Anthrax toxin is a complex of proteins produced by Bacillus anthracis, the bacterium responsible for anthrax. Its actions are central to the development of symptoms in infected individuals. The toxin interferes with normal cellular processes, leading to widespread disruption.
Understanding the Toxin’s Building Blocks
Anthrax toxin is composed of three distinct protein components: Protective Antigen (PA), Lethal Factor (LF), and Edema Factor (EF). Individually, these components are not harmful, but they become toxic when combined.
Protective Antigen (PA) is the binding and translocation unit of the toxin. It acts as the gateway, allowing Lethal Factor (LF) and Edema Factor (EF) to enter host cells. PA binds to specific receptors on target cells, initiating cellular entry.
Lethal Factor (LF) and Edema Factor (EF) are the enzymatic components. LF is a protease that breaks down proteins, while EF is an adenylate cyclase that produces cyclic AMP (cAMP). When PA combines with LF, it forms “lethal toxin,” causing cell death. When PA combines with EF, it forms “edema toxin,” leading to fluid accumulation and swelling.
The Toxin’s Journey Inside Cells
The anthrax toxin mechanism begins with Protective Antigen (PA) binding to specific receptors on host cell surfaces. This binding causes a conformational change in PA, making it susceptible to cleavage by cellular furin-like proteases. This cleavage splits the 83 kDa PA protein (PA83) into a smaller 20 kDa fragment (PA20), which dissociates, and a larger 63 kDa fragment (PA63) that remains attached to the cell.
The PA63 fragments then assemble into a ring-shaped heptamer. This heptamer forms a pore on the cell surface, serving as a binding platform for the enzymatic components, Lethal Factor (LF) and Edema Factor (EF). The entire complex, including the PA heptamer and bound LF and EF, is then internalized by the cell through endocytosis, forming a vesicle.
Once inside the cell, the vesicle containing the toxin complex undergoes acidification. This acidic environment triggers changes in the PA heptamer, causing it to insert into the endosomal membrane and form a channel. Through this channel, LF and EF translocate from the endosome into the cell’s cytoplasm. In the cytoplasm, LF, a zinc-dependent metalloprotease, cleaves and inactivates specific proteins called mitogen-activated protein kinase kinases (MAPKKs). This disruption interferes with cellular signaling pathways, including those involved in immune response and cell survival, ultimately leading to cell dysfunction and death.
Concurrently, Edema Factor (EF) acts as a calmodulin-dependent adenylate cyclase. In the presence of calmodulin, a calcium-binding protein, EF rapidly converts adenosine triphosphate (ATP) into cyclic AMP (cAMP). This increase in intracellular cAMP levels disrupts the cell’s water balance and signaling pathways. Elevated cAMP levels also impair the function of immune cells like macrophages, allowing bacteria to proliferate and evade host defenses.
How the Toxin Affects the Body
The cellular disruptions caused by anthrax toxin lead to physiological effects throughout the body, depending on the route of infection. In cutaneous anthrax, which occurs when spores enter through a break in the skin, the toxin causes localized swelling and the formation of a painless ulcer with a black center, known as an eschar. This localized tissue damage results from the edema toxin causing fluid accumulation and the lethal toxin initiating cell death.
Inhalational anthrax, the most severe form, begins with flu-like symptoms, including fever and chest pain, as spores are taken up by immune cells in the lungs and transported to lymph nodes. As the bacteria multiply and release toxins, they cause widespread damage. This can lead to hemorrhagic inflammation in the mediastinal lymph nodes and surrounding tissues, resulting in severe chest pain, shortness of breath, and potentially coughing up blood. The systemic spread of the toxins can then lead to respiratory failure and circulatory collapse, a condition known as shock.
Gastrointestinal anthrax, caused by ingesting contaminated meat, presents with abdominal pain, nausea, vomiting, and diarrhea, which may contain blood. The toxins cause ulcerations and bleeding within the digestive tract. In severe cases, this can progress to widespread inflammation and fluid accumulation in the abdomen. All forms of anthrax can ultimately lead to systemic toxemia, where toxins circulate throughout the bloodstream, causing organ failure and, if untreated, can be fatal.
Counteracting Anthrax Toxin
Counteracting anthrax toxin involves prevention and treatment. Vaccination plays a significant role in preventing infection by targeting Protective Antigen (PA). Current anthrax vaccines, such as Anthrax Vaccine Adsorbed (AVA), primarily work by stimulating the immune system to produce antibodies against PA. These antibodies neutralize the toxin by blocking PA from binding to host cells, preventing PA heptamer assembly, or inhibiting LF and EF binding to PA.
Antibiotics are a primary treatment for anthrax infection, as they eliminate the Bacillus anthracis bacteria that produce the toxin. Medications like ciprofloxacin and doxycycline are commonly used. A typical course of antibiotics for anthrax prophylaxis after exposure lasts approximately 60 days, due to the potential for spores to remain dormant for an extended period before becoming active.
When the toxin has already been released and is causing severe illness, antitoxin therapies are employed. These therapies, such as human anthrax immune globulin (Anthrasil) or monoclonal antibodies like obiltoxaximab (Anthim), directly neutralize circulating anthrax toxins. These antitoxins work by binding to Protective Antigen, preventing the toxin from entering and damaging host cells. Antitoxin therapy is administered with antibiotics to neutralize existing toxin and eliminate the bacteria producing it, highlighting the importance of early diagnosis and a comprehensive treatment strategy.