Fifty Shades of Erns: Innate Immune Evasion by the Viral Endonucleases of All Pestivirus Species

Abstract

The genus Pestivirus, family Flaviviridae, includes four historically accepted species, i.e., bovine viral diarrhea virus (BVDV)-1 and -2, classical swine fever virus (CSFV), and border disease virus (BDV). A large number of new pestivirus species were identified in recent years. A common feature of most members is the presence of two unique proteins, Npro and Erns, that pestiviruses evolved to regulate the host’s innate immune response. In addition to its function as a structural envelope glycoprotein, Erns is also released in the extracellular space, where it is endocytosed by neighboring cells. As an endoribonuclease, Erns is able to cleave viral ss- and dsRNAs, thus preventing the stimulation of the host’s interferon (IFN) response. Here, we characterize the basic features of soluble Erns of a large variety of classified and unassigned pestiviruses that have not yet been described. Its ability to form homodimers, its RNase activity, and the ability to inhibit dsRNA-induced IFN synthesis were investigated. Overall, we found large differences between the various Erns proteins that cannot be predicted solely based on their primary amino acid sequences, and that might be the consequence of different virus-host co-evolution histories. This provides valuable information to delineate the structure-function relationship of pestiviral endoribonucleases.

Congenital tremor and splay leg in Swedish piglets : a study of the viral causes and routes of transmission

“…Further, the absence of cytokines in the APPV-infected brain tissue supports the proposed regulatory effect of the STING pathway to protect the brain from damage from high levels of type-I IFNs (Reinert et al 2021). However, the low occurrence of cytokines in the APPV-infected brain may also be attributed to the suggested immunoregulatory potential of APPV (Mou et al 2021;de Martin & Schweizer 2022). The immunoregulatory effect as interferon antagonists of the N pro and E rns proteins encoded in the APPV genome is well described for other pestiviruses (Tautz et al 2015).…”

“…;) and has been detected in Sweden, CT type A-II and its' causative agent are easier to address. Since APPV has an immunoregulatory effect on the host(Mou et al 2021;de Martin & Schweizer 2022;Stenberg et al 2022), can induce persistent infections, and may circulate on a farm for ages once introduced (Folgueiras-González et al 2020a), control of the virus should be urgent for the porcine industry.…”

Pestiviruses infection: Interferon-virus mutual regulation

“…The envelope protein E rns could interact with receptors on the cell surface and via energy-dependent clathrin-mediated endocytosis internalized into the cell to participate in the regulation of IFN-I (Zurcher et al, 2014a). Soluble BVDV E rns could curb IFN-I induced by ssRNA and extracellular (rather than intracellular) dsRNA with its RNase activity (Magkouras et al, 2008;Matzener et al, 2009;Zurcher et al, 2014a;de Martin & Schweizer, 2022). The RNase activity of BVDV E rns was essential for blocking IFN-I, and the C-terminus of BVDV E rns also played a vital role in suppressing the IFN-I (Zurcher et al, 2014a).…”

Immune evasion strategies of bovine viral diarrhea virus

“…For successful infection, most pestiviruses have evolved two proteins, the non-structural protein N pro and the envelope glycoprotein E rns to prevent the activation of innate immunity ( De Martin and Schweizer, 2022 ). E rns has been reported to inhibit dsRNA-mediated signaling pathways, depending on its dsRNA binding properties and RNase activity ( Iqbal et al., 2004 ).…”