A paper on cytokine storm

In the 1918 pandemic deaths occurred either from the usual secondary bacterial infections or the rapidly advancing acute respiratory distress syndrome. The latter, at least, seems also characteristic of the current human cases of H5N1, and in both the 1918 virus and the contemporary H5N1 there is strong evidence that a dysregulated immune system resulting in a "cytokine storm" may be involved (see our brief description of cytokine storm at The Flu Wiki). But what are the details of a cytokine storm and how does the virus cause it? A new paper in the Journal of Virology on an entirely different virus discusses the topic (Bowick et al., Journal of Virology, February 2007, p. 1923-1933, Vol. 81, No. 4).

The virus in question, the Pichidne virus, is a member of the arenavirus family, which includes the deadly Lassa Fever virus. The authors had two variants of the virus, one that produced a mild, self-limiting disease in guinea pigs, the other a lethal form that induces the kind of cytokine storm seen in Ebola, Marburg and H5N1. They then used a newly developed protein-scanning chip coupled with a large database of biological pathways and relationships to begin to unravel what the difference was.

Cytokine storm is not just "an over active immune system" but a lethally dysregulated one. The immune system consists of many moving parts that must be coordinated and sequenced in precise ways. Like an army or police force with no supervision, it can go out of control and severe harm to innocent people. That's a pretty good description of a cytokine storm, where beneficial cells called in to combat pathogens don't receive a stop signal and run amok. Unfortunately we don't know much about the signaling network. We see it only in isolated pieces and it is hard to see how the parts interconnect and what might make them go wrong.

Cell signaling and coordination in the immune is done with chemical messengers called cytokines and chemokines. There are quite a few of them and they interact in complex ways, with lots of positive and negative feedback. One of the ways signaling is turned on and off is by a modification of proteins called phosphorylation, the attachment of a phosphate group to specific amino acids in the protein chain. Phosphorylation can turn in inactive protein into an active one. The process is under the control of other proteins, which themselves might be turned on and off by phosphorylation by still others, etc.

By infecting guinea pig cells and then using phosphorylation patters via the protein chip to check almost 1200 protein interactions researchers at the University of Texas Medical Branch in Galveston have started to get a handle on what is happening to the regulatory spider web during a cytokine storm. The picture is still hazy, but it appears the mild form leads to a normal immune response while the lethal form to a suppression of part of the immune system that might call a halt to the inflammatory process. What is being suppressed is the braking mechanism.

But it is apparent that many pathways, many not now thought connected to the immune system, are affected. Rather than providing a simple answer, this work verifies what most people thought, that there are a lot of things going on in the cytokine storm dysregulation. On the other hand, this kind of work can sometimes identify critical node points where an intervention through a drug might restore order. Consider the chaos that resulted in the 9/11 disaster from failure of fire and police to be able to communicate with each other because they used incompatible systems. Looking at it from the outside one sees many things going wrong, but restoring the communication channel would have cured many of them at once.

The cytokine storm story probably isn't so simple. But we can hope.