Pestiviral E rns blocks TLR-3-dependent IFN synthesis by LL37 complexed RNA

Zürcher, Christoph Martin; Sauter, Kay Sara; Schweizer, Matthias

doi:10.1016/j.vetmic.2014.09.028

Cited by 16 publications

(18 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These slower migrating fragments were also visible upon digestion of ssRNA when overexposing the images. In order to confirm these data, we reassessed the experiment using subgenomic BVD viral dsRNA of 200–300 bp in length as was used in previous experiments 28 , 47 . In addition to Strep-tag purified E rns of the strain Ncp7 (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 97%

“…Nevertheless, the degradation of ssRNA substrates was clearly more efficient than that of dsRNA, as higher concentrations of the viral RNase were required to degrade double-stranded polynucleotides to a similar degree. Thus, it might be envisaged that cleavage of dsRNA prevents activation of TLR-3 47 whereas the high efficiency of ssRNA degradation to very small fragments impedes activation of TLR-7/8 by guanosine and uridine combined with short ssRNA, respectively 69 .…”

Section: Discussionmentioning

confidence: 99%

“…DsRNA or hybrids were obtained by incubating together the single strands at 95 °C for 5 min followed by slowly cooling down to ambient temperature. Long viral dsRNA of the 3′- or 5′-region of BVDV was prepared as described 47 , whereas all short oligonucleotides were synthetized and labeled by Microsynth (Balgach, Switzerland). Sequences of all short substrates and their 5′- and 3′-modification by either Dyomics 681 (red) or 781 (green) that were used in the RNase activity assays are shown in Table 1 .…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Homodimerisation-independent cleavage of dsRNA by a pestiviral nicking endoribonuclease

Lussi¹,

Sauter

Schweizer

2018

Sci Rep

Self Cite

View full text Add to dashboard Cite

The glycoprotein Erns plays a central role in the biology of the pestivirus bovine viral diarrhea virus (BVDV). This soluble endonuclease mediates the escape from an interferon (IFN) response in the infected fetus, thereby permitting the establishment of persistent infection. Viral single-stranded (ss) and double-stranded (ds) RNA act as potent IFN inducing signals and we previously showed that Erns efficiently cleaves these substrates, thereby inhibiting an IFN response that is crucial for successful fetal infection. Considering that a large variety of RNases and DNases require dimerisation to cleave double-stranded substrates, the activity of Erns against dsRNA was postulated to depend on homodimer formation mediated by disulfide bonds involving residue Cys171. Here, we show that monomeric Erns is equally able to cleave dsRNA and to inhibit dsRNA-induced IFN synthesis as the wild-type form. Furthermore, both forms were able to degrade RNA within a DNA/RNA- as well as within a methylated RNA/RNA-hybrid, with the DNA and the methylated RNA strand being resistant to degradation. These results support our model that Erns acts as ‘nicking endoribonuclease’ degrading ssRNA within double-stranded substrates. This efficiently prevents the activation of IFN and helps to maintain a state of innate immunotolerance in persistently infected animals.

show abstract

Section: Resultsmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Homodimerisation-independent cleavage of dsRNA by a pestiviral nicking endoribonuclease

Lussi¹,

Sauter

Schweizer

2018

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

“…This is confirmed by the fact that in vitro transcribed ssRNA of the BVD viral genome possess highly structured regions resistant to serum RNases and to RNase A (preferentially ssRNases) that are able to induce activation of TLR-3 [20,48]. The 5 0 -und 3 0 -UTRs and long-range interactions between these two regions might be especially immunostimulatory [49,50], but most regions within the BVD viral genome seem to possess high-ordered structures able to induce TLR activation [48].…”

Section: Ifn Induction By Pestivirusesmentioning

confidence: 86%

What can pestiviral endonucleases teach us about innate immunotolerance?

Lussi

Schweizer

2016

Cytokine & Growth Factor Reviews

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…Guanylate-binding protein 4 (GBP4), an IFN-inducible GTPase, can also inhibit this pathway while leaving NF-jB signaling intact [19]. In addition, the secreted BVDV structural protein E rns degrades viral RNA through its extracellular function as a ribonuclease [20].…”

Section: Bovine Viral Diarrhea Virusmentioning

confidence: 99%

Importance of Viral Disease in Dairy Cow Fertility

et al. 2020

View full text Add to dashboard Cite

a b s t r a c tMany viral diseases are endemic in cattle populations worldwide. The ability of many viruses to cross the placenta and cause abortions and fetal malformations is well understood. There is also significant evidence that viral infections have additional actions in dairy cows, which are reflected in reduced conception rates. These effects are, however, highly dependent on the time at which an individual animal first contracts the disease and are less easy to quantify. This paper reviews the evidence relating to five viruses that can affect fertility, together with their potential mechanisms of action. Acute infection with non-cytopathic bovine viral diarrhea virus (BVDV) in mid-gestation increases abortion rates or causes the birth of persistently infected calves. BVDV infections closer to the time of breeding can have direct effects on the ovaries and uterine endometrium, which cause estrous cycle irregularities and early embryo mortality. Fertility may also be reduced by BVDV-induced immunosuppression, which increases the susceptibility to bacterial infections. Bovine herpesvirus (BHV)-1 is most common in pre-pubertal heifers, and can slow their growth, delay breeding, and increase the age at first calving. Previously infected animals subsequently show reduced fertility. Although this may be associated with lung damage, ovarian lesions have also been reported. Both BHV-1 and BHV-4 remain latent in the host following initial infection and may be reactivated later by stress, for example associated with calving and early lactation. While BHV-4 infection alone may not reduce fertility, it appears to act as a co-factor with established bacterial pathogens such as Escherichia coli and Trueperella pyogenes to promote the development of endometritis and delay uterine repair mechanisms after calving. Both Schmallenberg virus (SBV) and bluetongue virus (BTV) are transmitted by insect vectors and lead to increased abortion rates and congenital malformations. BTV-8 also impairs the development of hatched blastocysts; furthermore, infection around the time of breeding with either virus appears to reduce conception rates. Although the reductions in conception rates are often difficult to quantify, they are nevertheless sufficient to cause economic losses, which help to justify the benefits of vaccination and eradication schemes.

show abstract

Pestiviral E rns blocks TLR-3-dependent IFN synthesis by LL37 complexed RNA

Cited by 16 publications

References 56 publications

Homodimerisation-independent cleavage of dsRNA by a pestiviral nicking endoribonuclease

Homodimerisation-independent cleavage of dsRNA by a pestiviral nicking endoribonuclease

What can pestiviral endonucleases teach us about innate immunotolerance?

Importance of Viral Disease in Dairy Cow Fertility

Contact Info

Product

Resources

About