Identification of the RNA Pseudoknot within the 3' End of the Porcine Reproductive and Respiratory Syndrome Virus Genome as a Pathogen-Associated Molecular Pattern To Activate Antiviral Signaling via RIG-I and Toll-Like Receptor 3.
Once infected by viruses, cells can detect pathogen-associated molecular patterns (PAMPs) on viral nucleic acid by host pattern recognition receptors (PRRs) to initiate the antiviral response. Porcine reproductive and respiratory syndrome virus (PRRSV) is the causative agent of porcine reproductive and respiratory syndrome (PRRS), characterized by reproductive failure in sows and respiratory diseases in pigs of different ages. To date, the sensing mechanism of PRRSV has not been elucidated. Here, we reported that the pseudoknot region residing in the 3' untranslated regions (UTR) of the PRRSV genome, which has been proposed to regulate RNA synthesis and virus replication, was sensed as nonself by retinoic acid-inducible gene I (RIG-I) and Toll-like receptor 3 (TLR3) and strongly induced type I interferons (IFNs) and interferon-stimulated genes (ISGs) in porcine alveolar macrophages (PAMs). The interaction between the two stem-loops inside the pseudoknot structure was sufficient for IFN induction, since disruption of the pseudoknot interaction powerfully dampened the IFN induction. Furthermore, transfection of the 3' UTR pseudoknot transcripts in PAMs inhibited PRRSV replication in vitro Importantly, the predicted similar structures of other arterivirus members, including equine arteritis virus (EAV), lactate dehydrogenase-elevating virus (LDV), and simian hemorrhagic fever virus (SHFV), also displayed strong IFN induction activities. Together, in this work we identified an innate recognition mechanism by which the PRRSV 3' UTR pseudoknot region served as PAMPs of arteriviruses and activated innate immune signaling to produce IFNs that inhibit virus replication. All of these results provide novel insights into innate immune recognition during virus infection.IMPORTANCE PRRS is the most common viral disease in the pork industry. It is caused by PRRSV, a positive single-stranded RNA virus, whose infection often leads to persistent infection. To date, it is not yet clear how PRRSV is recognized by the host and what is the exact mechanism of IFN induction. Here, we investigated the nature of PAMPs on PRRSV and the associated PRRs. We found that the 3' UTR pseudoknot region of PRRSV, which has been proposed to regulate viral RNA synthesis, could act as PAMPs recognized by RIG-I and TLR3 to induce type I IFN production to suppress PRRSV infection. This report is the first detailed description of pattern recognition for PRRSV, which is important in understanding the antiviral response of arteriviruses, especially PRRSV, and extends our knowledge on virus recognition.
['Xie|Sha|S|', 'Chen|Xin-Xin|XX|', 'Qiao|Songlin|S|', 'Li|Rui|R|', 'Sun|Yangang|Y|', 'Xia|Shuangfei|S|', 'Wang|Lin-Jian|LJ|', 'Luo|Xuegang|X|', 'Deng|Ruiguang|R|', 'Zhou|En-Min|EM|', 'Zhang|Gai-Ping|GP|']
D020413:3' Untranslated Regions D000818:Animals D002460:Cell Line D002522:Chlorocebus aethiops D000071457:DEAD Box Protein 58 D016679:Genome, Viral D000072640:Interferon-Induced Helicase, IFIH1 D016898:Interferon-alpha D016899:Interferon-beta D055029:Inverted Repeat Sequences D000069452:Pathogen-Associated Molecular Pattern Molecules D019318:Porcine Reproductive and Respiratory Syndrome D019316:Porcine respiratory and reproductive syndrome virus D059370:RNA Folding D034622:RNA Interference D034741:RNA, Small Interfering D034421:Sus scrofa D013552:Swine D013553:Swine Diseases D051196:Toll-Like Receptor 3 D051199:Toll-Like Receptor 7
pseudoknot PAMPs PRRs PRRSV IFN