Inhibition of cyclooxygenase 2 blocks human cytomegalovirus replication

Abstract

Cyclooxygenase 2 (COX-2) mRNA, protein, and activity are transiently induced after infection of human fibroblasts with human cytomegalovirus. Prostaglandin E 2, the product of COX-2 activity, is transiently increased by a factor of >50 in cultures of virusinfected fibroblasts. Both specific (BMS-279652, 279654, and 279655) and nonspecific (indomethacin) COX-2 inhibitors can abrogate the virus-mediated induction of prostaglandin E2 accumulation. Levels of COX-2 inhibitors that completely block the induction of COX-2 activity, but do not compromise cell viability, reduce the yield of human cytomegalovirus in human fibroblasts by a factor of >100. Importantly, the yield of infectious virus can be substantially restored by the addition of prostaglandin E 2 together with the inhibitory drug. This finding argues that elevated levels of prostaglandin E 2 are required for efficient replication of human cytomegalovirus in fibroblasts. H uman cytomegalovirus (HCMV) is a ubiquitous member of the herpesvirus family. HCMV infection of healthy adults is generally subclinical. However, the virus is a major infectious cause of birth defects, and it is an adventitious pathogen that causes disease and mortality in immunocompromised individuals (1).HCMV infection dramatically alters the steady state levels of many cellular mRNAs (2-4). The quantity of 1,425 cellular mRNAs, of Ϸ12,600 assayed, changed by a factor of Ն3 during the first 48 h after infection of human fibroblasts (3).The mRNAs encoding several constituents of the pathway that produces prostaglandin H 2 (PGH 2 ) from arachidonic acid are among those modulated by HCMV infection (2, 3). The mRNAs encoding cytosolic phospholipase A2 (cPLA2) and cyclooxygenase 2 (COX-2) increase, and the mRNA encoding lipocortin 1, also known as annexin 1, decreases after infection. When activated by phosphorylation, cPLA2 cleaves and releases arachidonic acid from membranes (5, 6), which can then be converted by COX-2 to PGH 2 . Lipocortin 1 binds to cPLA2 and inhibits its activation (7-9), blocking the release of arachidonic acid that can serve as a substrate for COX-2. If mRNA levels reflect enzymatic activity, then one would expect that the production of PGH 2 and its metabolites is strongly induced after HCMV infection. Consistent with this prediction, arachidonic acid release (10-12) and prostaglandin E 2 synthesis (PGE 2 is made from PGH 2 by PGE 2 synthase) are induced after infection of monocytes with HCMV (10, 13). Prostaglandins serve as second messages that elicit a wide range of physiological responses in cells and tissues. They have the potential to exert profound effects on HCMV replication and pathogenesis, given their ability to modulate gene expression and immune function.A specific inhibitor of COX-2 has been shown to block the accumulation of PGE 2 after HCMV infection (13), and nonspecific inhibitors of the enzyme, i.e., compounds that affect COX-2, as well as other targets, reduce virus yields in cultured cells (13,14). The mechanism for this inhibition is not clear, ...

Rhesus CMV: an emerging animal model for human CMV

“…HCMV, while not having a COX-2 homolog, does upregulate cellular COX-2 upon infection, and COX-2 inhibitors prevent normal viral replication [65]. Lastly, RhCMV is able to block expression of interferon-stimulated genes (ISGs) by preventing activation of interferon regulatory factor-3 (IRF3) [66].…”

Acetylsalicylic acid inhibits hepatitis C virus RNA and protein expression through cyclooxygenase 2 signaling pathways

“…Previous studies have reported that production of COX-2 and PGE 2 modulates replication of human cytomegalovirus, gammaherpesvirus, and hepatitis B virus. [18][19][20] To investigate the possible mechanism(s) responsible for ASA-mediated down-regulation of HCV-RNA expression, we examined COX-2 activity, mRNA, and protein levels in ASAtreated HCV replicon cells. In this study, we found that 4 mM ASA treatment down-regulated COX-2 protein (Fig.…”

Regulation of Cyclooxygenase-2 Expression by Macrophages in Response to Double-Stranded RNA and Viral Infection

“…Of the isoforms of COX, COX-2 expression is stimulated under inflammatory conditions (28). Virus infection has been shown to stimulate COX-2 expression (29 -32), and inhibitors of COX-2 enzymatic activity attenuate virus replication (33,34), suggesting that the expression of COX-2 and the increased production of PGs may play an important role in viral replication. In addition, we and others have shown that under proinflammatory conditions the expression of COX-2 and iNOS appear to be coordinately regulated (35)(36)(37)(38).…”