Virus self-improvement through inflammation: No pain, no gain

It is becoming increasingly clear that there are circumstances where human cytomegalovirus (CMV) benefits from inducing a strong host inflammatory response. The virus encodes a number of immunomodulatory functions, including proinflammatory cytokines and chemokines, and, like other viruses that persist in the host, commits many viral functions to avoidance of the host immune response (1, 2). The work reported in this issue of PNAS by Zhu et al. (3) shows that prostaglandin (PG) E₂, a key mediator in the inflammatory response, is induced and performs an important function to support viral replication. These authors show that PG synthesis follows induction of cyclooxygenase-2 (COX-2) and cytoplasmic phospholipase A₂ transcriptional activation (4) during CMV infection. The increased level of PGE₂ in turn influences the expression of the critical viral transcriptional regulatory protein (IE2) and through this impact, strongly reduces replication and production of progeny (3).

COX-2 (also known as PG H synthetase) catalyses the first two steps in the synthesis of PG from arachidonic acid to PGH_2, an intermediate that is rapidly converted by additional enzymes to any of a number of physiologically active, tissue-specific mediators, including PGD₂, PGE₂, PGF₂, PGI₂, and the related prostanoid, thromboboxane A₂ (5). COX-2 is one of the most strongly induced host genes following CMV infection of cultured primary human fibroblasts (4). PG levels are well known to increase rapidly in response to a number of cell activation and inflammatory signals such as bacterial lipopolysaccharide and stimulation by proinflammatory cytokines interleukin-1β and tumor necrosis factor α (5). Exposure of cultured cells to a variety of microbial and viral pathogens causes a strong activation of this gene (6–8). In the course of natural infection, CMV interacts with cell types in …