African swine fever virus protein MGF-505-7R promotes virulence and pathogenesis by inhibiting JAK1- and JAK2-mediated signaling

Abstract

African swine fever virus (ASFV) is a large DNA virus that is highly contagious and pathogenic in domestic pigs with a mortality rate up to 100%. However, how ASFV suppresses JAK-STAT1 signaling to evade the immune response remains unclear. In this study, we found that the ASFV-encoded protein MGF-505-7R inhibited proinflammatory IFN-γ-mediated JAK-STAT1 signaling. Mechanistically, MGF-505-7R was found to interact with JAK1 and JAK2 and mediate their degradation. Further study indicated that MGF-505-7R promoted degradation of JAK1 and JAK2 by upregulating the E3 ubiquitin ligase RNF125 expression and inhibiting expression of Hes5, respectively. Consistently, MGF-505-7R-deficient ASFV induced high levels of IRF1 expression and displayed compromised replication both in primary porcine alveolar macrophages and pigs compared with wild-type ASFV. Furthermore, MGF-505-7R deficiency attenuated the virulence of the ASFV and pathogenesis of ASF in pigs. These findings suggest that the JAK-STAT1 axis mediates the innate immune response to the ASFV and that MGF-505-7R plays a critical role in the virulence of the ASFV and pathogenesis of ASF by antagonizing this axis. Thus, we conclude that deletion of MGF-505-7R may serve as a strategy to develop attenuated vaccines against the ASFV. African swine fever virus (ASFV) is a large DNA virus that is highly contagious and pathogenic in domestic pigs with a mortality rate up to 100%. However, how ASFV suppresses JAK-STAT1 signaling to evade the immune response remains unclear. In this study, we found that the ASFV-encoded protein MGF-505-7R inhibited proinflammatory IFN-γ-mediated JAK-STAT1 signaling. Mechanistically, MGF-505-7R was found to interact with JAK1 and JAK2 and mediate their degradation. Further study indicated that MGF-505-7R promoted degradation of JAK1 and JAK2 by upregulating the E3 ubiquitin ligase RNF125 expression and inhibiting expression of Hes5, respectively. Consistently, MGF-505-7R-deficient ASFV induced high levels of IRF1 expression and displayed compromised replication both in primary porcine alveolar macrophages and pigs compared with wild-type ASFV. Furthermore, MGF-505-7R deficiency attenuated the virulence of the ASFV and pathogenesis of ASF in pigs. These findings suggest that the JAK-STAT1 axis mediates the innate immune response to the ASFV and that MGF-505-7R plays a critical role in the virulence of the ASFV and pathogenesis of ASF by antagonizing this axis. Thus, we conclude that deletion of MGF-505-7R may serve as a strategy to develop attenuated vaccines against the ASFV. African swine fever (ASF) is a devastating infectious disease in swine with a mortality rate approaching 100% (1Zhao D. Liu R. Zhang X. Li F. Wang J. Zhang J. Liu X. Wang L. Zhang J. Wu X. Guan Y. Chen W. Wang X. He X. Bu Z. Replication and virulence in pigs of the first African swine fever virus isolated in China.Emerg. Microbes Infect. 2019; 8: 438-447Crossref PubMed Scopus (107) Google Scholar). The causative agent, ASF virus (ASFV), infects macrophages and antagonizes host innate immune responses to enhance its pathogenicity. Currently, no effective vaccine is available to prevent ASF, resulting in the continuous spread of the virus in Africa, Europe, and Asia. The first ASF outbreak in China in 2018 and subsequently more than 160 outbreaks have been declared so far (2Wen X. He X. Zhang X. Zhang X. Liu L. Guan Y. Zhang Y. Bu Z. Genome sequences derived from pig and dried blood pig feed samples provide important insights into the transmission of African swine fever virus in China in 2018.Emerg. Microbes Infect. 2019; 8: 303-306Crossref PubMed Scopus (51) Google Scholar, 3Le V.P. Jeong D.G. Yoon S.W. Kwon H.M. Trinh T.B.N. Nguyen T.L. Bui T.T.N. Oh J. Kim J.B. Cheong K.M. Van Tuyen N. Bae E. Vu T.T.H. Yeom M. Na W. et al.Outbreak of African swine fever, Vietnam, 2019.Emerg. Infect. Dis. 2019; 25: 1433-1435Crossref PubMed Scopus (64) Google Scholar, 4Ge S. Li J. Fan X. Liu F. Li L. Wang Q. Ren W. Bao J. Liu C. Wang H. Liu Y. Zhang Y. Xu T. Wu X. Wang Z. Molecular characterization of African swine fever virus, China, 2018.Emerg. Infect. Dis. 2018; 24: 2131-2133Crossref PubMed Scopus (164) Google Scholar, 5Kim H.J. Cho K.H. Lee S.K. Kim D.Y. Nah J.J. Kim H.J. Kim H.J. Hwang J.Y. Sohn H.J. Choi J.G. Kang H.E. Kim Y.J. Outbreak of African swine fever in South Korea, 2019.Transbound. Emerg. Dis. 2020; 67: 473-475Crossref PubMed Scopus (40) Google Scholar). Unfortunately, ASF continues to spread across China, causing devastating consequences to the development of the pig industry and domestic food security (6De la Torre A. Bosch J. Iglesias I. Munoz M.J. Mur L. Martinez-Lopez B. Martinez M. Sanchez-Vizcaino J.M. Assessing the risk of African swine fever introduction into the European Union by wild boar.Transbound. Emerg. Dis. 2015; 62: 272-279Crossref PubMed Scopus (69) Google Scholar). Because the protective immunity and pathogenicity of ASFV are largely unknown, it is fundamentally important for us to explore the underlying mechanisms for the vaccine development and disease control. ASFV, the only member of the Asfarviridae family, is a linear, nonsegmented, double-stranded DNA virus with a genome length ranging from 170 to 193 kilo base pairs, which encodes about 151 to 167 open reading frames (7Chapman D.A. Tcherepanov V. Upton C. Dixon L.K. Comparison of the genome sequences of non-pathogenic and pathogenic African swine fever virus isolates.J. Gen. Virol. 2008; 89: 397-408Crossref PubMed Scopus (156) Google Scholar, 8Villiers E.P.D. Gallardo C. Arias M. Silva M.D. Upton C. Martin R. Bishop R.P. Phylogenomic analysis of 11 complete African swine fever virus genome sequences.Virology. 2010; 400: 128-136Crossref PubMed Scopus (94) Google Scholar, 9Dixon L.K. Chapman D.A.G. Netherton C.L. Upton C. 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Identification and utility of innate immune system evasion mechanisms of ASFV.Virus Res. 2013; 173: 87-100Crossref PubMed Scopus (95) Google Scholar). For instance, MGF360 and MGF505/530 are believed to inhibit the induction of type I IFNs and their downstream antiviral interferon stimulated genes (14Golding J.P. Goatley L. Goodbourn S. Dixon L.K. Taylor G. Netherton C.L. Sensitivity of African swine fever virus to type I interferon is linked to genes within multigene families 360 and 505.Virology. 2016; 493: 154-161Crossref PubMed Scopus (64) Google Scholar, 15Afonso C.L. Piccone M.E. Zaffuto K.M. Neilan J. Kutish G.F. Lu Z. Balinsky C.A. Gibb T.R. Bean T.J. Zsak L. Rock D.L. African swine fever virus multigene family 360 and 530 genes affect host interferon response.J. Virol. 2004; 78: 1858-1864Crossref PubMed Scopus (114) Google Scholar). DP96R of ASFV targets both TBK1 and IKKβ to negatively regulate induction of antiviral cytokines (16Wang X. Wu J. Wu Y. Chen H. Zhang S. Li J. Xin T. Jia H. Hou S. Jiang Y. Zhu H. Guo X. Inhibition of cGAS-STING-TBK1 signaling pathway by DP96R of ASFV China 2018/1.Biochem. Biophys. Res. Commun. 2018; 506: 437-443Crossref PubMed Scopus (40) Google Scholar). Additionally, ASFV Armenia/07 inhibits the cGAS-STING pathway by impairing STING activation during infection (17Garcia-Belmonte R. Perez-Nunez D. Pittau M. Richt Y. African swine fever virus Armenia/07 interferon the cGAS-STING Virol. 2019; PubMed Scopus Google Scholar). we found that ASFV MGF-505-7R with STING and it by the expression of the protein D. Li Li Z. Zhang J. Ren J.J. Y. Liu Liu African swine fever virus MGF-505-7R negatively signaling PubMed Scopus Google Scholar). have how ASFV antagonizes type I the underlying mechanisms of ASFV type interferon signaling pathway are is a critical for the innate and adaptive immunity against and of during innate and adaptive immune PubMed Scopus Google Scholar). The signaling pathway is by of The pathway PubMed Scopus Google Scholar). have that signaling are the of to and which in of JAK1 and to of and M. The for PubMed Scopus Google Scholar, to 67: PubMed Scopus Google Scholar). The activation of both JAK1 and JAK2 to the which the of genes in immune responses and to PubMed Scopus Google Scholar, C.A. T.J. M. R.P. W. J.G. B. K. with high to PubMed Scopus Google Scholar). The are from by the of and as of immune with a of and by PubMed Scopus Google Scholar, E. W. of 2013; PubMed Scopus Google Scholar, B. A. D. C. B. D. and of the J. PubMed Scopus Google Scholar). In this study, we ASFV MGF-505-7R as a of JAK-STAT1 signaling. ASFV MGF-505-7R with JAK1 and JAK2 proteins and by upregulating RNF125 expression respectively. of pigs with MGF-505-7R-deficient ASFV and attenuated virulence and findings suggest that the JAK-STAT1 axis mediates ASFV innate evasion of JAK-STAT1 signaling by MGF-505-7R to the virulence of the ASFV and pathogenesis of the the of ASFV signaling porcine alveolar with ASFV and with and the of downstream genes was by The that was a of and in than of we a in the in infection that IFN-γ-mediated signaling pathway was inhibited by ASFV ASFV infection in in with that in the These suggest that ASFV negatively signaling It been that the expression of Y. K. and analysis of the interferon PubMed Scopus Google Scholar). the ASFV proteins that are in signaling ASFV genes that inhibit IRF1 in It was that ASFV MGF-505-7R inhibited the activation of the IRF1 by Further indicated that ASFV MGF-505-7R inhibited the activation of the IRF1 in a of ASFV MGF-505-7R the of in These suggest that ASFV MGF-505-7R protein negatively signaling the of ASFV MGF-505-7R type signaling we the of a of downstream genes in ASFV by The that levels of the and in ASFV MGF-505-7R than in the wild-type The of ASFV MGF-505-7R of the and genes in These suggest that ASFV MGF-505-7R inhibits of downstream are in signaling in ASFV MGF-505-7R inhibited and signaling In we found that ASFV MGF-505-7R was in the of its we found that MGF-505-7R was in the of the ASFV and its In to the of the MGF-505-7R we the from the with ASFV. The that MGF-505-7R was of infection as the as which is ASFV of was than In to the of MGF-505-7R with ASFV disease virus The that ASFV and MGF-505-7R proteins in in that MGF-505-7R ASFV MGF-505-7R protein These suggest that ASFV MGF-505-7R inhibits signaling pathway JAK1 and JAK2 ASFV MGF-505-7R is with signaling in The that ASFV MGF-505-7R with JAK1 and with it was the in the with and for the of JAK1 and JAK2 with and respectively. JAK1 and JAK2 in the and that MGF-505-7R with JAK1 and JAK2 proteins in the findings that JAK1 and JAK2 interact with ASFV MGF-505-7R how ASFV MGF-505-7R JAK1 and JAK2 in signaling. with MGF-505-7R and JAK1 JAK2 genes to MGF-505-7R the expression of JAK1 and that of MGF-505-7R JAK1 and JAK2 protein levels and explore the of ASFV infection JAK1 and JAK2 with ASFV for indicated and to The that ASFV infection inhibited the expression of JAK1 and JAK2 proteins in and degradation is of the that to host protein during infection the and the mechanisms for MGF-505-7R the of JAK1 and we with the indicated and the with for protein degradation degradation of JAK1 was inhibited by the and found that JAK2 degradation by MGF-505-7R ASFV was inhibited by and These suggest that MGF-505-7R inhibit the signaling pathway by JAK1 and JAK2 The that MGF-505-7R JAK1 by the we MGF-505-7R expression in JAK1 which E3 ubiquitin ligase MGF-505-7R degradation of In the and we that MGF-505-7R and ASFV JAK1 inhibited JAK1 compared with ASFV and study reported that JAK1 with RNF125 H. D. M. Z. Y. C. L. Y. N. A. of the ubiquitin ligase RNF125 of to JAK1 2015; PubMed Scopus Google we RNF125 MGF-505-7R degradation of this we by with ASFV MGF-505-7R and RNF125 and infection in that ASFV MGF-505-7R with RNF125 and found that MGF-505-7R the expression of RNF125 in in a RNF125 inhibited the expression of JAK1 and In we found that RNF125 MGF-505-7R degradation of JAK1 These indicated that MGF-505-7R JAK1 by upregulating RNF125 It been reported that with JAK2 and its expression K. Y. N. M. G. to mediates and 2004; PubMed Scopus Google Scholar). MGF-505-7R with Hes5, we and found that MGF-505-7R was with in and the role of in the expression of we with expression the protein JAK2 with of and that the expression of JAK2 was by in a expression was inhibited by MGF-505-7R in a Furthermore, it was that JAK2 expression was by MGF-505-7R to explore the of RNF125 JAK1 JAK2 we RNF125 The that the expression of JAK1 JAK2 was in with ASFV and These that MGF-505-7R inhibited the expression of JAK2 the expression of In to the of ASFV MGF-505-7R in JAK-STAT1 we MGF-505-7R-deficient virus as by of the highly ASFV The MGF-505-7R was by a the the of ASFV The virus was 11 of by The of MGF-505-7R in the virus was by that MGF-505-7R was in the replication of in that are to ASFV A. S. E. Silva E. L. C. and of African swine fever virus in PubMed Scopus Google with ASFV and The that the replication of virus was as the ASFV in that the in than in with ASFV Consistently, in than with ASFV It was with the replication that the the compared with ASFV we that infection the and expression in the RNF125 and ASFV expression in with of Additionally, we found that the RNF125 and JAK1 was in compared with that of the the was inhibited in compared with that of the that the and JAK2 in the ASFV in the suggest that infection the type signaling in with ASFV. was attenuated in we pigs with of the virus ASFV and the pigs for The that of the pigs with ASFV within with and the pigs with wild-type ASFV of fever with up to with the virus displayed and and pigs from the infection with the virus in blood than pigs with wild-type ASFV with virus levels of and than with wild-type ASFV and that the of with ASFV by the K. Chapman D. J.M. E. of European domestic pigs from African of African swine fever virus by PubMed Scopus Google Scholar). The in this study that the of pigs with ASFV was than that of pigs with The of in pigs with ASFV more than in pigs with have indicated that the levels of as the against are important with immune responses J. V. M. L. S. of the host immune response with a attenuated African swine fever virus 2016; 8: Scopus Google Scholar). found that the pigs with the virus levels of the of infection that the attenuated virus induced The IRF1 in derived from pigs was than that of the suggest that is attenuated in pigs and is to swine ASFV 11 to multigene family 360 genes and genes C.L. Piccone M.E. Zaffuto K.M. Neilan J. Kutish G.F. Lu Z. Balinsky C.A. Gibb T.R. Bean T.J. Zsak L. Rock D.L. African swine fever virus multigene family 360 and 530 genes affect host interferon response.J. Virol. 2004; 78: 1858-1864Crossref PubMed Scopus (114) Google Scholar). It is that of 360 and are to type I that genes a role in inhibiting the responses antiviral (14Golding J.P. Goatley L. Goodbourn S. Dixon L.K. Taylor G. Netherton C.L. Sensitivity of African swine fever virus to type I interferon is linked to genes within multigene families 360 and 505.Virology. 2016; 493: 154-161Crossref PubMed Scopus (64) Google Scholar). The ASFV MGF-505-7R is a member of it serve as evasion In the study, we found that MGF-505-7R inhibited signaling pathway degradation of JAK1 and the of responses to type I is a strategy that for immune it is that no ASFV been to inhibit the signaling which is the pathway antiviral S. Ventura S. Parkhouse R.M. Identification and utility of innate immune system evasion mechanisms of ASFV.Virus Res. 2013; 173: 87-100Crossref PubMed Scopus (95) Google Scholar). study is the first to the of how ASFV MGF-505-7R protein inhibits the signaling have that ASFV the host innate immune responses type I IFNs (14Golding J.P. Goatley L. Goodbourn S. Dixon L.K. Taylor G. Netherton C.L. Sensitivity of African swine fever virus to type I interferon is linked to genes within multigene families 360 and 505.Virology. 2016; 493: 154-161Crossref PubMed Scopus (64) Google Scholar, 15Afonso C.L. Piccone M.E. Zaffuto K.M. Neilan J. Kutish G.F. Lu Z. Balinsky C.A. Gibb T.R. Bean T.J. Zsak L. Rock D.L. African swine fever virus multigene family 360 and 530 genes affect host interferon response.J. Virol. 2004; 78: 1858-1864Crossref PubMed Scopus (114) Google Scholar, X. Wu J. Wu Y. Chen H. Zhang S. Li J. Xin T. Jia H. Hou S. Jiang Y. Zhu H. Guo X. Inhibition of cGAS-STING-TBK1 signaling pathway by DP96R of ASFV China 2018/1.Biochem. Biophys. Res. Commun. 2018; 506: 437-443Crossref PubMed Scopus (40) Google Scholar). the role of signaling pathway in ASFV innate immune responses remains unclear. It is that the of type expression is induced by S. Ventura S. Parkhouse R.M. 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C. of a protein to African swine fever in Virol. 1995; PubMed Scopus Google Scholar). the of the we that was a ASFV infection and type JAK1 and JAK2 important role in signaling the JAK1 and JAK2 are with and and the and to its which the signaling In this we found that MGF-505-7R JAK1 upregulating RNF125 expression and JAK2 expression by to inhibit the signaling of the in ASF disease is the of a The of attenuated is the to develop effective ASF development of attenuated by is a and a compared with the of attenuated of genes a of genes by have been to effective of attenuated to against the virus T. Zsak L. Lu Z. Kutish G.F. Neilan J.G. Rock D.L. African swine fever virus and in macrophages and virulence in Virol. PubMed Scopus Google Scholar, Zsak L. Neilan J.G. Lu Z. Rock D.L. The African swine fever virus is for replication in swine macrophages and for virulence in Virol. PubMed Google Scholar, V. 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C. of the deletion of African swine fever virus genes in the induction of of the highly 2019; Scopus Google the by the MGF-505-7R is important have that attenuated ASFV by is effective for vaccine In findings that the ASFV MGF-505-7R antagonizes the JAK-STAT1 axis by impairing IFN-γ-mediated activation of JAK1 and JAK2 and as a critical of the virulence of ASFV. study important for the mechanisms of immune evasion by large DNA Identification of MGF-505-7R as important of innate immune responses and critical of its virulence provide the of MGF-505-7R-deficient attenuated vaccines for ASFV. was by as previously A.L. J.F. Viñuela E. and of African swine fever virus in porcine alveolar Virol. PubMed Scopus Google and in with and porcine and in with and in a with The ASFV D. Liu Y. X. Y. Li Z. Liu Y. H. Liu Z. African swine fever virus attenuated virulence in PubMed Scopus Google as previously (17Garcia-Belmonte R. Perez-Nunez D. Pittau M. Richt Y. African swine fever virus Armenia/07 interferon the cGAS-STING Virol. 2019; PubMed Scopus Google Scholar). The type was in and the of the and IRF1 and expression for and previously J. Guo W. H. Q. H. Li S. mediates signaling pathway and host against S. A. 2017; PubMed Scopus Google Scholar). expression for and RNF125 by For of the DNA the MGF-505-7R of ASFV was by from the of ASFV and into and against a ASFV MGF-505-7R and JAK1 and JAK2 from RNF125 and from and from and from and from was from and the by In the was to that the of for of was to a and the of MGF-505-7R to was by with the indicated expression with the and the the and to the indicated in the of The with for with by the with for and with for and with for The with The with with for and with a system with for The with ASFV for The as with The sequences are as the is Hes5, in for The with ASFV for with for with for was from and to the for was with system to the with The sequences as porcine and porcine and porcine and porcine and porcine and and and and and and and porcine for the of ASFV DNA was as previously Dixon L.K. of a with for the of African swine fever virus.J. Virol. PubMed Scopus Google Scholar). ASFV DNA was with the the DNA the was for the The for of the ASFV genome was the the and from was from of available ASFV sequences for the of Analysis was the and the the and The of ASFV genome was the and as genome For the the with the the and in of and For of was with of the indicated and of protein the with of by and to The with indicated primary in with with and to was by For the with ASFV for the indicated The as its multiple was as a the was the and the The a that is of to ASFV nucleotide to by the to ASFV nucleotide the to by and a by a that is downstream of to ASFV nucleotide to and by by and into to and was with virus for the and the with the was with of DNA and of The was by and for of the was to the and for of The into of respectively. from the by and to of the wild-type ASFV. as and with ASFV, the was the DNA was isolated as from with ASFV. The DNA was to sequence the DNA as previously V. B. B. I. J. Rodriguez L. The of a of African swine fever virus to to a of virulence in swine to of the Virol. 2015; 89: PubMed Scopus Google Scholar). In the ASFV DNA was for the of and of sequence that to the DNA a the of the was and this DNA for the the analysis was the of and the in virus DNA was from the virus and by with the of and The and was by with the of and and with within the in the of the of by the of and and China for in with to the and of the of China, and the study was by the of of the The wild-type ASFV and MGF-505-7R-deficient by the as previously D. and by African swine fever virus in swine and J. Res. Google with in The samples to the and in was and by the of and H. of J. Scholar). was for its virulence to the ASFV virus to pigs with of ASFV samples from pigs that with of ASFV for DNA and the cytokines expression The and of pigs to the system K. Chapman D. J.M. E. of European domestic pigs from African of African swine fever virus by PubMed Scopus Google Scholar). was and for porcine and and as by the ASFV was The of samples was The was by the and by with a have been within the The that have no of with the of this for and Zhu for this was by from the and and of China and for of of D. J. and H. Z. D. L. and H. Z. D. L. and H. Z. D. L. and J. Z. D. J. and H. Z. D. J. and H. Z. and J. W. L. and J. W. L. and W. K.

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