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, leading to life-threatening bacterial infections, has been identified by researchers at the University of California, San Diego (UCSD) School of Medicine.
The lab-culture research with mouse cells identifies a protein kinase called PKR that causes the death of macrophages, the large white blood cells that act as the body’s first defense against pathogens. Without macrophages to detect, engulf and stop the invading bacteria, the infection goes unnoticed by the immune system and spreads.
“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,” said the study’s senior author, Michael Karin, Ph.D., UCSD professor of pharmacology and an American Cancer Society Research Professor.
“In addition, these findings may be applicable to serious cases of the flu, where individuals also get bacterial super-infections,” Karin noted. “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.”
In the UCSD study, the researchers focused on macrophages, which act like a security force traveling throughout the body, looking for invaders. The macrophages have a receptor on their cell surface, called a Toll-Like Receptor 4 (TLR4), that alerts them to the invading pathogen by placing the macrophage in an activated state, ready to do combat. In addition to their importance in the direct killing of bacterial pathogens, macrophages alert other components of the immune system to the presence of an infection and secrete proteins that recruit other types of white blood cells to join the fight against the bacterial invaders.
Three different pathogens were used to activate TLR4 on the surface of macrophages: Bacillus anthracis, which causes anthrax; Yersiniae pseudotuberculosis, a less virulent substitute for Yersiniae pestis, the causative agent of bubonic plague; and Salmonella typhimurium, a similar substitute for Salmonella typhi, which causes typhoid fever. Both Yersiniae pestis and Salmonella typhi are too virulent to use in most laboratories.