Plague is determined by a bacillus (sticklike bacteria) named Yersinia pestis. Many related bacteria are also pathogen provoking food poisoning.
Plague bacteria has the ability to avoid the innate immune response, the body's front line of defense against invading pathogens, and - in many cases - the host dies before its specific antibacterial response reacts. This stealth and virulence has made plague one of the diseases which took the greatest toll in human history, more than 200 million victims.
Even if today in the developed countries plague is rare, a few thousands worldwide are infected annually and with the potential of using Yersinia pestis as a biological weapon, the efforts to develop better treatments and a vaccine are equally important as before.
A team at the University of Massachusetts Medical School modified Yp with a gene found in a common bacillus, Escherichia coli, rendering it unable to cause plague. Before the immune system release antibodies that precisely target
and combat pathogens that have entered the body, the innate immune system reacts first upon infection.
Recently, an important class of sensor molecules were discovered, known as Toll-like receptors (TLRs) that recognize the pathogens, activating the signaling pathways that stimulate this innate immune response.
Increasing the sensibility of the TLRs also improves the adaptive immune response; many vaccines include ingredients known as adjuvants that stimulate the innate immune response. But scientists have discovered that Yp has an unusual temperature-dependent ability to evade the innate immune system. The membrane of the bacteria is mainly composed of lipopolysaccharide (LPS) (fat molecules and polysacharids molecules). LPS typically provoke a strong response from the immune system.
At human body temperature (37ºC), Yp produces an LPS with a poor ability to activate mammalian TLRs; at lower temperatures (26º), for example that of vector flea (fleas transmits the pathogen from human to human and between rodents and people), the LPS produced was more potent and triggered TLRs response.
These traits do not exist in E. coli, a bacterium with some similarities to Y. pestis. Egil Lien PhD, assistant professor of medicine and molecular genetics & microbiology, identified an E. coli gene important for the production of LPS but missing in Yp. The scientists inoculated this gene in the Yp genome, producing Yp breeds that were easily recognized by TLRs at every temperature.
These new breeds could not cause the disease in normal mice; they were at least a million times less virulent than the original 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 Jon D. Goguen, PhD, associate professor of molecular genetics and microbiology.
"Apparently all of this is useless unless the bugs can also hide from TLR4. Stealth is important."
The new harmless strains of Yp can be used as vaccines. Experiments on mice showed that vaccinated animals were totally immune after 30 days to the virulent form of the bacteria.
The production of harmless bacterial strains can be used to make effective vaccines that stimulate the immune system.
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