Abstract
Porcine reproductive and respiratory syndrome virus (PRRSV) is an economically significant agent for which there currently are no effective treatments. Development of antiviral agents for PRRSV as well as many other viruses has been limited by toxicity of known antiviral compounds. In contrast, antibiotics for non-virus microbial infections have been widely useful, in part because of their acceptable toxicity in animals. We report here the discovery that the quinolone-containing compound Plasmocin™, as well as the quinolones nalidixic acid and ciprofloxacin, have potent anti-PRRSV activity in vitro. PRRSV replication was inhibited by these antibiotics in both cultured MARC-145 cells and cultured primary alveolar porcine macrophages (PAMs). Furthermore, sub-optimal concentrations of nalidixic acid synergized with antiviral cytokines (AK-2 or IFN-γ) to quantitatively and qualitatively inhibit PRRSV replication in MARC-145 cells or PAMs. The antiviral activity of Plasmocin and nalidixic acid correlated with reduced actin expression in MARC-145 cells. Replication of the related lactate dehydrogenase-elevating virus (LDV) was also inhibited in primary mouse macrophages by Plasmocin. These results are significant to the development of antiviral strategies with potentially reduced toxicity, and provide a model system to better understand regulation of arterivirus replication.
Highlights
Antimicrobial agents used to treat bacterial or fungal infections generally interfere with specific processes that are essential for microbe growth and/or division, for example cell wall synthesis, cytoplasmic membrane function, nucleic acid synthesis, or ribosome function (Neu and Gootz, 1996)
The first indication that some antibiotics were capable of inhibiting porcine reproductive and respiratory syndrome virus (PRRSV) replication emerged from studies with Plasmocin, a proprietary agent consisting of quinolone and macrolide antibiotics which has potent anti-mycoplasma activity
PRRSV replication in MARC-145 cells was inhibited by the quinolones nalidixic acid and ciprofloxacin (Table 1B and C)
Summary
Antimicrobial agents used to treat bacterial or fungal infections generally interfere with specific processes that are essential for microbe growth and/or division, for example cell wall synthesis, cytoplasmic membrane function, nucleic acid synthesis, or ribosome function (Neu and Gootz, 1996). Antiviral chemotherapy may target the cells supporting virus replication as well as events specific to the virus, with potentially toxic side effects (De Clerq, 1996). Previous studies have demonstrated that in some cases, antibiotics may have antiviral effects (SubakSharpe et al.1969; Macintyre et al 1991), most likely due to inhibition of host cell functions required for viral replication. Several antibiotics were screened for effects on porcine reproductive and respiratory syndrome virus (PRRSV) in vitro. The virus induces several cytokines including interferon-gamma (IFN-γ), which inhibits PRRSV replication in vitro (Aasted et al 2002; Cafruny et al 2006; Johnsen et al 2002; Rowland et al 2001). The IFN-γ response in pigs may be delayed or inhibited by unknown factors, and a poorly-neutralizing Th2
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