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Anthrax

Description
Anthrax is an acute infectious disease caused by a spore-forming bacterium that can infect all warm blooded animals including man. When anthrax affects humans, it is usually due to an occupational exposure to infected animals or animal products such as wool or hair from diseased animals. Most (95%) cases of anthrax infection in humans occur when the bacterium enters a cut or abrasion on the skin or by inhaling anthrax spores that have been aerolosized. Specific antibiotics can be prescribed by a doctor to treat anthrax. To be effective, treatment should be initiated immediately. If left untreated, the disease can be fatal.

Who is at Risk?
In October 2001, five workers died from inhalation anthrax and an additional 13 developed cutaneous or inhalational anthrax exposure disease as a result of international terrorist activity. In most cases seen so far, the disease was linked to unexpected workplace exposures to anthrax spores contained in letters mailed through the United States Postal Service. However, anthrax exposure is most common in animal handling and related occupations, where Bacillus anthracis spores can exist naturally.

Scientists Learn How Anthrax Creates Its Infectious Spores
In a collaboration funded by the U.S. Office of Naval Research and the National Institutes for Health, scientists from three major research institutions - TSRI, the University of Michigan, and The Institute for Genomic Research (TIGR) - are working together to identify the genes and proteins involved in anthrax's deadly metamorphosis.

Their work provides information other researchers can use to develop new vaccines and treatments targeted at specific points in the complex process of anthrax growth and spore formation. The study is the first analysis of a bacterial pathogen using the combined investigative tools of genomics and proteomics. It is also the first study to document, at a molecular level, all the genes and proteins involved in B. anthracis spore formation.

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TSRI Research Suggests Powerful Tool For Detection And Treatment Of Anthrax
Human antibodies against Bacillus spores, of which one species is the cause of anthrax, have been identified by TSRI researchers led by Kim D. Janda, Ph.D., who holds the Ely R. Callaway, Jr. Chair in Chemistry. These antibodies could be used to detect the presence of anthrax and other harmful spores in powders and to protect those exposed against lethal infections. The antibodies provide the ability to dissect very quickly what is there - whether it's hazardous spore preparation or just plain baby powder. Using donated blood, the researchers were able to find a number of human antibodies that were all highly specific for spores of Bacillus subtilis, a close cousin of Bacillus anthracis which is the causative agent of anthrax, and 11 other types of bacterial spores.

For the first time, human antibodies were shown to recognize spore surfaces. The antibodies might make a powerful and convenient tool for detecting anthrax. Moreover, antibodies that bind to spores have important implications for treating individuals who are exposed to anthrax. Since the antibodies come from humans, they could be given to individuals to passively immunize them - the antibodies would help to clear anthrax spores from the individual's system. And, because of the ease of producing and administering antibodies, they represent a simple, inexpensive, and potentially powerful therapy.

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$11.4 Million CDC Grant Goes To TSRI To Study Immune Response To Anthrax Toxins
The U.S. Centers for Disease Control and Prevention (CDC) has awarded a group of TSRI researchers a multi-year, $11.4 million grant to study the interaction of the human immune system with toxins of the bacterium Bacillus anthracis, the causative agent of the disease anthrax. The goal of the grant is to understand how B. anthracis toxins suppress immune responses in humans, circumventing the usual mechanisms by which the body would destroy the bacterium. Several TSRI scientists will define genetic and cellular elements that determine susceptibility to anthrax infection and progression which should facilitate the translation of basic research into clinical applications. TSRI Professor Gary Bokoch, Ph.D. is one of the lead investigators.

One thing that is not clearly understood is why some people are more susceptible to infection than others, and some of the projects in the grant will address this question. TSRI Professor Bruce Beutler, M.D., for instance, will investigate which host genes are required for susceptibility and/or resistance to the anthrax lethal toxin. Similarly, another project on the grant will look for polymorphisms - DNA variations that differ from person to person - that might make some people more susceptible to anthrax than others.

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Attacking Anthrax On Two Fronts
Because B. anthracis produces a virulent toxin that kills cells and, in high enough doses, infected people, the effectiveness of Cipro diminishes if exposure is not detected quickly enough. Finding a way to neutralize the effect of the toxins would be a great boon to public health preparedness against anthrax exposure. Now a team of scientists led by TSRI Professor Chi-Huey Wong, Ph.D., Ernest W. Hahn Professor and Chair of Chemistry, is reporting that it has found a potential way of improving treatment; it has discovered a class of antibiotic derivatives that targets not only the bacteria, but also the anthrax toxin. Protective antigen, lethal factor, and edema factor work together to make Bacillus anthracis deadly. Of the three, lethal factor makes a tantalizing target for drug design because strains of anthrax unable to produce lethal factor are not pathogenic, which means that blocking this protein may be enough to save lives.

Wong and his colleagues set out to design antitoxins that could be used to target lethal factor by using in vitro and cell-based assays to screen a library of about 3,000 chemical compounds for those that have the ability to bind to and inhibit anthrax's lethal factor. Among the compounds in this library were a number of aminoglycosides, including neomycin B, a common antibiotic and the main component of Neosporin. Neomycin B bound to lethal factor in the test tube and inhibited the lethal factor-induced signaling pathway in cell-bound assays. Wong and his colleagues then made derivatives of neomycin through chemical synthesis. When they tested these, several of them looked even more effective at binding to and inhibiting lethal factor. Significantly, because the neomycin derivatives are all aminoglycosides, they also have the ability to bind to the ribosomal RNA of the anthrax bacterium itself, thus inhibiting its normal functioning.

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$9.2 Million Grant Enables Scripps Scientists To Design Anthrax Antitoxin Nanosponges
A large, multi-center program project grant has been awarded to a team of scientists at TSRI, Harvard Medical School, and The Salk Institute for Biological Studies to discover and develop novel anthrax antitoxins and ways of delivering them. The overall goal of the program is to design anti-anthrax nanosponges - antitoxin particles that could be administered to someone who has been exposed to anthrax.

The nanosponges would basically bind up all the toxin and render it ineffective, according to TSRI Assistant Professor Marianne Manchester, Ph.D., who is the principal investigator of the grant. The scientists at TSRI are adapting technology that has been developed to display molecular decoys (anti-toxins that would grab the toxins out of the bloodsteam) in multiple numbers on the surface of nanoparticles - to make the antitoxin nanosponges.

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Working To Tease Out Bacteria's Secrets
The work of TSRI Associate Professor Marta Perego, Ph.D. focuses on Bacillus anthracis, which can cause anthrax. Humans acquire the disease directly from contact with infected herbivores or indirectly through their waste products. B. anthracis can exist in two different forms. When conditions for growth are good, with plentiful nutrients and water available, B. anthracis grows and divides. When conditions are unfavorable, each cell forms a resistant dormant spore able to survive extreme environmental conditions. Perego seeks to understand how and why this bacterium goes from one state to another. Her recent focus on B. anthracis evolved from 20 years of work with Bacillus subtilis, which is similar to B. anthracis except that B. subtilis doesn't cause disease. Using what she characterizes as routine molecular biology - cloning a gene, mutating a gene, and expressing a gene to make a protein - Perego is focusing on the signaling mechanisms of B. anthracis to better understand its ability to grow and form spores. Any bacterium or any cell, whether it's human or bacterium, is regulated by mechanisms called signal transduction. A bacterial cell receives signals from the environment or from itself, and it translates those signals into a response. In other words, something sends the cell a signal - the heat, too much salt - and through a series of chemical reactions transduces this signal to certain proteins that act and activate a response. Signal transduction involves kinases, enzymes that alter other proteins by attaching phosphate to them. Kinases direct the action by altering the shape of the proteins and enabling them to do the necessary work. Once there's a signal that sets off a series of responses, it's essential that, somewhere down the line, you can put the brakes on that signal and reset the system. Something needs to be introduced that counteracts the original directions of the kinases. That's the job of the phosphatases, which are also enzymes.

In some bacterial cell reactions, it's easy for scientists to determine the signals. But others, like TV static, aren't clear at all - one of these is the reaction that initiates the development of the bacterium into a spore. This is one of the mysteries Perego is trying to solve. Why does a cell that grows, divides, and divides again decide at a certain point to stop and transform itself into a spore, something that isn't really living anymore? Human infection from Bacillus anthracis is a result of this bacteria's ability to outwit the body's immune system. The pathogenic process is set in motion when B. anthracis acquires some extra DNA, called a plasmid, which is a vector for the introduction of new genes into a bacterial cell. Plasmids allow B. anthracis, an otherwise harmless bacterium, to produce deadly toxins and to build a protective shell called a capsule. The body's immune system does what it can: it easily destroys most of the spores that first infect a host. But a few spores escape and travel out from the lungs to the safe harbor of the lymph nodes or bloodstream. Once there, they start growing, each makes a protective capsule around itself, and then they can keep growing. In this protected state, the immune system is powerless, and the bacteria keep churning out toxin. This ability to escape the immune system, along with the fact that the cell's extra DNA is capable of making a toxin, is bad news. Toxemia and bacteremia can result and the patient can die. Scientists have known for some years that B. anthracis doesn't sporulate in the blood, and this fact was the starting point in Perego's research into this bacterium's mechanisms of infection. Her work has resulted in some surprises and the publication of two academic papers that shed light on this generative process. Her research has revealed that B. anthracis may have developed mechanisms that allow it to efficiently sporulate in the most favorable environments and to delay sporulation when sporulation would kill it.

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