Study By UCSD Researchers Gives
New Insight Into How
Anthrax Bacteria Can Evade A Host's Immune Response
By Sherry Seethaler
the University of California, San Diego have determined how
toxin produced by anthrax bacteria blocks a person’s normal
immune response, a discovery that could lead to new treatments
for anthrax infection.
In a paper to be published
in the January 15th issue of The Journal of Immunology
the UCSD scientists show why, in the presence of anthrax toxin,
human immune cells fail to respond normally to lipopolysaccharide
or lipoteichoic acid--components of the cell walls of many bacteria
including the bacteria that cause anthrax, Bacillus anthracis.
Bacterial invasion, or the presence of lipopolysaccharide, usually
causes immune cells known as macrophages to release cytokines—chemicals
that signal other cells about the presence of an invader. Release
of cytokines causes large numbers of immune cells to arrive
at the site of infection and destroy the bacteria. By blocking
this host immune response, anthrax bacteria are able to multiply
unchecked. According to the Centers for Disease Control, approximately
75 percent of people infected with inhalation anthrax die, even
with all possible supportive care including appropriate antibiotics.
was known for quite some time that anthrax toxins can suppress
cytokine production, the mechanism by which Bacillus anthracis
escapes the immune response isn’t really understood,”
says Michael David, a biology professor at UCSD who headed the
research team. “We have identified a protein molecule
targeted by the anthrax toxin and determined where it acts in
the sequence of steps involved in immune response.”
Macrophages have special receptors on their surfaces that bind
to lipopolysaccharide. The binding of lipopolysaccharide to
this receptor sets off a sequence of events inside the macrophage,
in which a series of proteins activate one another in turn.
This cascade of proteins activating one another ultimately turns
on cytokine genes, causing the macrophage to churn out large
quantities of cytokines.
It turns out that there
are two separate, sometimes cooperating, routes in the cell
by which series of proteins activate one another to switch on
production of cytokines. One of the routes has been recognized
for a long time, but researchers were sometimes puzzled when
cytokine production was turned on or off without the proteins
along this route being activated or deactivated. This puzzle
was resolved when the David group and other groups simultaneously
identified the second route, the IRF3 pathway. The anthrax toxin
targets the IRF3 pathway by cleaving MKK6—one of the proteins
in the series along the route. The cleavage of MKK6 prevents
the cytokine genes from being switched on.
When the researchers
made mutant macrophages with a variant of MKK6 that could not
be cleaved by the anthrax toxin, these macrophages responded
to lipopolysaccharide by producing cytokines even in the presence
of the anthrax toxin. This suggests that developing a drug that
could protect MKK6 and prevent anthrax toxin from cleaving it
could help to prevent an anthrax infection from getting out
of control. The anthrax bacteria would be unable to evade the
normal immune response.
results may not lead to a drug to cure anthrax in the next six
months, the more you understand about bacteria and how they
target the immune response the more options you have for developing
drugs to treat the infections,” says David.
Previous work by other
researchers has suggested that anthrax toxin evades the immune
system by killing macrophages; however, according to David,
cell death does not fully explain how anthrax bacteria evade
the immune system.
“Only some types
of macrophages are killed by anthrax toxins, but anthrax toxins
diminish the production of cytokines in all of the macrophages
we have tested,” David explains. “Also, less toxin
is needed to shut off the immune response than to kill the macrophages.”
The other UCSD researchers
involved with this project were Oanh Dang, a former graduate
student in the David laboratory and the first author of the
paper; Lorena Navarro, a former graduate student in the David
laboratory and first author on two other papers that initially
identified the IRF3 immune response pathway; and Keith Anderson,
a technician in the David laboratory. This work was supported
by a grant from the National Institutes of Health.
Media Contacts: Sherry
Seethaler (858) 534-4656
David (858) 822-1108