A new weapon to disable bacteria discovered

White blood cells imprison bacteria in tightly fitting compartments or vacuoles. Within these vacuoles, the cells release noxious substances that kill the bacteria. This is why most of the time our bodies can take care of small wounds or mild infections. Sometimes, however, we get infected with bacteria equipped with highly evolved defenses that target white blood cells, the very cells that are supposed to defend us. A case in point is dysentery, a serious, bloody form of diarrhea. It is caused by bacteria called Shigella. This is a devastating disease that claims millions of lives every year, especially among children in the developing world.

Shigella uses disease-causing (virulent) proteins to attack human cells. Shigella uses these virulent proteins to invade any cell in the body and then to escape from the cellular prison - the vacuole. Weinrauch and Zychlinsky recognized a contradiction: if Shigella escapes the vacuolar prison, the infection should always be lethal. Yet, most people recover after suffering an acute infection.

Weinrauch and Zychlinsky reasoned that the answer could be found in a specialized white blood cell - the neutrophil. Neutrophils were prime suspects for two reasons. Firstly, they are very abundant in the response to Shigella infections, and secondly, they are equipped with defense mechanisms that kill bacteria when confined to a vacuolar prison. In collaboration with Jerry Weiss, now at Iowa University, the investigators found that surprisingly, neutrophils, unlike any other type of cells, can enclose Shigella within the vacuoles.

Fig. 1a and 1b: Electron micrographs of human neutrophils infected with Shigella. The difference is that in one of them elastase is active and the Shigella is inside a vacuole, while in the other one elastase is inactive and therefore the Shigella is outside the vacuole. "S" indicate Shigella and an N the neutrophil. The bacteria are 10 times smaller than a neutrophil, so the pictures show detail of the neutrophil, where the Shigella are present. Enlarge image. (Photo: Max Planck Institute for Infection Biology) Full size image available through contact

Investigations into the reason why Shigella is enclosed within neutrophil vacuoles led Weinrauch and Zychlinsky to discover how the neutrophil can neutralize not only Shigella but also other disease causing bacteria. Neutrophils produce an enzyme, elastase, which can destroy Shigella's escape proteins with amazing efficiency before they can leave the vacuole. In this manner neutrophils retain the Shigella long enough to mobilize other defenses that can destroy the bacteria. Indeed, neutrophils with inactivated elastase cannot contain Shigella in a vacuole, and the bacteria remains virulent, as shown in collaboration with Steve Shapiro of Harvard Medical School. Interestingly, elastase destroys virulent proteins not only in Shigella, but also in Salmonella, the cause of typhoid fever and in Yersinia, the cause of Bubonic plague.

Many questions remain regarding the timely delivery of elastase and how it can recognize virulent proteins within bacteria. This new insight, however, may allow the development of a new generation of antibiotics that would rely on neutralizing the virulent proteins of disease-causing bacteria rather than indiscriminately killing microbes.

Original Publication:
Neutrophil elastase targets virulence factors of enterobacteria, Nature, 2. Mai 2002

Contact:
Prof. Arturo Zychlinsky
Max Planck Institute for Infection Biology
Campus Charite Mitte
Schumannstrasse 21/22
Berlin 10117
Phone: + 49 30 / 2846 - 0300
Fax: +49 30 / 2846 - 0301
E-mail: zychlinsky@mpiib-berlin.mpg.de

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