One of the things that bugs me a lot, in an entirely geeky way, is when people tell me they have the flu - most of the time, they really just have a cold, caused by a completely different pathogen. Influenza, the real cause of flu, can actually cause very serious disease, much more debilitating than a cold virus, and can even lead to death. Case in point: the Spanish flu is thought to have killed more than 20 million people during the first world war, many believe that was responsible for more deaths than the war itself.
But I digress. The rant was triggered by a very interesting paper that I spotted in this week's Immunity, which identified a new potential therapeutic target for influenza A: a group of molecules known as prostaglandins.
An involvement for prostaglandins, a group of lipid molecules with many roles including inflammation and immunity, in influenza infection is not new. A quick search in PubMed revealed that members of the prostaglandin family have previously been shown to block influenza replication and limit inflammation, and deficiency in the enzymes responsible for generating the prostaglandin PGE2 (COX1 and COX2) has revealed conflicting results.
The group of Divangahi and colleagues set out to determine the involvement, if any, of PGE2 during influenza A infection. They saw that mice lacking PGE2 had lower levels of the virus in their lungs than mice expressing this molecule. They also had more innate immune cells (monocytes and macrophages, acting as the first line of defense) in their lungs and higher levels of type I interferons (IFN), which are produced by these innate immune cells and are integral components of the fight against virus infections. What is more, injecting infected mice with PGE2-deficient macrophages had a protective effect, decreasing their viral burden and increasing their survival.
These findings suggest that PGE2 has a detrimental effect during influenza A infection, dampening the response of macrophages to the virus. But the effects were not limited to innate immunity: the authors also observed that PGE2 suppressed the responses of adaptive immune cells, specifically effector T cells (which, as you may remember from my previous post, are immune cells that directly kill invaders).
To put these findings into some context, aspirin (which inhibits COX1 and COX2, and thus PGE2 production) was first used to treat influenza infection over 100 years ago, and we now have evidence that PGE2 inhibition could be beneficial. Indeed, the authors directly show that blocking PGE2 or the PGE2 receptors on macrophages increased survival in infected mice. However, the use of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) has been somewhat controversial in this context,as they have been associated with mortality and Reye's syndrome. But the authors do suggest that these might be due to NSAID overuse and that selective inhibition of PGE2, rather than of COX1 and COX2, could be a viable therapeutic avenue that should be explored further.
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An involvement for prostaglandins, a group of lipid molecules with many roles including inflammation and immunity, in influenza infection is not new. A quick search in PubMed revealed that members of the prostaglandin family have previously been shown to block influenza replication and limit inflammation, and deficiency in the enzymes responsible for generating the prostaglandin PGE2 (COX1 and COX2) has revealed conflicting results.
The group of Divangahi and colleagues set out to determine the involvement, if any, of PGE2 during influenza A infection. They saw that mice lacking PGE2 had lower levels of the virus in their lungs than mice expressing this molecule. They also had more innate immune cells (monocytes and macrophages, acting as the first line of defense) in their lungs and higher levels of type I interferons (IFN), which are produced by these innate immune cells and are integral components of the fight against virus infections. What is more, injecting infected mice with PGE2-deficient macrophages had a protective effect, decreasing their viral burden and increasing their survival.
These findings suggest that PGE2 has a detrimental effect during influenza A infection, dampening the response of macrophages to the virus. But the effects were not limited to innate immunity: the authors also observed that PGE2 suppressed the responses of adaptive immune cells, specifically effector T cells (which, as you may remember from my previous post, are immune cells that directly kill invaders).
To put these findings into some context, aspirin (which inhibits COX1 and COX2, and thus PGE2 production) was first used to treat influenza infection over 100 years ago, and we now have evidence that PGE2 inhibition could be beneficial. Indeed, the authors directly show that blocking PGE2 or the PGE2 receptors on macrophages increased survival in infected mice. However, the use of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) has been somewhat controversial in this context,as they have been associated with mortality and Reye's syndrome. But the authors do suggest that these might be due to NSAID overuse and that selective inhibition of PGE2, rather than of COX1 and COX2, could be a viable therapeutic avenue that should be explored further.
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