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Abstract
Infection with influenza A viruses (IAV) provokes activation of cellular defence mechanisms contributing to the innate immune and inflammatory response. In this process the cyclooxygenase-2 (COX-2) plays an important role in the induction of prostaglandin-dependent inflammation. While it has been reported that COX-2 is induced upon IAV infection, in the present study we observed a down-regulation at later stages of infection suggesting a tight regulation of COX-2 by IAV. Our data indicate the pattern-recognition receptor RIG-I as mediator of the initial IAV-induced COX-2 synthesis. Nonetheless, during on-going IAV replication substantial suppression of COX-2 mRNA and protein synthesis could be detected, accompanied by a decrease in mRNA half-life. Interestingly, COX-2 mRNA stability was not only imbalanced by IAV replication but also by stimulation of cells with viral RNA. Our results reveal tristetraprolin (TTP), which is known to bind COX-2 mRNA and promote its rapid degradation, as regulator of COX-2 expression in IAV infection. During IAV replication and viral RNA accumulation TTP mRNA synthesis was induced, resulting in reduced COX-2 levels. Accordingly, the down-regulation of TTP resulted in increased COX-2 protein expression after IAV infection. These findings indicate a novel IAV-regulated cellular mechanism, contributing to the repression of host defence and therefore facilitating viral replication.
Highlights
While COX-1 is constitutively expressed maintaining housekeeping functions, COX-2 transcription is rapidly inducible by bacterial endotoxins (e.g. LPS), cytokines including IL-1 and TNF-αor growth factors[10]
In a first set of experiments we investigated the impact of COX-2 on Influenza A viruses (IAV) replication
A maximum increase in viral titres was observed when COX-2 was inhibited at 6 h p.i. compared to other times of CAY10404 addition (Fig. 1e +6 h P < 0.0001), while a maximum decrease in viral titres was visible upon PGE2 treatment at 4 h p.i. compared to other times of PGE2 addition (Fig. 1f)
Summary
While COX-1 is constitutively expressed maintaining housekeeping functions, COX-2 transcription is rapidly inducible by bacterial endotoxins (e.g. LPS), cytokines including IL-1 and TNF-αor growth factors[10]. Several studies showed virus-dependent regulation of COX-2 to support viral replication. While increased production of PGE2 results in inhibited replication of certain viruses (e.g. adenovirus, parainfluanza virus and measles virus) it induces viral replication of others (e.g. CMV, VSV, BLV, HSV-1)[8]. We show that in IAV-infected cells, COX-2 expression is tightly regulated. While the protein is induced at early times of infection[20,21,22,23] via recognition of IAV vRNA by RIG-I, COX-2 expression is reduced again during on-going replication. Our data reveal that this is due to destabilisation of COX-2 mRNA by IAV-induced TTP, indicating that IAV leads to early induction of inflammatory mediators and to its suppression later in the infection cycle
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