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    Cytokine storm issue poses another big H5N1 question

    Robert G. Webster, PhD

    “Will it or won’t it?”

    That question has sparked a lot of controversy among infectious disease experts and the general public. Will the bird flu virus H5N1 accumulate enough of the “right” mutations to let it readily infect humans and spread from human to human like a seasonal flu virus? If that happens, experts say, we could be in for a devastating pandemic (worldwide epidemic).

    But there is another question that is not widely discussed by the general public but is of great interest to researchers trying to develop effective drugs to treat H5N1 human infections. These investigators are asking: “Is the immune system ‘cytokine storm’ the main cause of death caused by H5N1 infection?”

    The cytokine storm is an example of too much of a good thing. It’s a blizzard of signaling proteins called cytokines that is generated by various immune system cells as they coordinate an attack on an invading microorganism. But if this response runs out of control, it can cause potentially fatal inflammation and damage to the lungs. And that is what many researchers have thought kills people who are infected with H5N1.

    But now a team of St. Jude investigators have raised issues about that widely held theory by showing that depression of cytokines in mice infected with a particularly virulent strain of the virus still causes the mice to die. The team said the new finding suggests that pathogenicity is a complex question of host response and virus load. Scientists should concentrate on finding ways to reduce the amount of the virus in an infected person as well as analyzing the concept of the cytokine storm—a storm that is, caused by a sustained infection with the virus itself.

    “The H5N1 cytokine storm appears to erupt when there is no resolution to the viral infection,” said Robert Webster, PhD, Infectious Diseases. “However, we found that preventing components of the cytokine storm from erupting fails to protect mouse models of H5N1 infection against death. This strongly suggests that it’s necessary to focus on limiting the multiplication of the virus itself as well, and more fully understand the cytokine storm.”

    Webster is the senior author of a report on this work that appeared in the July 24 issue of Proceedings of the National Academy of Sciences.

    The St. Jude team made their discovery by comparing the response of normal mice to H5N1 compared to the response of mice that either lacked or were genetically unable to respond to one of three specific cytokines that are known to trigger damaging inflammation in response to infections—TNF-alpha, CCL2 and IL-6. The St. Jude team then compared the results of infection with H5N1 between normal mice and mice that were first treated with glucocorticoids. Glucocorticoids are drugs that suppress the immune response, and therefore prevent the eruption of cytokine storms. The investigators infected all mice with A/Vietnam/1203/04, a strain of H5N1 that has infected and killed people in Vietnam.

    The investigators found that whether mice lacked specific cytokines, couldn’t respond to them, or were treated with glucocorticoids to suppress the immune response, H5N1 infections were still fatal. These results suggest that much more work remains to be done to understand the interplay between the highly pathogenic virus and the host. The study does not entirely explain the role of cytokines in H5N1 infections, said Rachelle Salomon, PhD, the paper’s first author and a postdoctoral fellow in Webster’s laboratory.

    “Cytokines play an extremely important role in the immune system’s defense against infection,” Salomon said. “So we need to learn much more about the role and effects of cytokines during an H5N1 infection. We don’t fully understand the effects of intervening with the cytokine response, since this can alter the balance between the protective and damaging effects of these signaling molecules during an infection.”

    Webster’s team previously showed that there is only a narrow time window during which certain anti-viral drugs are effective. Therefore, the investigators are trying to identify the most effective way to treat H5N1 infections. For example, the investigators have recently published a study reporting that drugs that target a specific viral enzyme called polymerase might be effective in treating bird flu infections.
    October 2007