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Studies reveal how plague disables immune system, and how to exploit the process to make a vaccine

ry specific weapons targeted at those individual pieces.

"This is a very clever system for this particular kind of bacteria," said Schneewind. It can take eight to 10 days for the B and T cells to multiply and fully engage. "By that time, with plague," he said, "the host is dead."

The bacteria's Achilles heel, however, may be a protein called LcrV, which Y. pestis transports through the needle and uses to inject its toxins. LcrV plays two roles. It helps the needle to penetrate the membrane surrounding the target cell. It also suppresses the immune response. LcrV causes affected cells to release 40 times the normal levels of interleukin 10 (IL-10), which dampens down the immune response. LcrV also prevents secretion of tumor necrosis factor (TNF), which causes inflammation.

"LcrV is secreted in massive amounts via the type-III pathway during an infection," Schneewind said. "Without it, the bacteria are relatively harmless."

Consequently, researchers have tried to use LcrV alone as a vaccine. Unfortunately, because it suppresses the immune system, immunization with this molecule may be harmful.

Schneewind and colleagues, however, tested 11 truncated versions of LcrV, snipping out, from different locales, 30 of the protein's 326 amino acids in hopes of eliminating the elements that suppressed the immune response but retaining enough of the normal protein's structure to generate protective antibodies.

Out of 11 altered versions they found one that met both criteria. In mouse and human macrophages, version rV10, missing amino acids 271 through 300, triggered only small amounts of IL-10 and had little effect on TNF secretion. Mice immunized twice over six weeks with rV10 developed antibodies that protected them from many times the lethal dose of the bacteria.

"Our data, the authors conclude, "provide the first evidence of plague vaccines that do not suppress innate immune responses ?and that may be useful for plague
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Source:University of Chicago Medical Center


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