The great white hope

Scientists have found the bacterial protein thatkills WBCs. Now it's time to turn the tables

By Henry Peters

It's a well-known axiom in today's US research community that if you mention terrorism in your grant application, you can expect to be buried under a pile of money. The result has been a glut of research, much of it of dubious utility.

But the effort deployed has occasionally led to some genuinely useful insights to help us better understand infectious diseases and the immunology process.

A paper in the March 18 issue of Nature is an example of this. Researchers at the University of California, San Diego School of Medicine have identified the mechanism used by the bacteria that cause anthrax, bubonic plague and typhoid fever to avoid detection and destruction by the body's normal immune response.

The research identified a protein kinase called PKR that causes the death of macrophages. This effectively disables the body's first line of defence, allowing the infection to spread unnoticed by the immune system.

"These findings may be applicable to serious cases of the flu, where individuals also get bacterial super-infections," said the study's lead author, Dr Michael Karin. "Every year, you have tens of thousands of deaths among people infected with the flu. We believe this super-lethal type of flu is not due to the virus alone, but to a bacterial super-infection that follows the viral infection, and because of that, can lead to macrophage death."

A receptor on macrophages known as TLR4 normally acti-vates them in the presence of pathogens. But the researchers found that virulence factors produced by the B anthracis, Yersinia and Salmonella bacteria caused TLR4 to trigger not activation, but apoptosis, or cell death.

PKR appears to be the third ingredient necessary for the combination of bacterial toxins and TLR4 to result in macrophage death. Mice bred with PKR suffered severe infections. Those without PKR retained strong immune responses capable of preventing serious infection.

"This suggests that some people who have the flu and then get a secondary bacterial infection, are probably more prone to a life-threatening infection due to the bacteria acting together with the virus to kill macrophages through PKR," Dr Karin said.

"If we are able to develop specific inhibitors for PKR, and the drug industry can easily produce them, we may be able to control these nasty infections," added Dr Karin.