What can pestiviral endonucleases teach us about innate immunotolerance?

Highlights

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  In this review, we describe the identification of the PRRs involved in the recognition of pestiviruses, and the mechanisms of these viruses to prevent the activation of host’s innate immune response with special emphasis on viral RNases.

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  Most importantly, we extend these data and present our model of innate immunotolerance requiring continuous prevention of detection of immunostimulatory self nucleic acids, in contrast to the well-known long-term tolerance of the adaptive immune system targeted predominantly against proteins.

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  This hypothesis is very likely relevant beyond the bovine species and might answer more fundamental questions on the discrimination between “self” and “viral nonself RNA”, which are relevant also for the prevention and treatment of chronic IFN induction and autoimmunity induced by “self-RNAs”.

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.