May 7, 2004

New countermeasure against bioweapon

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Jacek Hawiger, M.D., Ph.D

New countermeasure against bioweapon

Bacterial “superbugs” responsible for many hospital-based infections produce toxins that aggravate the body’s immune system. The resulting inflammation can cause a life-threatening condition called toxic shock.

A few years ago, Jacek Hawiger, M.D., Ph.D., Oswald T. Avery professor and chair of Microbiology and Immunology, and colleagues developed a compound, cSN50, to study this process and to find a way to block it.

This research, initially aimed at dealing with a hospital-based infection, suddenly took on a new relevance after Sept. 11, 2001. One of the same toxins Hawiger studied, staphylococcal enterotoxin B (SEB), could be used as a biological weapon by terrorists, according to the Centers for Disease Control and Prevention.

SEB was included on the CDC’s list of category B bioagents, in part, because it can be easily aerosolized. If SEB is inhaled, it can cause severe respiratory symptoms, such as coughing and difficulty breathing. Also, inhaled SEB can be fatal to non-human primates, highlighting its potential for use as a bioweapon.

With SEB’s new distinction as a potential weapon, the compound Hawiger developed years ago, with purely scientific intentions, now had potential value as a countermeasure to a bioweapon.

“This research was not initiated in response to Sept. 11. We were just thinking about the mechanism of toxemia which complicates most severe methicillin-resistant staph infections,” Hawiger said. “These infections occur with increasing frequency in U.S. hospitals and in the community, reaching an estimated two million in each environment.”

In the April 30 edition of The Journal of Biological Chemistry, Hawiger and colleagues reported that this compound, called cSN50, blocked a critical communication step between the toxin and the cell nucleus. It effectively prevented the inflammation and tissue damage caused by SEB and drastically reduced mortality in mice exposed to the toxin.

SEB’s assault begins when it attaches to a type of immune cell—T lymphocytes. Sensing SEB’s attack, chemical “messengers” inside the cell instruct the nucleus to turn on the production of inflammatory chemicals (cytokines), which help the cell fight the bacterial invasion. The resulting surge of cytokines triggers toxic shock, a severe inflammatory response.

To do their job of instigating inflammation, these chemical “messengers” must be ferried into the nucleus by a protein called the nuclear import receptor. The compound Hawiger’s team developed blocks this crucial step.

“We postulated that we can block this nuclear import with our compound (cSN50). If the block is effective, then the nucleus is not receiving those signals. Therefore, the genes that encode mediators of inflammation, such as cytokines, are not expressed, and there would be no excessive cytokine production,” Hawiger said.

To test his hypothesis, Hawiger examined the effects of cSN50 treatment in cultured cells and in mice exposed to SEB.

Hawiger and colleagues found that cSN50 blocked the production of inflammatory cytokines in both situations. In addition, the mice treated with cSN50 had significantly less liver damage than the control group.

Most striking, however, was the treatment’s effect on mortality. Nearly all of the SEB-exposed mice that did not receive cSN50 died within 40 hours of the exposure. In contrast, all but one of the cSN50-treated mice recovered completely after SEB exposure—an 87 percent increase in survival.

Before these findings can be applied clinically or to national defense, a number of experiments still must be done to assess the compound’s efficacy and safety. For now, Hawiger will continue this research in animal models.

Currently, there are no approved vaccines for SEB exposure. After a recent, multicenter study led by Gordon Bernard, M.D., chief of Allergy, Pulmonary, and Critical Care Medicine, the FDA approved a drug called Xigris for the treatment of toxic shock sepsis, a type of “blood poisoning” that can involve toxic shock. Xigris acts primarily by inhibiting blood clots, a complication of toxic shock.

Hawiger’s compound goes one step further—it works inside the cell to halt inflammation and has the potential to stop the process before it gets started.

Hawiger noted that, since many other potential biological agents act similarly to SEB, his compound might be useful in countering many of the instruments in a bioterrorist’s arsenal.

“In terms of bioweapons, the approach that we developed suppresses harmful systemic inflammation. Most of the agents listed by CDC, including such organisms as tularemia, Ebola virus, and smallpox, all cause systemic inflammation. So we believe that our approach to suppress inflammation by targeting the nuclear import receptor will be potentially useful in the other conditions,” Hawiger said.

“We also have our own kind of ‘bioweapons’ waiting to attack us among common strains of pathogenic bacteria which we face in the community and the hospital,” Hawiger said. Combating this everyday threat was, in fact, this compound’s original purpose.

Co-authors of the paper included Danya Liu, Xue Yan Liu, Daniel Robinson, Christie Burnett, Charity Jackson, Louis Seele, Ruth Ann Veach and Dean Ballard of the department of Microbiology and Immunology, Sheila Downs, and Robert Collins of the department of Pathology. The research was supported by a grant from the National Institutes of Health.