Antiviral Activity Of A Selective Cox-2 Inhibitor Ns-398 On Avian Influenza H5n1 Infection
INFLUENZA AND OTHER RESPIRATORY VIRUSES(2011)
摘要
Background Highly pathogenic H5N1 virus continues to pose a serious threat to human health and appears to have the capacity to cause severe disease in previously healthy young children and adults. At present, antiviral therapy by oseltamivir remains the mainstay for managing H5N1 patients. While early treatment improves survival, approximately 50% of patients treated within 4 days of illness still succumb to the disease. In addition to the role of viral replication, there is good evidence that the host pro-inflammatory responses contributes to H5N1 pathogenesis. This suggests that both antiviral and immune-modulatory drugs may have a role in therapy. We previously demonstrated that cyclooxygenase 2 (COX-2) plays a regulatory role in H5N1 hyperinduced pro-inflammatory responses, and its inhibitor has potent effects at modulating this host response. Now we demonstrate that, in addition to its immune-modulatory effect, a selective COX-2 inhibitor, NS-398 has a direct antiviral effect against H5N1 infection.Materials and methods Human primary monocyte-derived macrophages or alveolar epithelial cells (A549) were pre-treated with NS-398 or drug-vehicle for 1 hour before H5N1 virus infection. H5N1 viruses at multipicity of infection (MOI) of 2 was used to infect the cells. Following virus adsorption for 30 mins, the virus inoculum was removed, and the cells were washed and incubated in corresponding medium with NS-398 or drug-vehicle as controls for 3, 6, 24, 48, and 72 hours post-infection. Cells were harvested for RNA isolation at 6 hours post-infection to study viral matrix (M) gene expression. Supernatants were collected for 50% tissue culture infection dose (TCID50) assay to determine the virus titers at 3, 24, 48, and 72 hours after H5N1 infection.Results NS-398 was found to suppress virus gene transcription and infectious virus yield in H5N1-infected human cells.Conclusion We demonstrate that a selective COX-2 inhibitor, NS-398, shows an inhibitory effect on H5N1 viral replication in addition to its immune-modulatory effect that could counter the detrimental effects of excessive pro-inflammatory cytokine production. The findings suggest that selective COX-2 inhibitors may be a therapeutic target for treating H5N1 disease in combination with appropriate antiviral therapy.
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关键词
Antiviral, H5N1, NS-398, selective COX-2 inhibitor
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