Volunteer for NIAID-funded clinical studies related to anthrax on ClinicalTrials.gov.
Anthrax is the disease caused by the bacterium Bacillus anthracis, which lives in soil. The bacterial cell lives as a hardy spore to survive harsh conditions. The spores germinate into thriving colonies of bacteria once inside an animal or person. Anthrax usually affects livestock far more than humans, but—as we know from the 2001 anthrax attacks in the United States—anthrax is feared as a modern biological weapon.
Anthrax occurs in three forms:
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 or black scab, which is actually dead tissue. 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.
When a person inhales the spores of Bacillus anthracis, they germinate and the bacteria infect the lungs, spreading 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 75 percent, even with appropriate treatment. But inhalational anthrax is rare. In the 2001 anthrax attacks, 11 people were infected with inhalational anthrax and 6 survived. 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.
People can get 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 left untreated, it may kill half of those who get it.
Gastrointestinal anthrax occurs naturally in warm and tropical regions of Asia, Africa, and the Middle East. It is the least common form of anthrax in the United States.
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 which can 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.
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.
In 1970, the Food and Drug Administration approved an anthrax vaccine for humans which is licensed for limited use. The vaccine is currently used to protect members of the military and people 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, so people cannot get anthrax infection from the vaccine.
Health experts currently do not recommend the vaccine for general use by the public because anthrax illness is rare and the vaccine potentially can cause adverse side effects in some people. Researchers have not determined the safety and efficacy of the vaccine in children, the elderly, and people with weakened immune systems. Although the vaccine trials indicate that three to four doses of anthrax vaccine can generate significant protective immunity, the recommended vaccination schedule is five doses given over an 18-month period and efforts are underway to reduce the number of doses further. Nonetheless, to enhance public protection in the event of an anthrax bioterror attack, scientists are seeking to develop an improved anthrax vaccine.
NIAID conducts and funds research to improve our ability to prevent, diagnose, and treat anthrax. Anthrax research was under way prior to the 2001 bioterror attack, but it has expanded significantly since then. New research findings are improving our understanding of how Bacillus anthracis causes disease and how to better prevent and treat it.
Several biologic factors contribute to B. anthracis’ ability to cause disease. NIAID researchers and grantees are uncovering the molecular pathways that enable the bacterium to form spores, survive in people, and cause illness. Scientists envision this basic research to be the pathway to new vaccines, drugs, and diagnostic tools.
Natural History of Anthrax
One goal of NIAID physician-researchers 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 are enrolled in a long-term clinical study for this purpose. Many years of clinical observation are needed for this type of study to yield definitive results. 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 healthcare workers.
Scientists are studying anthrax toxins to learn how to block their production and action. Recently, NIAID-supported scientists have shown that protective antigen can bind edema factor and lethal factor at the same time, forming a greater variety of toxin complexes than were previously known. This finding could help researchers develop antitoxin therapies.
Previously, 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. 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.
NIAID-funded scientists also had 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.
Scientists anticipate that these findings will lead to new and effective treatments.
Anthrax Bacterium Genome
Genes are the instructions for making proteins, which in turn build components of the cell or carry out its biochemical processes. 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 Bacillus 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 those genes interact with each other or with host-cell components to cause disease. Knowing the sequence of B. anthracis genes will help scientists discover key bacterial proteins that can then be targeted by new drugs or vaccines.
Bacillus 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 in B. anthracis spores.
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.
In another study, NIAID-supported scientists have discovered a potential target for developing new measures to prevent and treat anthrax toxicity. Their study shows that a human gene called LRP6 plays a role in the delivery of anthrax toxins into cells. Antibodies directed against LRP6 protected cell cultures from anthrax lethal toxin. These results suggest that targeting LRP6 may prove useful in developing ways to protect against the effects of accumulated toxin.
NIAID is supporting research on next-generation anthrax vaccines designed to prevent infection using fewer doses than the currently licensed vaccine. Other vaccine technologies that might provide protective immunity more quickly and that could be stored and delivered more easily are also being pursued. One of the most promising concepts for a new anthrax vaccine is based on recombinant protective antigen (rPA). These vaccines provide excellent protection for rabbits and monkeys and have been used in two phases of human clinical trials. The rPA vaccines appear to produce an effective immune response in people with intact immune systems. In general, the goal is to make rPA vaccines that are safer, more reliable, can be produced in large quantities, and may also be given to people with compromised immune systems.
In 2012, scientists at NIAID and the Centers for Disease Control and Prevention learned that a blood-based assay for measuring antibodies induced by the anthrax vaccine could detect a protective response across several species. Their findings suggest that the assay could potentially be used to predict how anthrax vaccines might work in humans. Read more about this study.
Research is under way to develop improved techniques for spotting B. anthracis in the environment and diagnosing it in infected individuals. As mentioned previously, 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.
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 the Food and Drug Administration (FDA), Centers for Disease Control and Prevention, and U.S. 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 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 Bacillus anthracis at different 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.
NIAID-supported scientists have solved the structure of enzymes called sortases, which are known to anchor bacterial surface proteins to the cell walls. These enzymes may be essential to bacterial survival, and therefore could be an attractive potential target for therapies.
Scientists have designed a compound that blocks anthrax toxins from attaching to receptors on the surface of host cells in animal models. If the toxin cannot attach to and enter the cell, it is effectively neutralized. The new inhibitor is much more potent than current therapies and shows promise against some antibiotic-resistant strains as well. The general concept could also be applied to designing inhibitors for other pathogens.
Researchers have also found that human monoclonal antibodies protect against inhalation anthrax in three animal models. New anthrax therapies, such as monoclonal and polyclonal antibodies that can neutralize anthrax toxins, are being further developed.
Last Updated September 30, 2013
Last Reviewed August 04, 2010