|Viral pneumonia (from influenza possibly) results from an accumulation of immune cells and fluid in the lung tissue. But how can we stop it?|
In the northern hemisphere it's coming up to 'flu season - the time when many of us will be getting our yearly influenza vaccinations. In the coming months during the thousands of potential viral infections, some form of disease/clinical symptoms may set in (maybe not if you're vaccinated) - think of that headache, cough, runny nose, etc. We can think of these as a function of both the virus replicating and your response (i.e the host) to that same infection. And, in infections such as influenza, the ramping up of the cellular immune response in an organ like the lung is responsible for much of the clinical course of the disease (the pneumonia - see above).
The strange thing is that a lot of our therapies are only targeted to the virus aspect (antivirals) of this: blocking particular enzymes, receptor binding molecules etc. But, what if we could target the host response? And through doing this eliminate disease, while potentially allowing the virus to infect, replicate and ultimately use us without inflicting damage.
A number of groups have recently reported the discovery of host antiviral targets yet none have proven successful (see my analysis here). Well, a paper (get it here) published recently in the journal Cell, suggests that yes this could all be possible - at least in a mouse model of influenza that is and through doing so they have also unveiled an hitherto unknown inflammatory pathway in your lungs.
Here, through the use of an S1P1 receptor subtype-selective agonist as well as genetic and biochemical tools, we define a crucial endothelial signaling loop that is important for the initiation of cytokine storm. We reveal that cytokine secretion and immune cell infiltration are separable events that are both regulated by the pulmonary endothelium. Further, we demonstrate that suppression of early innate immune responses through S1P1 signaling results in reduced mortality during human pathogenic influenza virus challenge. Thus, S1P1 receptor signaling in endothelium provides a mechanism for attenuation of influenza virus-induced morbidity and reveals an unexpected role for endothelial cells as regulators of cytokine storm.
|Atomic structure of sphingosine 1 phosphate - inhibition of it's activity may prevent influenza-associated disease|
Check out Cell's editorial here.
This group responsible for this discovery - hailing from the Scripps institute in California, tested a previously identified drug AAL-R (a sphingosine-1-phosphate (S1P) receptor agonist) in several transgenic mouse models of flu. Sphingosine-1 phosphate is a lipid metabolite that acts a chemical messenger in our immune response. Their identified compound was able to significantly blunt the damaging immune response via inhibiting this S1P receptor, thereby preventing a massive upregulation of signalling molecules (aptly known as a cytokine storm) and infiltration of immune cells into the lung. What wasn't known however was the mechanism of action of this molecule; what cells did it act on?
Using a fluorescent tagged version of the S1P protein, the group narrowed down the mediator of this inhibition to the cells making up the blood vessels - the endothelial cells - found in the mouse lung tissue. It was shown that the administration of the drug reduced the amount of immune-signalling proteins released by these cells and also prevented the entry of immune cells into the lungs. Goodbye viral pneumonia.
Their model of action is shown here:
This paper elegantly shows that one of the major contributors to influenza-induced pathology are the endothelial cells (in the mouse model). These cells are very close to the infected epithelial cells and so are in a prime position to elicit an immune response - and also hold the gateway to allowing the infiltration of immune cells in to the lung. While influenza was the model system in the instance, I'm sure this research will spark the consideration of the role of endothelial cells in other infections and tissues.
This molecule interestingly prevented disease without inhibiting viral replication - which is really the opposite to what previous antiviral therapies are doing. By allowing the virus to get on with it's life cycle while removing our deadly immune response may work in this case, that's not to say the same is possible of all infections. After all, our immune response is direly needed to limit infections and to generate adaptive immunity. Either way, this and other papers clearly show that targeting the host may be an alternative position to defend against viral - and maybe bacterial - infections.