Mechanism Leading To Life-Threatening
Identified By UCSD School Of Medicine Researchers
By Sue Pondrom
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.
Published in the March
18, 2004 issue of the journal Nature, 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
“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.
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.
TLR4 activation normally
results in signals for both survival and death of macrophages,
with the survival signal almost always dominating. However,
virulence factors produced by the B. anthracis, Yersiniae and
Salmonella bacteria caused TLR4 to generate only the macrophage
“Instead of the
macrophage being able to swallow the bacteria and recruit other
white blood cells to the battle, it kills itself in a process
called apoptosis,” Karin said.
To find out why the
toxin-TLR4 combination elicited a death signal, the Karin team
used further lab tests to determine the molecular components
involved in the pathogen-activated TLR4 death signal. One of
these was the dsRNA responsive kinase PKR. In subsequent experiments
in mice bred with and without PKR, the team found that those
without PKR retained healthy macrophages that are resistant
to killing by the B. anthracis, Yersiniae and Salmonella bacteria,
and could prevent bacterial infection.
In preliminary studies
not yet published, the Karin team activated PKR first with a
viral nucleic acid and then with bacteria. The result was an
especially vigorous infection.
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,” Karin said.
In addition to Karin,
the study was conducted by the paper’s first author, Li-Chung
Hsu, Ph.D., and by Jin Mo Park, Ph.D., Jun-Li Luo, Ph.D., and
Shin Maeda, M.D., Ph.D., UCSD Laboratory of Gene Regulation
and Signal Transduction, UCSD Department of Pharmacology; Lars
Eckmann, M.D. and Donald G. Guiney, M.D., UCSD Department of
Medicine; and Kezhong Zhang, Ph.D. and Randel J. Kaufman, Ph.D.,
Howard Hughes Medical Institute and Department of Biological
Chemistry, University of Michigan, Ann Arbor.
The study was supported
by grants from the National Institutes of Health.
Media Contacts: Sue
Pondrom (619) 543-6163