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African swine fever virus Armenia/07 virulent strain controls IFN-β production through cGAS-STING pathway.

Journal of Virology 2019 March 28
African swine fever virus (ASFV) is a complex, cytoplasmic dsDNA virus, currently expanding throughout the world. Currently circulating virulent genotype II Armenia/07-like viruses causes fatal disease in pigs and wild boar, whereas attenuated strains induce infections with varying levels of chronic illness.Sensing cytosolic dsDNA, mainly by the key DNA sensor cGAS, leads to the synthesis of type I interferon, and involves signaling through STING, TBK1 and IRF3. After phosphorylation, STING translocates from the ER to the Golgi and to the perinuclear region, therefore being an indispensable adaptor connecting the cytosolic detection of DNA to theTBK1-IRF3 signaling pathway.We demonstrate that attenuated NH/P68, but not virulent Armenia/07, activates the cGAS-STING-IRF3 cascade very early during infection, inducing STING phosphorylation and trafficking through a mechanism involving cGAMP. Both TBK1 and IRF3 are subsequently activated, and in response to this, high level of IFN-β production was produced during NH/P68 infection; in contrast, Armenia/07 infection generated IFN-β levels below those of uninfected cells. Our results show that virulent Armenia/07 ASFV controls the cGAS-STING pathway, but these mechanisms are not at play when porcine macrophages are infected with the attenuated NH/P68 ASFV.These findings show for the first time the involvement of the cGAS-STING-IRF3 route in ASFV infection, where IFN-β production or inhibition was found after infection by attenuated or virulent ASFV strains, respectively, thus reinforcing the idea that ASFV virulence vs. attenuation may be a phenomenon grounded in ASFV-mediated innate immune modulation where the cGAS-STING pathway might play an important role. IMPORTANCE African swine fever, a devastating disease for domestic pigs and wild boar is currently spreading in Europe, Russia and China, becoming a global threat with huge economic and ecological consequences. One interesting aspect of ASFV biology is the molecular mechanism leading to high virulence of some strains compared to more attenuated strains, which produce subclinical infections. In this work, we show that the presently circulating virulent Armenia/07 virus blocks the synthesis of IFN-β, a key mediator between the innate and adaptive immune response. Armenia/07 inhibits the cGAS-STING pathway by impairing STING activation during infection. In contrast, the cGAS-STING pathway is efficiently activated during NH/P68 attenuated strain infection, leading to the production of high amounts of IFN-β. Our results show for the first time the relationship between the cGAS-STING pathway and ASFV virulence, contributing to uncover the molecular mechanisms of ASFV virulence and to the rational development of ASFV vaccines.

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