Inhibition of cyclooxygenase activity blocks cell-to-cell spread of human cytomegalovirus

Department of Molecular Biology, Princeton University, Princeton, NJ 08540, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 12/2008; 105(49):19468-73. DOI: 10.1073/pnas.0810740105
Source: PubMed


Human cytomegalovirus has previously been shown to induce the accumulation of cyclooxygenase-2 RNA, protein, and enzyme activity. High doses of cyclooxygenase inhibitors substantially block viral replication in cultured fibroblasts. However, doses corresponding to the level of drug achieved in the plasma of patients have little effect on the replication of human cytomegalovirus in cultured cells. Here, we demonstrate that two nonsteroidal anti-inflammatory drugs, tolfenamic acid and indomethacin, markedly reduce direct cell-to-cell spread of human cytomegalovirus in cultured fibroblasts. The block is reversed by addition of prostaglandin E2, proving that it results from the action of the drugs on cyclooxygenase activity. Because direct cell-to-cell spread likely contributes importantly to pathogenesis of the virus, we suggest that nonsteroidal anti-inflammatory drugs might help to control human cytomegalovirus infections in conjunction with other anti-viral treatments.

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Available from: Thomas Shenk, Oct 24, 2014
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    • "NSAIDs can pharmacologically target cyclooxygenase (COX) isozymes, COX-1 and COX-2, finally inhibiting the expression of prostaglandin (PG), which is an important proinflammatory mediator of inflammatory response. Previous studies have shown that NSAIDs were able to suppress HSV reactivation in murine trigeminal ganglions (TGs) [14] [15], as well as inhibit the multiplication of some other types of virus in cell lines [16] [17]. In light of these, we suppose that COX might intensify attacks of MD through promoting viral production or enhancing the severity of nerve inflammation. "
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    • "nature, to be able to get to the site of cell-to-cell spread, examples in the literature indicated that CMV antibodies were capable of preventing this mode of transmission in cultured fibroblasts (Navarro et al., 1993; Frenzel et al., 2012; Takada et al., 2012). This is in contrast to other studies where CMV-IG was specifically used in media to prevent extracellular spread without affecting cell-to-cell transmission (Silva et al., 2005; Ryckman et al., 2006; Schroer and Shenk, 2008; O'Connor and Shenk, 2011). Moreover, sera from CMV-infected patients was used to demonstrate that while lab isolates of CMV show both intracellular and extracellular spread in vitro, CMV clinical isolates are strictly cellassociated and therefore inaccessible to neutralizing antibodies (Sinzger et al., 2007). "
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    • "COX-2 inhibition reduces levels of the immediate-early 2 mRNA and protein in addition to viral DNA replication and transcription of some early and late mRNAs. Treatment of HCMV-infected fibroblasts with COX inhibitors inhibits cell-to-cell spread of virus [142]. Of note, while many reports with other viruses have shown inhibition of viral replication or gene transcription by COX inhibitors at non-physiologic concentrations, these results with HCMV were obtained with concentrations of COX inhibitors that are achievable in human plasma. "
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    ABSTRACT: Viruses are frequent causes of respiratory infection, and viral respiratory infections are significant causes of hospitalization, morbidity, and sometimes mortality in a variety of patient populations. Lung inflammation induced by infection with common respiratory pathogens such as influenza and respiratory syncytial virus is accompanied by increased lung production of prostaglandins and leukotrienes, lipid mediators with a wide range of effects on host immune function. Deficiency or pharmacologic inhibition of prostaglandin and leukotriene production often results in a dampened inflammatory response to acute infection with a respiratory virus. These mediators may, therefore, serve as appealing therapeutic targets for disease caused by respiratory viral infection.
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