Anthrax News and Articles

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What is anthrax?

Bacillus anthracis is a bacterium that lives in soil and has developed a survival tactic that allows it to endure for decades under the harshest conditions. An anthrax bacterial cell can transform itself into a spore, a very hardy resting phase, to withstand extreme heat, cold, and drought, without nutrients or air. When environmental conditions are favorable, the spores will germinate into thriving colonies of bacteria. For example, a grazing animal may ingest spores that begin to grow, spread, and eventually kill the animal. The bacteria will form spores in the carcass and then return to the soil to infect other animals in the future.

While its spore form allows the bacteria to survive in any environment, the ability to produce toxins is what makes the bacteria such a potent killer. Together, the hardiness and toxicity of B. anthracis make it a formidable bioterror agent. Its toxin is made of three proteins: protective antigen, edema factor, and lethal factor.

Protective antigen binds to select cells of an infected person or animal and forms a channel that permits edema factor and lethal factor to enter those cells.

Once inside the cell, edema factor causes fluid to accumulate at the site of infection. Edema factor can contribute to a fatal build-up of fluid in the cavity surrounding the lungs. It also can inhibit some of the body's immune functions.

Lethal factor also works inside the cell, disrupting a key molecular switch that regulates the cell's functions. Lethal factor can kill infected cells or prevent them from working properly.

Cutaneous anthrax

Cutaneous anthrax is the most common form of the disease. People with cuts or open sores can get cutaneous anthrax if they come in direct contact with the bacteria or its spores, usually through contaminated animal products. The skin will redden and swell, much like an insect bite, and then develop a painless blackened lesion or ulcer that may form a brown scab. Cutaneous anthrax responds well to antibiotics but may spread throughout the body if untreated. People who work with certain animals or animal carcasses are at risk of getting this form of the disease. Cutaneous anthrax is rare in the United States. According CDC, there are only one to two U.S. cases per year.

Inhalational anthrax

When spores of B. anthracis are inhaled, they germinate and the bacterial cells infect the lungs and then spread to the lymph nodes in the chest. As the bacteria grow, they produce two kinds of deadly toxins. Symptoms usually appear 1 to 7 days after exposure, but they may first appear more than a month later. Fever, nausea, vomiting, aches, and fatigue are among the early symptoms of inhalational anthrax; it progresses to labored breathing, shock, and often death. Historically, the mortality rate for naturally occurring inhalational anthrax has been high-about 75 percent. But inhalational anthrax is also rare. Prior to 2001, the last known U.S. case was in 1976 when a California craftsman died after getting the infection from imported yarn contaminated with anthrax spores.

Gastrointestinal anthrax

People can acquire gastrointestinal anthrax from eating meat contaminated with anthrax bacteria or their spores. Symptoms are stomach pain, loss of appetite, diarrhea, and fever. Antibiotic treatment can cure this form of anthrax, but untreated, it may kill half of those who get it. It occurs naturally in warm and tropical regions of Asia, Africa, and the Middle East. There have been no confirmed cases of gastrointestinal anthrax in the United States, although a Minnesota farm family may have experienced symptoms of the disease in 2000 after eating meat from a steer that had anthrax.

What are the treatment and prevention options for anthrax?

Antibiotics

If diagnosed early, anthrax is easily treated with antibiotics. Unfortunately, infected people often confuse early symptoms with more common infections and do not seek medical help until severe symptoms appear. By that time, the destructive anthrax toxins have already risen to high levels, making treatment difficult. Antibiotics can kill the bacteria, but antibiotics have no effect on anthrax toxins.

Vaccines

An existing anthrax vaccine is licensed for limited use. The vaccine is currently used to protect members of the military and individuals most at risk for occupational exposure to the bacteria, such as slaughterhouse workers, veterinarians, laboratory workers, and livestock handlers. The vaccine does not contain the whole bacterium; rather, it is made mostly of the anthrax protective antigen protein.

Health experts currently do not recommend the vaccine for general use by the public because anthrax illness is rare and the vaccine has potential adverse side effects. Researchers have not determined the safety and efficacy of the vaccine in children, the elderly, and people with weakened immune systems. Although the results of recently conducted CDC vaccine trials indicate that three to four doses of anthrax vaccine can generate significant protective immunity, the recommended vaccination schedule is six doses given over an 18-month period. To quickly protect the public during a bioterror attack, scientists are seeking to develop a new vaccine.

Toxin biology

Scientists are studying anthrax toxins to learn how to block their production and action. Recently, scientists discovered the three-dimensional molecular structure of the anthrax protective antigen protein bound to one of the receptors (CMG2) it uses to enter cells. The separate structures of protective antigen and CMG2 previously had been determined, but the structure of both bound together is more valuable, much as a roadmap connecting two cities is more useful than separate maps of the cities. Using a specific fragment of the CMG2 receptor protein, researchers have been able to block the attachment of protective antigen in test-tube experiments, thereby inhibiting all anthrax toxin activity.

Previously, NIAID grantees had determined the three-dimensional structure of the lethal factor protein as it attaches to its target inside cells. Their research showed that lethal factor uses a long groove on its side to latch onto the target.

In another recent advance, NIAID and other scientists have synthesized a small cyclic molecule that blocks anthrax toxin in cell culture and in rodents. The molecule blocks the pore formed by anthrax protective antigen. Blocking the pore effectively prevents lethal factor and edema factor toxins from entering cells. The scientists anticipate that this discovery will lead to new and effective treatments for anthrax.

Anthrax bacterium genome

The instructions that dictate how a microbe works are encoded within its genes. Bacteria keep most of their genes in a chromosome, a very long stretch of DNA. Smaller circular pieces of DNA called plasmids also carry genes that bacteria may exchange with each other. Because plasmids often contain genes for toxins and antibiotic resistance, knowing the DNA sequence of such plasmids is important. Scientists have sequenced plasmids carrying the toxin genes of B. anthracis. In addition, researchers have sequenced the complete chromosomal DNA sequence of several B. anthracis strains, including one that killed a Florida man in the 2001 anthrax bioterror attack.

By comparing the DNA blueprints of different B. anthracis strains, researchers are learning why some strains are more virulent than others. Small variations among the DNA sequences of different strains may also help investigators pinpoint the origin of an anthrax outbreak. Knowing the genetic fingerprint of B. anthracis might lead to gene-based detection mechanisms that can alert scientists to the bacteria in the environment or allow rapid diagnosis of anthrax in infected people. Variations between strains might also point to differences in antibiotic susceptibility, permitting doctors to immediately determine the appropriate treatment.

Scientists are now analyzing the B. anthracis genome sequence to determine the function of each of its genes and to learn how its genes interact with each other or with host-cell components to cause disease. Genes are the instructions for making proteins, which in turn build components of the cell or carry out its biochemical processes. Knowing the sequence of B. anthracis genes will help scientists discover key bacterial proteins that can then be targeted by new drugs or vaccines.

Spore biology

B. anthracis spores are essentially dormant and must 'wake up,' or germinate, to become reproductive, disease-causing bacteria. Researchers are studying the germination process to learn more about the signals that cause spores to become active once inside an animal or person. Efforts are under way to develop models of spore germination in laboratory animals. Scientists hope those models will enable discoveries leading to drugs that block the germination process.

Host immunity

People who contract anthrax produce antibodies to protective antigen protein. Similar antibodies appear to block infection in animals. Recent studies also suggest that some animals can produce antibodies to components of B. anthracis spores. Those antibodies, when studied in a test tube, prevent spores from germinating and increase their uptake by the immune system's microbe-eating cells. These discoveries suggest that scientists might be able to develop a vaccine to fight both B. anthracis cells and spores.

Researchers also are studying how the immune system responds to B. anthracis infection. Part of the immune system response, known as adaptive immunity, consists of B and T cells that specifically recognize components of the anthrax bacterium. The other type of immune response-innate immunity-aims more generally to combat a wide range of microbial invaders and likely plays a key role in the body's front-line defenses. Scientists are conducting studies of how those two arms of the immune system act to counter infection, including how B. anthracis spore germination affects individual immune responses.

Natural history of anthrax

In 2002, NIAID physician researchers initiated a clinical protocol to study the natural history of anthrax. The goal is to look at the infectious disease process over time, from initial infection through the clinical course and beyond recovery. A small number of anthrax survivors from the 2001 attacks have enrolled. Because the medical literature on anthrax does not include any findings regarding long-term complications in survivors, information gained in this study will be valuable to patients and doctors.

Vaccines

Researchers have developed new, more effective anthrax vaccines intended for broad use. If approved by the Food and Drug Administration (FDA), it could be given to children, the elderly, and those with weakened immune systems more easily than the existing military anthrax vaccine. NIAID is currently funding two companies to develop, produce, and perform clinical trials of a next-generation vaccine based on a genetically modified recombinant protective antigen (rPA) protein. Antibodies produced by the immune system in response to rPA are thought to be the primary mode of protection against anthrax spores. NIAID is also funding research on the application of new vaccination technologies and novel compounds that can boost the immune response to a vaccine.

Diagnostics

Research is under way to develop improved techniques for spotting B. anthracis in the environment and diagnosing it in infected individuals. A key part of that research is the functional genomic analysis of the bacterium, which should lead to new genetic markers for sensitive and rapid identification. Genomic analysis will also reveal differences in individual B. anthracis strains that may affect how those bacteria cause disease or respond to treatment.

Therapies

Following the discoveries of how the protective antigen and lethal factor proteins interact with cells, researchers are screening thousands of small molecules in hopes of finding an anti-anthrax drug. In addition, NIAID is working with FDA, CDC, and the Department of Defense to accelerate testing of collections of compounds for their effectiveness against inhalational anthrax. Many of those compounds already have been approved by the FDA for other conditions and therefore could quickly be approved for use in treating anthrax, should they prove effective.

NIAID is also seeking new drugs that attack B. anthracis at many levels. These include agents that prevent the bacterium from attaching to cells, compounds that inhibit spore germination, and inhibitors that block the activity of key enzymes such as anthrax lethal factor. NIAID also will develop the capacity to synthesize promising anti-anthrax compounds in sufficient purity and quantity for preclinical testing.

Source: National Institutes of Health

Recent Anthrax News and Articles

Patent Issued for Designer Ubiquitin Ligases Having a Non-Cleavable SNAP25 Domain and E3-Ligase Domain

2013 JAN 15 (NewsRx) -- By a News Reporter-Staff News Editor at Life Science Weekly -- From Alexandria, Virginia, NewsRx journalists report that a patent by the inventors Oyler, George A. (Baltimore, MD); Tsai, Yien Che (Frederick, MD), filed on June 10, 2009, was cleared and issued on January 1, 2013.

The patent's assignee for patent number 8343743 is Synaptic Research, LLC (Baltimore, MD).

News editors obtained the following quote from the background information supplied by the inventors: "Intoxication with biological toxins is a serious health and bioterrorism threat problem. Our inability to effectively treat toxin exposure makes certain toxins particularly dangerous agents for terrorist attacks. Treatment options for individuals after toxin infection are limited. For example, once someone is intoxicated with botulinum neurotoxin, the individual is paralyzed for periods up to 4 to 6 months or longer depending on the toxin serotype because the toxin is slow to degrade. During this time the patient is entirely dependent on ventilatory assistance.

"Hence, a need exists for an effective treatment after intoxication by toxin. A further need exists for a composition that can inhibit the toxin but also cause the toxin to be degraded to alleviate symptoms of the toxin infection."

As a supplement to the background information on this patent, NewsRx correspondents also obtained the inventors' summary information for this patent: "The present invention relates to a recombinant ubiquitin ligase molecule that includes a toxin binding domain that has an affinity for an enzymatically active fragment of one or more toxins or toxin serotypes; and an E3-ligase domain that comprises an E3-ligase or polypeptide that facilitates E2-mediated ubiquitination of the toxin enzymatically active fragment. The toxin binding domain, in an embodiment, can be a non-cleavable SNARE polypeptide or fragment thereof that binds to the enzymatically active fragment of a botulinum neurotoxin (BoNT). In particular, the enzymatically active fragments of BoNT include those known in the art or from later discovered serotypes, such as BoNT serotypes A-G. Examples of SNARE polypeptides include a non-cleavable SNAP-25, syntaxin, or synaptobrevin. In another embodiment, wherein the toxin binding domain includes a G protein .alpha..sub.s polypeptide or fragment thereof that has affinity to the enzymatically active fragment of a cholera toxin. The toxin binding domain that has an affinity for an enzymatically active fragment of one or more of the following toxins The toxin includes, botulinum neurotoxin (BONT) (serotypes A-G), Clostridia difficile toxins A and B (Tcd A and Tcd B), Clostridium Lethal Toxin, Anthrax Lethal Factor (LF), Ricin, Exotoxin A, Diphtheria toxin, Cholera toxin, Tetanus toxin, Shiga toxin, and any combinations thereof In one aspect, a polypeptide that facilitates E2-mediated ubiquitination is an antibody specific to E2. Another aspect of the invention includes a recombinant ubiquitin ligase having one or more of the following E3 ligase domains: RING, HECT, U-box, RIBRR, F-box domain, DCAF domain, DDS2, HIF-mimetic peptides, IkB-mimetic sequences, BTB domain or combination thereof.

"In particular, the recombinant ubiquitin ligase molecule of the present invention includes a non-cleavable SNARE polypeptide or fragment thereof is encoded by a nucleic acid molecule that comprises one or more of the following nucleic acid sequences: a nucleic acid sequence having greater than or equal to about 70% identity with SEQ ID NO: 5; a nucleic acid sequence complement having greater than or equal to about 70% identity with of SEQ ID NO: 5; a nucleic acid molecule having greater than or equal to about 70% identity with a molecule that hybridizes to SEQ ID NO: 5; and a nucleic acid sequence that encodes an amino acid sequence having greater than or equal to about 70% similarity to a sequence set forth in SEQ ID NO: 6. Similarly, the present invention further relates to a recombinant ubiquitin ligase molecule, wherein the non-cleavable SNARE polypeptide or fragment thereof that comprises one or more of the following amino acid sequences: an amino acid sequence encoded by a nucleic acid having greater than or equal to about 70% identity with SEQ ID NO: 5; an amino acid sequence encoded by a complement having greater than or equal to about 70% identity with of SEQ ID NO: 5; an amino acid sequence encoded by a nucleic acid molecule having greater than or equal to about 70% identity with a molecule that hybridizes to SEQ ID NO: 5; and an amino acid sequence having greater than or equal to about 70% similarity to a sequence set forth in SEQ ID NO: 6.

"The recombinant ubiquitin ligase molecule of the present invention includes a SNARE polypeptide or fragment that has been mutated to be non-cleavable. In particular, the molecule of the present invention is encoded by a nucleic acid molecule that comprises one or more of the following nucleic acid sequences: a nucleic acid sequence having greater than or equal to about 70% identity with SEQ ID NO: 1 or 3; a nucleic acid sequence complement having greater than or equal to about 70% identity with of SEQ ID NO: 1 or 3; a nucleic acid molecule having greater than or equal to about 70% identity with a molecule that hybridizes to SEQ ID NO: 1 or 3; and a nucleic acid sequence that encodes an amino acid sequence having greater than or equal to about 70% similarity to a sequence set forth in SEQ ID NO: 2 or 4. These nucleic acid molecules include one or more mutations to render the polypeptide non-cleavable. Along the same lines, the present invention relates to a recombinant ubiquitin ligase molecule that comprises one or more of the following amino acid sequences: an amino acid sequence encoded by a nucleic acid having greater than or equal to about 70% identity with SEQ ID NO: 1 or 3; an amino acid sequence encoded by a complement having greater than or equal to about 70% identity with of SEQ ID NO: 1 or 3; an amino acid sequence encoded by a nucleic acid molecule having greater than or equal to about 70% identity with a molecule that hybridizes to SEQ ID NO: 1 or 3; and an amino acid sequence having greater than or equal to about 70% similarity to a sequence set forth in SEQ ID NO: 2 or 4; wherein the nucleic acid molecule comprises one or more mutations to render the polypeptide non-cleavable.

"The present invention pertains to a recombinant ubiquitin ligase molecule having a E3 ligase domain that is encoded by a nucleic acid molecule that comprises one or more of the following nucleic acid sequences: a nucleic acid sequence having greater than or equal to about 70% identity with SEQ ID NO: 9; a nucleic acid sequence complement having greater than or equal to about 70% identity with of SEQ ID NO: 9; a nucleic acid molecule having greater than or equal to about 70% identity with a molecule that hybridizes to SEQ ID NO: 9; and a nucleic acid sequence that encodes an amino acid sequence having greater than or equal to about 70% similarity to a sequence set forth in SEQ ID NO: 10. Similarly, the present invention includes a recombinant ubiquitin ligase molecule having a E3 ligase domain that comprises one or more of amino acid sequences: an amino acid sequence encoded by a nucleic acid having greater than or equal to about 70% identity with SEQ ID NO: 9; an amino acid sequence encoded by a complement having greater than or equal to about 70% identity with of SEQ ID NO: 9; an amino acid sequence encoded by a nucleic acid molecule having greater than or equal to about 70% identity with a molecule that hybridizes to SEQ ID NO: 9; and an amino acid sequence having greater than or equal to about 70% similarity to a sequence set forth in SEQ ID NO: 10.

"Additionally, the present invention relates to a recombinant ubiquitin ligase molecule that is encoded by a nucleic acid molecule that comprises one or more of the following nucleic acid sequences: a nucleic acid sequence having greater than or equal to about 70% identity with SEQ ID NO: 11 or 13; a nucleic acid sequence complement having greater than or equal to about 70% identity with of SEQ ID NO: 11 or 13; a nucleic acid molecule having greater than or equal to about 70% identity with a molecule that hybridizes to SEQ ID NO: 11 or 13; and a nucleic acid sequence that encodes an amino acid sequence having greater than or equal to about 70% similarity to a sequence set forth in SEQ ID NO: 12 or 14. Also, the present invention includes a recombinant ubiquitin ligase molecule that comprises one or more of the following amino acid sequences: an amino acid sequence encoded by a nucleic acid having greater than or equal to about 70% identity with SEQ ID NO: 11 or 13; an amino acid sequence encoded by a complement having greater than or equal to about 70% identity with of SEQ ID NO: 11 or 13; an amino acid sequence encoded by a nucleic acid molecule having greater than or equal to about 70% identity with a molecule that hybridizes to SEQ ID NO: 11 or 13; and an amino acid sequence having greater than or equal to about 70% similarity to a sequence set forth in SEQ ID NO: 12 or 14.

"The present invention pertains to an isolated polypeptide molecule that includes a non-cleavable SNARE polypeptide or fragment thereof that has affinity to the enzymatically active fragment of a BoNT; a BoNT holotoxin, wherein the BoNT holotoxin comprises a deletion in the light chain, a mutation of the heavy chain, or both, wherein the deletion, mutation or both renders BoNT holotoxin atoxic; and an E3-ligase domain that comprises an E3-ligase or polypeptide that facilitates E2-mediated degradation of the toxin enzymatically active fragment of a BoNT. The non-cleavable SNARE polypeptide and the BoNT atoxic holotoxin can be fused e.g., the non-cleavable SNARE polypeptide or fragment thereof is fused to the N-terminus of the BoNT atoxic holotoxin. The present invention further relates to fusion proteins that include the isolated polypeptide of the present invention.

"In yet another embodiment, the recombinant ubiquitin ligase molecule of the present invention relates to a non-cleavable SNARE polypeptide or fragment thereof that has affinity to the enzymatically active fragment of a BoNT; an E3-ligase domain that comprises an E3-ligase or polypeptide that facilitates E2-mediated ubiquitination of the toxin enzymatically active fragment; and a translocation/cellular binding domain. The translocation/cellular binding domain binds to the cellular membrane of a cell and delivers the recombinant ubiquitin ligase into the cell. Examples of the translocation/cellular binding domain include an antennapedia protein, HIV TAT protein, herpes simplex virus VP22 protein, penetratin-derived peptides, kFGF, human .beta.3 integrin, L- and D-arginine oligomers, SCWK.sub.n, (LARL).sub.n, HA2; RGD; K.sub.1 6RGD oligomer; AlkCWK.sub.18, DiCWK18, DipaLytic; Plae, Kplae, MPG peptide, Pep-1, or an atoxic neurotoxin.

"Methods of degrading or inhibiting one or more BoNT serotypes that have intoxicated one or more cells are include in the present invention. The steps of the method include contacting an amount of the recombinant ubiquitin ligase of the present invention with the intoxicated cells; wherein the recombinant ubiquitin ligase degrades or inhibits at least one BoNT serotype. An amount of recombinant ubiquitin ligase ranges from e.g., about 1 pM to about 100 mM. The time for contacting the designer ligase of the present invention with intoxicated cells ranges from about 1 minute and about 1 week.

"The present invention also relates to methods of treating an individual having one or more cells intoxicated with one or more BoNT serotypes. The steps of the present invention include administering to the individual an amount of recombinant ubiquitin ligase of present invention in a carrier; wherein one or more symptoms associated with BoNT intoxication are reduced or reversed. One or more symptoms associated with BoNT intoxication that are reduced or revised include blurred vision, dry mouth, difficulty swallowing, difficulty speaking, paralysis, muscle weakness; respiratory failure, and decreased nerve conduction. The amount of recombinant ubiquitin ligase administered to the individual ranges from e.g., about 10 ng to about 5 gm. The recombinant ubiquitin ligase can be administered intravenously, parenterally, orally, nasally, by inhalation, by implant, by injection, or by suppository, and can be administered once or periodically. Additionally, the present invention relates to pharmaceutical compositions comprising the recombinant ubiquitin ligase molecule of the present invention and a carrier."

For additional information on this patent, see: Oyler, George A.; Tsai, Yien Che. Designer Ubiquitin Ligases Having a Non-Cleavable SNAP25 Domain and E3-Ligase Domain. U.S. Patent Number 8343743, filed June 10, 2009, and issued January 1, 2013. Patent URL: http://patft.uspto.gov/netacgi/nph-Parser'Sect1=PTO2&Sect2=HITOFF&p=83&u=%2Fnetahtml%2FPTO%2Fsearch-bool.html&r=4107&f=G&l=50&co1=AND&d=PTXT&s1=20130101.PD.&OS=ISD/20130101&RS=ISD/20130101

Keywords for this news article include: Ligases, Peptides, Proteins, Ubiquitins, Amino Acids, Neurotoxins, Enzymes and Coenzymes, Synaptic Research LLC.

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