of UBCv1 impaired activation of NF-κB and AP-1 transcription factors induced by several agonists of these pathways. In contrast, activation of IRF3 and ISRE signaling upon stimulation with TRIFΔRIP, cGAS/STING or RIG-I-CARD remained unaltered. Experiments aimed at mapping UBCv1 inhibitory activity indicated that this viral protein acts upstream or at the level step of IKKβ. In agreement with this, UBCv1 was able to block p65 nuclear translocation upon cytokine stimulation, a key event in NF-ĸB signaling. Additionally, A549 stably transduced for UBCv1 showed a significant decrease in the levels of NF-ĸB dependent genes. Interestingly, despite the well-defined capacity of UBCv1 to conjugate ubiquitin chains, a mutant disabled for ubiquitylation activity retained similar immunomodulatory activity as the wild-type enzyme, suggesting that the two functions are segregated. Altogether these data suggest that ASFV UBCv1 manipulates the innate immune response targeting the NF-κB and AP-1 pathways and opens new questions about the multifunctionality of this enzyme.

| S-EPMC8233900 | biostudies-literature

Screening of host proteins interacting with African swine fever virus MGF360-9L

Project description:To identify the potential host protein binding to African swine fever virus MGF360-9L, the 3 × FLAG tag MGF360-9L plasmid and empty FLAG were transfected into PK-15 cells for co-immunoprecipitation and LC-MS analysis. The cell lysates were immunoprecipitated using anti-FLAG antibody. Immunoprecipitation samples of cells transfected with empty FLAG were used as negative controls to eliminate non-specific interactions. LC-MS identified the interaction between MGF360-9L and PK-15 cell proteome. The final MGF360-9L binding protein data eliminated the nonspecific interaction through empty FLAG control. The interactions that remained were analyzed by significance analysis of interactome. Finally, 268 cellular proteins interacting with MGF360-9L were identified.

2022-02-17 | PXD027260 | Pride

Swine Interferon-Inducible Transmembrane Proteins Potently Inhibit African Swine Fever Virus Replication.

Project description:African swine fever virus (ASFV) causes an acute, hemorrhagic, and highly contagious disease in domestic swine, leading to significant economic losses to the global porcine industry. Restriction factors of innate immunity play a critical in host antiviral action. However, function of swine restriction factors of innate immunity on ASFV has been seldomly investigated. In this study, we determined five homologues of swine interferon-induced transmembrane proteins (SwIFITM [named SwIFITM1a, -1b, -2, -3, and -5]), and we found that they all exhibit potent antiviral activity against ASFV. Expression profile analysis indicated that these SwIFITMs are constitutively expressed in most porcine tissues. Whether infected with ASFV or treated with swine interferon, the expression levels of SwIFITMs were induced in vitro. The subcellular localization of SwIFITMs was similar to that of their human homologues. SwIFITM1a and -1b localized to the plasma membrane, SwIFITM2 and -3 focused on the cytoplasm and the perinuclear region, while SwIFITM5 accumulated in the cell surface and cytoplasm. The overexpression of SwIFITM1a, -1b, -2, -3, or -5 could significantly inhibit ASFV replication in Vero cells, whereas knockdown of these genes could enhance ASFV replication in PAMs. We blocked the constitutive expression of endogenous IFITMs in Vero cells using a CRISPR-Cas9 system and then infected them with ASFV. The results indicated that the knockout of endogenous IFITMs could enhance ASFV replication. Finally, we expressed five SwIFITMs in knockout Vero cell lines and then challenged them with ASFV. The results showed that all of the SwIFITMs had a strong antiviral effect on ASFV. This research will further expand the understanding of the anti-ASFV activity of porcine IFITMs.

| S-EPMC8989734 | biostudies-literature

Construction, Identification and Analysis of the Interaction Network of African Swine Fever Virus MGF360-9L with Host Proteins.

Project description:African swine fever virus (ASFV) is prevalent in many countries and is a contagious and lethal virus that infects pigs, posing a threat to the global pig industry and public health. The interaction between the virus and the host is key to unlocking the mystery behind viral pathogenesis. A comprehensive understanding of the viral and host protein interaction may provide clues for developing new antiviral strategies. Here, we show a network of ASFV MGF360-9L protein interactions in porcine kidney (PK-15) cells. Overall, 268 proteins that interact with MGF360-9L are identified using immunoprecipitation and liquid chromatography-mass spectrometry (LC-MS). Accordingly, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted, and the protein-protein interaction (PPI) network was created. It was speculated that the cellular proteins interacting with MGF360-9L are involved in protein binding, metabolism, and the innate immune response. Proteasome subunit alpha type (PSMA3), 26S protease regulatory subunit 4 (PSMC1), autophagy and beclin 1 regulator 1 (AMBRA1), and DEAD-box helicase 20 (DDX20) could interact with MGF360-9L in vitro. PSMA3 and PSMC1 overexpression significantly promoted ASFV replication, and MGF360-9L maintained the transcriptional level of PSMA3 and PSMC1. Here, we show the interaction between ASFV MGF360-9L and cellular proteins and elucidate the virus-host interaction network, which effectively provides useful protein-related information that can enable further study of the potential mechanism and pathogenesis of ASFV infection.

| S-EPMC8473002 | biostudies-literature

Chlorine Dioxide Inhibits African Swine Fever Virus by Blocking Viral Attachment and Destroying Viral Nucleic Acids and Proteins.

Project description:African swine fever (ASF) is a highly contagious disease and provokes severe economic losses and health threats. At present no effective vaccine or treatment is available to prevent or cure ASF. Consequently, there is an urgent need to develop effective drugs against ASF virus (ASFV). Chlorine dioxide (ClO2), an ideal biocide, has broad-spectrum antibacterial activity and no drug resistance. Here, we found that ClO2 strongly inhibited ASFV replication in porcine alveolar macrophages (PAMs). The inhibitory effect of ClO2 occurred during viral attachment rather than entry, indicating that ClO2 suppressed the early stage of virus life cycle. ClO2 showed a potent anti-ASFV effect when added either before, simultaneously with, or after virus infection. Furthermore, ClO2 could destroy viral nucleic acids and proteins, which may contribute to its capacity of inactivating ASFV virions. The minimum concentration of degradation of ASFV nucleic acids by ClO2 is 1.2 μg/mL, and the degradation is a temperature-dependent manner. These have guiding significance for ClO2 prevention and control of ASFV infection in pig farms. In addition, ClO2 decreased the expression of ASFV-induced inflammatory cytokines. Overall, our findings suggest that ClO2 may be an ideal candidate for the development of novel anti-ASFV prophylactic and therapeutic drugs in swine industry.

| S-EPMC8968399 | biostudies-literature

Species-specific variation in RELA underlies differences in NF-κB activity: a potential role in African swine fever pathogenesis.

Project description:African swine fever virus (ASFV) is a highly infectious disease of domestic pigs, with virulent isolates causing a rapidly fatal hemorrhagic fever. In contrast, the porcine species endogenous to Africa tolerate infection. The ability of the virus to persist in one host while killing another genetically related host implies that disease severity may be, in part, modulated by host genetic variation. To complement transcription profiling approaches to identify the underlying genetic variation in the host response to ASFV, we have taken a candidate gene approach based on known signaling pathways that interact with the virus-encoded immunomodulatory protein A238L. We report the sequencing of these genes from different pig species and the identification and initial in vitro characterization of polymorphic variation in RELA (p65; v-rel reticuloendotheliosis viral oncogene homolog A), the major component of the NF-κB transcription factor. Warthog RELA and domestic pig RELA differ at three amino acids. Transient cell transfection assays indicate that this variation is reflected in reduced NF-κB activity in vitro for warthog RELA but not for domestic pig RELA. Induction assays indicate that warthog RELA and domestic pig RELA are elevated essentially to the same extent. Finally, mutational studies indicate that the S531P site conveys the majority of the functional variation between warthog RELA and domestic pig RELA. We propose that the variation in RELA identified between the warthog and domestic pig has the potential to underlie the difference between tolerance and rapid death upon ASFV infection.

| S-EPMC3126315 | biostudies-literature

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