Classical swine fever virus NS5A protein changed inflammatory cytokine secretion in porcine alveolar macrophages by inhibiting the NF-κB signaling pathway

Dong, Xiaoying; Tang, Sheng-Qiu

doi:10.1186/s12985-016-0545-z

Cited by 14 publications

(8 citation statements)

References 46 publications

(49 reference statements)

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“…Subversion of the antiviral activities of macrophages by viruses such as HIV, severe acute respiratory syndrome (SARS) virus, African swine fever virus (ASFV), and porcine reproductive and respiratory syndrome virus (PRRSV) can facilitate viral replication and viral spread and can even enhance the intensity of immune responses, which leads to severe immune-mediated disease (32)(33)(34)(35). Recently, the subversion of macrophages by flaviviruses has been reported for tick-borne encephalitis virus (TBEV), WNV, DENV, Zika virus, and classical swine fever virus (CSFV) (36)(37)(38)(39)(40)(41). Antibody-dependent enhancement of TMUV infection has been observed in mice, indicating the potential interaction between TMUV and mouse macrophages (42).…”

Section: Discussionmentioning

confidence: 99%

Avian Flavivirus Infection of Monocytes/Macrophages by Extensive Subversion of Host Antiviral Innate Immune Responses

Liang

Wang

et al. 2019

J Virol

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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-α) and IFN-β 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.

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Section: Discussionmentioning

confidence: 99%

Avian Flavivirus Infection of Monocytes/Macrophages by Extensive Subversion of Host Antiviral Innate Immune Responses

Liang

Wang

et al. 2019

J Virol

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“…Many viruses therefore have developed various strategies targeting NF-κB to evade host immune response. Unexceptionally, CSFV infection fails to activate NF-κB signaling pathway (31) and NS5A protein suppresses NF-κB signaling induced by poly(I:C) (18). However, the mechanism of the inhibition of NF-κB signaling by NS5A is was not elucidated.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, two other NS5A binding partners, HSP70 (16) and FKBP8 (17), have been shown to facilitate viral proliferation. NS5A also inhibits the secretion of inflammatory cytokines induced by poly(I:C) by suppression of the NF-κB signaling pathway (18). However, the mechanism of inhibition of the NF-κB signaling by NS5A remains obscure.…”

Section: Introductionmentioning

confidence: 99%

Classical swine fever virus NS5A inhibits NF-κB signaling by targeting NEMO

Jiang

et al. 2021

Preprint

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The NS5A non-structural protein of classical swine fever virus (CSFV) is a multifunctional protein involved in viral genomic replication, protein translation and regulation of cellular signaling pathways, and assembly of infectious virus particles. Previous report showed that NS5A inhibited nuclear factor kappa B (NF-κB) signaling induced by poly(I:C); however, the mechanism was not elucidated. Here, we report that NS5A interacts with NF-κB essential modulator (NEMO), a regulatory subunit of the IκB kinase (IKK) complex, and that the zinc finger domain of NEMO essential for NEMO ubiquitination and IKK activation is required for the interaction of NEMO with NS5A. Viral infection or NS5A expression by itself reduced the protein level of NEMO. Mechanistic analysis revealed that NS5A mediated proteasomal degradation of NEMO. Ubiquitination assay showed that NS5A induced K27- but not K48-linked polyubiquitination of NEMO. In addition, NS5A blocked k63-linked polyubiquitination of NEMO, thereby inhibiting activation of IKK and NF-κB. These findings indicate that NS5A inhibits NF-κB signaling by mediating proteasomal degradation of NEMO and blocking k63-linked polyubiquitination of NEMO, thereby revealing a novel mechanism by which CSFV inhibits host innate immunity.

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“…Recent studies revealed that NS5A induces autophagy to enhance replication of CSFV ( 14 , 15 ). It has also been shown that CSFV NS5A protein could inhibit the secretion of inflammatory cytokines by suppressing the NF-κB pathway ( 16 ). Although the effect of CSFV NS5A on type I IFNs pathway is not well understood, sufficient studies have shown that many flaviviruses NS5 have an antagonism of type I IFN ( 17 ).…”

Section: Introductionmentioning

confidence: 99%

HSP90AA1 interacts with CSFV NS5A protein and regulates CSFV replication via the JAK/STAT and NF-κB signaling pathway

et al. 2022

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Classical swine fever (CSF), caused by the classical swine fever virus (CSFV), is a highly contagious and fatal viral disease, posing a significant threat to the swine industry. Heat shock protein 90 kDa alpha class A member 1 (HSP90AA1) is a very conservative chaperone protein that plays an important role in signal transduction and viral proliferation. However, the role of HSP90AA1 in CSFV infection is unknown. In this study, we found that expression of HSP90AA1 could be promoted in PK-15 and 3D4/2 cells infected by CSFV. Over-expression of HSP90AA1 could inhibit CSFV replication and functional silencing of HSP90AA1 gene promotes CSFV replication. Further exploration revealed that HSP90AA1 interacted with CSFV NS5A protein and reduced the protein levels of NS5A. Since NS5A has an important role in CSFV replication and is closely related to type I IFN and NF-κB response, we further analyzed whether HSP90AA1 affects CSFV replication by regulating type I IFN and NF-κB pathway responses. Our research found HSP90AA1 positively regulated type I IFN response by promoting STAT1 phosphorylation and nuclear translocation processes and promoted the nuclear translocation processes of p-P65. However, CSFV infection antagonizes the activation of HSP90AA1 on JAK/STAT and NF-κB pathway. In conclusion, our study found that HSP90AA1 overexpression significantly inhibited CSFV replication and may inhibit CSFV replication by interacting with NS5A and activating JAK/STAT and NF-κB signaling pathways. These results provide new insights into the mechanism of action of HSP90AA1 in CSFV infection, which abundant the candidate library of anti-CSFV.

show abstract

Classical swine fever virus NS5A protein changed inflammatory cytokine secretion in porcine alveolar macrophages by inhibiting the NF-κB signaling pathway

Cited by 14 publications

References 46 publications

Avian Flavivirus Infection of Monocytes/Macrophages by Extensive Subversion of Host Antiviral Innate Immune Responses

Avian Flavivirus Infection of Monocytes/Macrophages by Extensive Subversion of Host Antiviral Innate Immune Responses

Classical swine fever virus NS5A inhibits NF-κB signaling by targeting NEMO

HSP90AA1 interacts with CSFV NS5A protein and regulates CSFV replication via the JAK/STAT and NF-κB signaling pathway

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