Zürcher Christoph, Sauter Kay-Sara, Schweizer Matthias
Institute of Veterinary Virology (current name: Institute of Virology and Immunology), Vetsuisse Faculty University of Bern, Laenggass-Str. 122, CH-3001 Bern, Switzerland; Graduate School for Cellular and Biomedical Sciences, University of Bern, Switzerland.
Institute of Veterinary Virology (current name: Institute of Virology and Immunology), Vetsuisse Faculty University of Bern, Laenggass-Str. 122, CH-3001 Bern, Switzerland.
Vet Microbiol. 2014 Dec 5;174(3-4):399-408. doi: 10.1016/j.vetmic.2014.09.028. Epub 2014 Oct 13.
The ribonuclease activity of the soluble glycoprotein E(rns) of pestiviruses represents a unique mechanism to circumvent the host's innate immune system by blocking interferon type-I synthesis in response to extracellularly added single- (ss) and double-stranded (ds) RNA. However, the reason why pestiviruses encode a ribonuclease in addition to the abundant serum RNases remained elusive. Here, we show that the 5' UTR and NS5B regions of various strains of the RNA genome of the pestivirus bovine viral diarrhea virus (BVDV) are resistant to serum RNases and are potent TLR-3 agonists. Inhibitory activity of E(rns) was restricted to cleavable RNA products, and did not extend to the synthetic TLR-7/8 agonist R-848. RNA complexed with the antimicrobial peptide LL37 was protected from degradation by E(rns)in vitro but was fully inhibited by E(rns) in its ability to induce IFN in cell cultures, suggesting that the viral protein is mainly active in cleaving RNA in an intracellular compartment. We propose that secreted E(rns) represents a potent IFN antagonist, which degrades viral RNA that is resistant to the ubiquitous host RNases in the extracellular space. Thus, the viral RNase prevents its own pathogen-associated molecular pattern (PAMP) to inadvertently activate the IFN response that might break innate immunotolerance required for persistent pestivirus infections.
瘟病毒可溶性糖蛋白E（rns）的核糖核酸酶活性代表了一种独特的机制，可通过阻断对细胞外添加的单链（ss）和双链（ds）RNA作出反应的I型干扰素合成来规避宿主的先天免疫系统。然而，瘟病毒除了具有丰富的血清核糖核酸酶外还编码一种核糖核酸酶的原因仍然不明。在此，我们表明瘟病毒牛病毒性腹泻病毒（BVDV）RNA基因组各毒株的5'非翻译区（UTR）和NS5B区域对血清核糖核酸酶具有抗性，并且是有效的Toll样受体3（TLR-3）激动剂。E（rns）的抑制活性仅限于可切割的RNA产物，并不延伸至合成的TLR-7/8激动剂R-848。与抗菌肽LL37复合的RNA在体外受到E（rns）的保护而不被降解，但在细胞培养物中其诱导干扰素的能力被E（rns）完全抑制，这表明该病毒蛋白主要在细胞内区室中切割RNA时具有活性。我们提出，分泌的E（rns）代表一种有效的干扰素拮抗剂，它可降解细胞外空间中对普遍存在的宿主核糖核酸酶具有抗性的病毒RNA。因此，病毒核糖核酸酶可防止其自身的病原体相关分子模式（PAMP）意外激活可能破坏瘟病毒持续感染所需的先天免疫耐受的干扰素反应。
