New Tool for PRRSV Control: A High-Throughput Screening and Preclinical Study of Antiviral Drugs

Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) is a significant pathogen that threatens the swine industry. Through high-throughput screening (HTS), we have identified Nitazoxanide (NTZ) as an effective compound for inhibiting PRRSV replication.
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 Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) has inflicted significant losses on the global swine industry[1], with current control strategies primarily dependent on vaccination. Our objective was to identify an alternative method to mitigate PRRSV outbreaks beyond the scope of vaccination. Nonetheless, reversing the current trend of PRRSV epidemics necessitates the development of highly effective antiviral drugs. Developing novel antiviral agents from the ground up is a time-consuming endeavor, particularly given the multitude of animal viruses. Additionally, the mechanisms of action (MOA) for each distinct pathogen remain incompletely understood. Substantial efforts by veterinary virologists are still needed to elucidate the MOA of PRRSV and its interactions with the host.

 

In this study, we opted against the commonly employed target-based screening strategy in antiviral drug development, choosing instead a phenotypic screening approach. By screening over 3,000 compounds in vitro, we identified 16 potential inhibitors of PRRSV. Nitazoxanide (NTZ) was validated as an effective inhibitor of PRRSV replication in both in vitro and in vivo experiments, suggesting its potential as a valuable tool in combating PRRSV epidemics. However, we believe the promising antiviral effects of NTZ are currently confined to the laboratory, necessitating further clinical data to ascertain its specific effects in clinical settings. Additionally, time is needed to investigate potential resistance issues associated with NTZ. Without addressing these concerns, we caution against the premature clinical application of NTZ. Moreover, our study demonstrated that Ribavirin (RBV) is ineffective in inhibiting PRRSV replication, underscoring the need to prevent its misuse in clinical practice.

 

Although we have shown that NTZ can inhibit PRRSV viremia, the MOA of PRRSV-induced viremia remains unclear[2]. Viremia is a crucial indicator of infectious disease severity, but PRRSV-induced viremia is transient, occurring only in the early stages of infection or during severe infection [3]. In most cases, PRRSV resides latently in the lymph nodes[4]. While NTZ was found to impede PRRSV transmission among animals, it does not ensure that all cohabiting animals will remain uninfected. We hypothesize that the 25 mg/kg dose may not be optimal for clinical use.

 

Identifying and confirming the primary targets through which NTZ exerts its antiviral effects presents a significant challenge, given that small molecule compounds often have multiple targets. In this study, we identified 26 potential NTZ targets in the host using isothermal shift assay (ITSA). Validation suggested that PRRSV NSP1α, NSP12, and host proteins GATM and NMRAL1 could be potential targets of NTZ. Previous research has indicated that one of the key factors behind NTZ's broad-spectrum antiviral activity is its enhancement of the host's type I interferon pathway[5]. We discovered that NTZ's primary metabolite, tizoxanide (TIZ), increases the stability of the NMRAL1 dimer conformation. We hypothesize that NTZ may enhance the host's type I interferon pathway by stabilizing NMRAL1 dimers, thereby reducing the presence of NMRAL1 monomers in cells and exerting its antiviral effects.

 

In conclusion, our study identified NTZ as an effective compound for inhibiting PRRSV replication, potentially serving as a crucial research tool and theoretical basis for future efforts to control PRRSV outbreaks.

 

For further information, please contact the first author or corresponding author at tata989837@gmail.com and luzengjun@caas.cn.

Reference

 

  1. Montaner-Tarbes S, del Portillo HA, Montoya M, Fraile L. Key Gaps in the Knowledge of the Porcine Respiratory Reproductive Syndrome Virus (PRRSV). Frontiers in Veterinary Science. 2019;6.
  2. Go N, Touzeau S, Islam Z, Belloc C, Doeschl-Wilson A. How to prevent viremia rebound? Evidence from a PRRSv data-supported model of immune response. BMC Syst Biol. 2019;13:15.
  3. Lunney JK, Fang Y, Ladinig A, Chen N, Li Y, Rowland B, et al. Porcine reproductive and respiratory syndrome virus reverse genetics and the major applications. Annual Review of Animal Biosciences. 2016;4:129–54.
  4. Bassaganya-Riera J, Thacker BJ, Yu S, Strait E, Wannemuehler MJ, Thacker EL. Impact of immunizations with Porcine Reproductive and Respiratory Syndrome Virus on lymphoproliferative recall responses of CD8+ T Cells. Viral Immunology. 2004;17:25–37.
  5. Jasenosky LD, Cadena C, Mire CE, Borisevich V, Haridas V, Ranjbar S, et al. The FDA-approved oral drug nitazoxanide amplifies host antiviral responses and Inhibits ebola virus. iScience. 2019;19:1279–90.

 

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Veterinary Science
Life Sciences > Biological Sciences > Veterinary Science
Veterinary Microbiology
Life Sciences > Biological Sciences > Veterinary Science > Veterinary Microbiology
Antivirals
Life Sciences > Biological Sciences > Microbiology > Virology > Antivirals

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