The Storm Within
This spring the flu emerged along the Yangtze River on China’s Eastern shore. This particular strain of the flu has an unusually high mortality rate. Of the 134 people it’s infected, its killed 44. At a hospital in Shanghai two men were admitted with this flu, called H7N9. The men were similar in age, 53 and 56-years old respectively. They were both fit with no underlying medical conditions. Yet one man would leave the hospital healthy while the other would die within its walls. What separated these two men? A study published last week suggests that the answer lies not in the virus but within their bodies.
A cytokine storm begins in the body for reasons we don’t fully understand. Cytokines are proteins that do a million different things. They signal immune cells to attack pathogens, promote inflammation necessary to create a physical barrier, and signal cells far and wide. You can’t possibly survive without cytokines. But you can also have too much of a good thing. In response to a pathogen, the immune system responds. The storm begins when the response is not proportional to the threat. Instead, the immune system mounts the attack of its life. The cytokines that are produced signal more immune cells that in turn stimulate the release of even more cytokines. Over 150 kinds of cytokines are released. The cytokine storm uncontrollably kills everything in its proximity, including the very immune cells the proteins are designed to protect.
Cytokine storms have been described for a range of diseases from SARS to Multiple Sclerosis to Strep. In HIV, they’ve been blamed for killing massive numbers of cells, causing the progression from infection to AIDS. In graft-versus-host disease, a cytokine storm contributes to the body rejecting a transplant. Despite their prevalence, cytokine storms didn’t gain widespread attention until the avian influenza outbreak in 2005. During that outbreak, samples from the lungs of those that died of avian flu contained the debris characteristic of a cytokine storm.
Now, looking at a different influenza in a different country, the pieces are beginning to come together. Once again evidence of cytokine storms lies in the lungs of those that succumb to the infection while those who recover, have, ironically, a reduced immune response. This is seen most clearly in the case of the two middle-aged men in China where it seems the difference between life and death may lie in the concentration of cytokines in their lungs. The study describing their cases, as well as others, goes a step farther, showing that one mutation between these two men differs, potentially explaining why the cytokine storm started in the first place.
This mutation lies in the IFITM3 protein, short for interferon-induced transmembrane protein-3. This protein is special as it physically prevents viruses from getting to the cell’s inner machinery. This phenomenon is not unique to influenza. IFITM3 has shown to inhibit a wide range of pathogens including West Nile Virus, SARS, HIV, Dengue and others. In addition to this physical barrier, IFTM3 also seems to be important in regulating cytokines. Mice without the protein in the lungs have elevated cytokines, similar to the high levels found in the lungs of influenza victims.
For the two middle-aged men in China, there was only one small difference in their IFTM3 genes. The man who died had a cytosine (C) at one position in the gene while the man who didn’t had a thymidine (T). The cytosine at that position told the cell to cut off the protein. With a shortened protein the man who died may have not been able to regulate his cytokines leading to what the researchers found in his lungs: the remnants of the cytokine storm. A humble C instead of a T may have made all the difference.
With all we know about cytokine storms the question now remains what can we do to combat them. The answer may give us insight into not only how to treat influenza victims that harbor rare mutations but also how to treat the plethora of diseases impacted by cytokine storms. This approach is already commonly used to prevent the intense immune attack that occurs in patients receiving organ and stem cell transplants. Given the sheer number of drugs available to dampen the immune system it seems probable that they’ll find their way into new infectious disease trials. In fact, this is already starting. Researchers at the Gladstone Institutes are hoping to use a drug called VX-765 to subdue the immune system in people with HIV. While it’s unknown if this specific approach will be successful, it heralds the beginning of a new era, one in which we fight against our immune systems instead of for them.