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Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) is a significant pathogen in the swine industry. MicroRNAs (miRNAs), a class of small non-coding RNA molecules, have risen to prominence as key regulators of gene expression at the post-transcriptional level. Their significance in regulating virus-host interactions is now widely acknowledged. So far, more than 30 miRNAs have been found to play a role in PRRSV infection. They can regulate viral genome stability and protein synthesis by targeting PRRSV RNA, and modulate the host immune response, thus affecting PRRSV replication. Understanding the role of miRNAs in PRRSV infection can further elucidate the pathogenesis of PRRSV and pave the way for the development of new antiviral strategies through miRNA-based therapies. This review will focus on how host miRNAs alter PRRSV infection, underscoring their multifaceted involvement in the interplay between virus and host., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Porcine respiratory and reproductive syndrome (PRRS) is one of the most devastating infectious diseases of pigs, causing reproductive failures in sows and severe respiratory symptoms in piglets and growing pigs. MicroRNAs (miRNAs) are reported to play an essential role in virus-host interactions. In this study, we demonstrated that miR-451 enhanced type I interferon (IFN-I) production through targeting proteasome subunit β8 (PSMB8), therefore restricting PRRS virus (PRRSV) replication. We showed that the expression of PSMB8 was upregulated by PRRSV infection, and knockdown of PSMB8 inhibited PRRSV replication by promoting IFN-I production. Moreover, we demonstrated that PSMB8 interacted with the regulatory domain of IRF3 to mediate K48-linked polyubiquitination and degradation of IRF3. Also, importantly, we showed that PSMB8, as a target gene of miR-451, negatively regulated IFN-I production by promoting IRF3 degradation, which is a previously unknown mechanism for PSMB8 to modulate innate immune responses., Importance: Porcine respiratory and reproductive syndrome virus (PRRSV), as a huge threat to the swine industry, is a causative agent that urgently needs to be solved. The dissecting of PRRSV pathogenesis and understanding of the host-pathogen interaction will provide insights into developing effective anti-PRRSV strategies. In this study, we showed that miR-451 dramatically inhibited PRRSV replication by targeting proteasome subunit β8 (PSMB8), a subunit of the immunoproteasome. Mutation of PSMB8 is often related to autoinflammatory diseases due to the elevated IFN production. We revealed that PSMB8 downregulated IFN production by promoting IRF3 degradation. In addition, we showed that PRRSV infection upregulated PSMB8 expression. Taken together, our findings reveal that miR-451 is a negative regulator of PRRSV replication, and PSMB8, a target gene of miR-451, negatively regulates IFN-I production by promoting IRF3 degradation, which is a previously unknown mechanism for PSMB8 to regulate innate immune responses., Competing Interests: The authors declare no conflict of interest.

Porcine reproductive and respiratory syndrome (PRRS) caused by PRRS virus (PRRSV) has been regarded as a persistent challenge for the swine farms worldwide. microRNAs (miRNAs) play key roles in regulating almost every important biological process, including virus-host interaction. In this study, we found that miR-204 was highly expressed in cells that were not permissive to PRRSV infection compared with cells susceptible to PRRSV infection. Subsequently, we demonstrated that overexpression of miR-204 significantly inhibited PRRSV replication in porcine alveolar macrophages (PAMs). Through bioinformatic analysis, we found that there existed a potential binding site of miR-204 on the 3'UTR of microtubule associated protein 1 light chain 3B (MAP1LC3B, LC3B), a hallmark of autophagy. Applying experiments including luciferase reporter assay and UV cross-linking and immunoprecipitation (CLIP) assay, we demonstrated that miR-204 directly targeted LC3B, thereby downregulating autophagy. Meanwhile, we investigated the interplay between autophagy and PRRSV replication in PAMs, confirming that PRRSV infection induces autophagy, which in turn facilitates viral replication. Overall, we verify that miR-204 suppresses PRRSV replication via inhibiting LC3B-mediated autophagy in PAMs. These findings will provide a novel potential approach for us to develop antiviral therapeutic agents and controlling measures for future PRRSV outbreaks., Competing Interests: Conflict of interest Prof. Wenhai Feng is an Editorial Board member for Virologica Sinica and was not involved in the editorial review or the decision to publish this article. The authors declare that they have no conflict of interest., (Copyright © 2023 The Authors. Publishing services by Elsevier B.V. All rights reserved.)

Porcine reproductive and respiratory syndrome (PRRS) caused by PRRS virus (PRRSV) has been recognized as one of the severest epidemics in pigs worldwide. microRNAs (miRNAs) play important roles in a variety of biological processes, including cell differentiation, proliferation and death, as well as viral infections and antiviral immune responses. In this study, we found that miR-142-3p was expressed lower in cells susceptible to PRRSV infection than in cells less or no permissive to PRRSV infection. Subsequently, we showed that overexpression of miR-142-3p remarkably inhibited PRRSV infection in PAMs, while blockage of endogenous miR-142-3p significantly enhanced PRRSV replication. Then, we demonstrated that miR-142-3p directly targeted Ras-related C3 botulinum toxin substrate 1 (Rac1), a member of Rho GTPases family, by using luciferase reporter assay and UV cross-linking and immunoprecipitation (CLIP) assay. Importantly, we verified that miR-142-3p inhibited PRRSV entry into PAMs and accordingly suppressed PRRSV infection by downregulating Rac1 expression. These findings reveal an important role of miR-142-3p in modulating PRRSV infection and provide us with some ideas for developing novel antiviral therapy against PRRSV infection., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Porcine reproductive and respiratory syndrome (PRRS) is one of the most important diseases in pigs. MicroRNAs (miRNAs) have emerged as an important regulator of virus-host cell interactions and miR-30c has been found to facilitate PRRSV replication. Here, we found that the interferon-alpha/beta receptor beta chain (IFNAR2) was down-regulated, while miR-30c was up-regulated during HV (a highly pathogenic type 2 PRRSV strain) and CH-1a (a classic type 2 PRRSV strain) infection. Subsequently, using bioinformatics analysis, we predicted that the IFNAR2 was targeted by miR-30c. A luciferase assay verified that the 3' UTR of IFNAR2 was targeted by miR-30c, as a mutation on either the target sequence or the miR-30c seed sequence reversed the luciferase activity. In addition, miR-30c and IFNAR2 mRNA were physically co-localized in RNA-induced silencing complex (RISC). Importantly, we showed that miR-30c also impaired the induction of IFN-stimulated genes (ISGs) by targeting IFNAR2. Our findings further reveal the mechanism of miR-30c promoting PRRSV replication.

Porcine reproductive and respiratory syndrome (PRRS) is one of the most important diseases in pigs, leading to significant economic losses in swine industry worldwide. PRRS virus (PRRSV) is an enveloped positive single-stranded RNA virus, which mainly infects cells of monocyte/macrophage lineage. MicroRNAs (miRNAs) are small non-coding RNAs and have emerged as important regulators of virus-host cell interactions. In the past several years, scientists have been trying to understand the interaction between host miRNAs and PRRSV infection. This review describes the mechanism of host miRNAs modulating the infection and replication of PRRSV, the approaches of delivering miRNAs into hosts, and the transcriptom of host cells during PRRSV infection. miRNAs including miR-181, miR-23, miR-30c, and miR-24-3p are reported to play important roles in PRRSV infection and replication, and in modulating host antiviral responses, while others, for example miR-204, miR-221, miR-219, need more explorations. Importantly, combining with the reverse genetic technique and current miRNAs delivery approaches such as pcDNA, recombinant lentivirus, and exosomes, we propose that miRNAs contribute to and could be used as one of potent factors in controlling PRRSV infection., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Porcine reproductive and respiratory syndrome virus (PRRSV) is an economically important pathogen and has evolved several mechanisms to evade IFN-I responses. We report that a host microRNA, miR-30c, was upregulated by PRRSV via activating NF-κB and facilitated its ability to infect subject animals. Subsequently, we demonstrated that miR-30c was a potent negative regulator of IFN-I signaling by targeting JAK1, resulting in the enhancement of PRRSV infection. In addition, we found that JAK1 expression was significantly decreased by PRRSV and recovered when miR-30c inhibitor was overexpressed. Importantly, miR-30c was also upregulated by PRRSV infection in vivo, and miR-30c expression corresponded well with viral loads in lungs and porcine alveolar macrophages of PRRSV-infected pigs. Our findings identify a new strategy taken by PRRSV to escape IFN-I-mediated antiviral immune responses by engaging miR-30c and, thus, improve our understanding of its pathogenesis., (Copyright © 2016 by The American Association of Immunologists, Inc.)

MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression post-transcriptionally and play critical roles in intricate networks of host-pathogen interactions and innate immunity. Porcine reproductive and respiratory syndrome (PRRS) is one of the most important diseases affecting swine industry worldwide. Here, we demonstrated that miR-23, miR-378, and miR-505 were antiviral host factors against PRRS virus (PRRSV). Over-expression of the three miRNAs inhibited PRRSV infection in a dose-dependent manner, respectively. Blockage of the three endogenously expressed miRNAs significantly enhanced PRRSV replication. Different type 2 PRRSV strains harbored conserved miR-23, miR-378, and miR-505 target sites (TSs) that were sufficient to confer miRNA-mediated repression of PRRSV replication. Interestingly, miR-23 was capable of inducing type I interferon expression during PRRSV infection through IRF3/IRF7 activation, which might further lead to the inhibition of virus infection. These results suggest that miR-23, miR-378, and miR-505, especially miR-23, may have the potential to be used as antiviral therapy against PRRSV infection., (Copyright © 2013 Elsevier Inc. All rights reserved.)

We previously showed that microRNA 181 (miR-181) can inhibit PRRSV replication by directly targeting its genomic RNA. Here, we report that miR-181 can downregulate the PRRSV receptor CD163 in blood monocytes and porcine alveolar macrophages (PAMs) through targeting the 3' untranslated region (UTR) of CD163 mRNA. Downregulation of CD163 leads to the inhibition of PRRSV entry into PAMs and subsequently suppresses PRRSV infection. Our findings indicate that delivery of miR-181 can be used as antiviral therapy against PRRSV infection.

Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most important viral pathogens in the swine industry. Emerging evidence indicates that the host microRNAs (miRNAs) are involved in host-pathogen interactions. However, whether host miRNAs can target PRRSV and be used to inhibit PRRSV infection has not been reported. Recently, microRNA 181 (miR-181) has been identified as a positive regulator of immune response, and here we report that miR-181 can directly impair PRRSV infection. Our results showed that delivered miR-181 mimics can strongly inhibit PRRSV replication in vitro through specifically binding to a highly (over 96%) conserved region in the downstream of open reading frame 4 (ORF4) of the viral genomic RNA. The inhibition of PRRSV replication was specific and dose dependent. In PRRSV-infected Marc-145 cells, the viral mRNAs could compete with miR-181-targeted sequence in luciferase vector to interact with miR-181 and result in less inhibition of luciferase activity, further demonstrating the specific interactions between miR-181 and PRRSV RNAs. As expected, miR-181 and other potential PRRSV-targeting miRNAs (such as miR-206) are expressed much more abundantly in minimally permissive cells or tissues than in highly permissive cells or tissues. Importantly, highly pathogenic PRRSV (HP-PRRSV) strain-infected pigs treated with miR-181 mimics showed substantially decreased viral loads in blood and relief from PRRSV-induced fever compared to negative-control (NC)-treated controls. These results indicate the important role of host miRNAs in modulating PRRSV infection and viral pathogenesis and also support the idea that host miRNAs could be useful for RNA interference (RNAi)-mediated antiviral therapeutic strategies.