Researchers uncover a secret of Black Death

[Guest guest]

http://www.physorg.com/printnews.php?newsid=77811326

9/18/2006 11:45 PM

Researchers Uncover a Secret of the Black Death

Yersinia pestis, the bacteria that causes plague, is a sneaky little

intruder with a remarkable ability to evade the body’s immune

system. Upon entering an organism, Y. pestis employs a variety

of strategies to slip below the radar of the innate immune

response—the body’s front line of defense against invading

pathogens—and in many cases kills the host before its more

specific antibacterial response can develop.

It is this stealth and virulence that has made plague one of the most

feared diseases in human history, blamed for more than 200 million

deaths. While human cases of plague in the United States are now

rare, a few thousands worldwide are infected each year and with the

potential of intentional misuse of Y. pestis, the efforts to develop

better treatments and a vaccine are now no less important than they

were when the bacterium was first identified.

Researchers at the University of Massachusetts Medical School have

made a significant breakthrough in the field, modifying Y. pestis

with a gene found in another commonly known bacterium,

effectively rendering it unable to cause plague. In “Virulence factors

of Yersinia pestis are overcome by a strong LPS response,” to be

published in the October issue of Nature Immunology, Egil Lien,

PhD, assistant professor of medicine and molecular genetics &

microbiology, Jon D. Goguen, PhD, associate professor of molecular

genetics and microbiology, graduate student Sara Montminy and

colleagues, also describe the effectiveness of the modified bacteria

as a vaccine.

Innate immunity—the precursor to the adaptive immune system in

mammals—acts as the first line of defense against a range of

pathogens. Prior to the adaptive immune response that involves the

body’s production of antibodies that precisely target and combat the

invader, the innate immune system reacts immediately upon

infection. Recent research has described an important class of sensor

molecules, collectively known as Toll-like receptors (TLRs) that

recognize pathogens right away, activating the critical signaling

pathways that stimulate this initial immune response. Activation of

the TLRs also improves the adaptive immune response; in fact,

Print the story http://www.physorg.com/printnews.php?newsid=77811326

2 of 3 9/18/2006 11:45 PM

many vaccines include ingredients known as adjuvants that stimulate

the innate immune response.

Intriguingly, the bacteria Y. pestis has an unusual

temperature-dependent ability to evade this system.

Lipopolysaccharide, or LPS, is a major component of the membrane

of this type of bacteria, contributing to structural integrity but also

typically provoking a strong response from the immune system.

When at human body temperature (37ºC), Y. pestis produces an LPS

with a poor ability to activate TLR4, one of the major mammalian

innate immunity toll-like receptors; at lower temperatures, for

example that of a flea that transmits the disease (26º), the LPS

produced was distinctly more potent and thus triggered TLR4.

Recognizing that this difference was not found in E. coli, a common

bacterium with some similarities to Y. pestis, Lien identified an E.

coli gene that was important for the production of LPS but that was

missing in Y. pestis. Using this gene to generate new strains of Y.

pestis, researchers produced Y. pestis strains that were recognized

much more easily by innate immunity and TLR4 at both

temperatures. Importantly, the investigators found that the new

strains were unable to cause plague and mortality in normal mice;

the strains were at least a million times less virulent than the wild

type bacteria.

“Our findings describe one of the secrets of the Black Death,” Lien

said. “These results suggest that the production of surface lipids

with poor ability to activate innate immunity is essential for Y. pestis

to be so deadly, and, in fact, for the ability of the bacteria to cause

plague. We expect this strategy to also be important for various

other human bacterial pathogens.”

“This result is quite surprising, in part because plague research has

focused on many active things that the bacteria do to protect

themselves from host defenses, including injecting toxins directly

into cells of the immune system that try to engulf them, " notes

Goguen. “Apparently all of this is useless unless the bugs can also

hide from TLR4. Stealth is important.”

Significantly, Lien and colleagues also determined that these new

harmless strains of Y. pestis could serve as vaccines. After

vaccinating mice with the modified strain of Y. pestis, the

Print the story http://www.physorg.com/printnews.php?newsid=77811326

3 of 3 9/18/2006 11:45 PM

investigators re-introduced the virulent strain after 30 days and

found that all of the animals were protected from developing plague.

These findings show that the production of avirulent bacterial strains

with enhanced ability to stimulate the immune system could

constitute a new general method for generating effective vaccines.

Source: University of Massachusetts Medical School

This news is brought to you by PhysOrg.com

 

 

 

Talk is cheap. Use Messenger to make PC-to-Phone calls. Great rates

starting at 1 & cent;/min.