pK205R targets the proximal element of IFN-I signaling pathway to assist African swine fever virus to escape host innate immunity at the early stage of infection

Abstract

African swine fever virus (ASFV) is a nuclear cytoplasmic large DNA virus (NCLDV) that causes devastating hemorrhagic diseases in domestic pigs and wild boars, seriously threatening the development of the global pig industry. IFN-I plays an important role in the body’s antiviral response. Similar to other DNA viruses, ASFV has evolved a variety of immune escape strategies to antagonize IFN-I signaling and maintain its proliferation. In this study, we showed that the ASFV early protein pK205R strongly inhibited interferon-stimulated genes (ISGs) as well as the promoter activity of IFN-stimulated regulatory elements (ISREs). Mechanistically, pK205R interacted with the intracellular domains of IFNAR1 and IFNAR2, thereby inhibiting the interaction of IFNAR1/2 with JAK1 and TYK2 and hindering the phosphorylation and nuclear translocation of STATs. Subsequently, we generated a recombinant strain of the ASFV-pK205R point mutation, ASFV-pK205R ^7PM. Notably, we detected higher levels of ISGs in porcine alveolar macrophages (PAMs) than in the parental strain during the early stages of ASFV-pK205R ^7PM infection. Moreover, ASFV-pK205R ^7PM attenuated the inhibitory effect on IFN-I signaling. In conclusion, we identified a new ASFV immunosuppressive protein that increases our understanding of ASFV immune escape mechanisms.

Author summary

African Swine fever virus (ASFV) causes a deadly swine disease that originated in Africa and has since spread to Europe, Asia, and Oceania, severely impacting the global pig industry. Although ASFV protein functions have been extensively studied, many remain unknown. pK205R is abundantly expressed during the early stages of ASFV infection and participates in viral replication during the late stages of infection. Our research reveals how pK205R inhibits IFN-I signaling by interacting with IFNAR1 and IFNAR2, blocking downstream signaling. These results improve our understanding of the immune escape process of ASFV, which may have implications for future vaccine development.