What can pestiviral endonucleases teach us about innate immunotolerance?

Abstract

Pestiviruses including bovine viral diarrhea virus (BVDV), border disease virus (BDV) and classical swine fever virus (CSFV), occur worldwide and are important pathogens of livestock. A large part of their success can be attributed to the induction of central immunotolerance including B- and T-cells upon fetal infection leading to the generation of persistently infected (PI) animals. In the past few years, it became evident that evasion of innate immunity is a central element to induce and maintain persistent infection. Hence, the viral non-structural protease N(pro) heads the transcription factor IRF-3 for proteasomal degradation, whereas an extracellularly secreted, soluble form of the envelope glycoprotein E(rns) degrades immunostimulatory viral single- and double-stranded RNA, which makes this RNase unique among viral endoribonucleases. We propose that these pestiviral interferon (IFN) antagonists maintain a state of innate immunotolerance mainly pertaining its viral nucleic acids, in contrast to the well-established immunotolerance of the adaptive immune system, which is mainly targeted at proteins. In particular, the unique extension of 'self' to include the viral genome by degrading immunostimulatory viral RNA by E(rns) is reminiscent of various host nucleases that are important to prevent inappropriate IFN activation by the host's own nucleic acids in autoimmune diseases such as Aicardi-Goutières syndrome or systemic lupus erythematosus. This mechanism of "innate tolerance" might thus provide a new facet to the role of extracellular RNases in the sustained prevention of the body's own immunostimulatory RNA to act as a danger-associated molecular pattern that is relevant across various species.

Homodimerisation-independent cleavage of dsRNA by a pestiviral nicking endoribonuclease

“…In addition to its location on the surface of virus particles, the viral glycoprotein E rns is secreted from infected cells and inhibits IFN expression induced by ss- and dsRNA by virtue of its RNase activity. Therefore, we proposed that E rns acts as an enzymatically active decoy receptor that degrades any extracellular pestiviral RNA that might act as a PAMP to prevent it from being recognized by PRRs activating the innate immune response (for reviews, see refs 2 , 5 , 17 , 18 ).…”

“…Cap-independent translation is started by an internal ribosomal entry site (IRES), and the polyprotein is then further processed by cellular and viral proteases into four structural and at least eight non-structural viral proteins 15 – 17 . The N-terminal autoprotease N pro and the structural protein E rns are exclusively present in viruses of the pestivirus genus within the flaviviridae family, and both were implicated to be involved in the evasion of the host’s type-I IFN defense 2 , 17 , 18 . N pro activates the proteasomal degradation of the interferon regulatory factor (IRF)-3 19 – 22 , and possibly also IRF-7 23 , thus preventing the transcriptional activation of the IFN genes.…”

Abrogation of the RNase activity of Erns in a low virulence classical swine fever virus enhances the humoral immune response and reduces virulence, transmissibility, and persistence in pigs

“…Nevertheless, the in vivo implications of these mechanisms has not been demonstrated yet. In the case of bovine viral diarrhea virus (BVDV), another important member of the Pestivirus genus, this function may help to establish and maintain persistent infections in cattle [ 10 , 15 ]. Previous studies showed that abrogation of the E rns RNase activity in virulent pestiviruses including CSFV may reduce replication and clinical signs in vivo [ 8 , 9 ].…”

Positively Charged Amino Acids in the Pestiviral Erns Control Cell Entry, Endoribonuclease Activity and Innate Immune Evasion

“…Our previous results indicated that E rns is required to enter the cells by endocytosis to block the activation of the host’s IFN response [ 23 , 27 , 28 ]. To provide further evidence for intracellular localization of E rns , we analyzed its uptake by immunofluorescence microscopy.…”