Pathogenicity of B. anthracis Course of Anthrax

Anthrax is mainly an epizootic disease of wild and domesticated herbivores, but all mammals including humans are susceptible [37, 57]. The disease affects primarily livestock, but it can occasionally be transmitted to humans who come in contact with infected animals or animal products. For this reason it was once called "woolsorter's disease," as workers commonly contracted it by handling wool or hides from infected animals. Anthrax has been known since ancient times, and is speculated to have been the cause of two of the Egyptians plagues described in the Old Testament, the death of cattle and the appearance of boils. It also played an important role in the history of bacteriology: in 1876 Koch identified B. anthracis as the cause of anthrax in animals, and later formulated his famous postulates. Anthrax was also the subject of important work by Pasteur in 1881, when he used heat treatment to isolate an attenuated strain that could be used for vaccinating sheep and cattle against the disease [58].

Anthrax appears when endospores of B. anthracis penetrate the tissue of a host. With animals this usually happens by ingestion, whereas in humans anthrax comes in three major forms: cutaneous, gastrointestinal, and inhalational or pulmonary.

Cutaneous or skin anthrax results from spores entering gaps in the skin barrier. Within a few days the characteristic skin lesions develop with a black eschar of coal-like appearance that gave the name to the disease (anthrax is the Greek word for coal). With antibiotic treatment the lesions usually heal within weeks, but there is the threat of systemic spread as a fatal complication.

Gastrointestinal anthrax, the second form, is analogous to the main route of infection in animals, but occurs rarely in man in developed countries. It results from eating tainted meat, and has the clinical picture of severe gastroenteritis with abdominal pain, fever, vomiting, bloody diarrhea, and shock. Mortality is high, and autopsy reveals hemorrhagic inflammation of the small intestine and bowel perforation.

The most feared variety is inhalational or pulmonary anthrax, which results in immediate septicemia when spores gain access to their hosts by inhalation. Early diagnosis is difficult as the mild symptoms resemble those of flu, with fever, cough, and malaise. After a few days inhalational anthrax takes an abrupt turn with increasing respiratory distress, shock, and coma. Patients develop a characteristic chest X-ray with massive lymph nodes as well as pleural effusions resulting in bloody fluid around the lungs. Inhalational anthrax is virtually always fatal. Intense supportive care is only able to reduce mortality to slightly below 50% [59]. During the course of infection a point is reached where antibiotics can clear the bacteremia, but are unable to prevent death, most likely due to the circulating toxin. In animals the infection cycle closes once the host is dead, and its carcass decays when bacteria come into contact with oxygen and sporulate. Anthrax spores are highly resistant and survive many years in the soil, where they can infect their next host. Virulence Factors of B. anthracis

Regardless of the route of entry, spores are phagocytosed by macrophages where they germinate [60]. Spore germination may be triggered within the macrophage by host-specific signals. The vegetative bacteria circumvent or escape the antimicrobial environment of the phagolysosome by an unknown mechanism, and are released to the host tissue, where they appear as large, encapsulated, nonmotile rods often forming long chains of characteristic "bamboo-like" appearance. The B. anthracis capsule is currently considered one of its major virulence factors, as it inhibits phagocytosis, and its monotonous linear polymer of c-D-glutamic acid is only weakly immunogenic [37]. In the further course of infection the bacteria replicate as an extracellular pathogen to high titers of up to 109 cells per milliliter of blood. The toxins play a key role in pathogenesis of anthrax, and are composed of three polypeptides: the protective antigen (PA), named for its ability to elicit a protective immune response, the lethal factor (LF), and the edema factor (EF). They were named because intravenous injection of PA and LF result in the death of the animal [61], whereas intradermal injection of PA and EF produces edema in the skin [62].

Anthrax toxin belongs to the family of bacterial "AB" toxins. Generally, these toxins work by the combined action of the cell-binding B subunit which is responsible for binding and translocation of the enzymatically active A subunit into the target cell. Anthrax toxin is unique in that it has one B subunit, the PA, which combines with two different enzymatically active subunits to form the lethal toxin (LeTx) from the combination of PA and LF and the edema toxin (EdTx) from a combination of PA and EF. The structure and function of LeTx and EdTx have been reviewed in detail recently [12, 58]. In short, PA binds to its cellular receptors, which are located on the surface of many cell types. Two possible receptors were identified in recent work as the tumor endothelial marker-8 (TEM-8) [63] and the capillary morphogenesis protein 2 (CMG2) [64], which are both widely expressed. Once bound to a receptor, PA can be cleaved by furin or a furin-like membrane endoprotease [65], and the remaining 63-kDa fragment (PA63) oligo-merizes instantly into a heptamer [66] and associates with EF or LF to yield the assembled toxic complex. The oligomerization triggers the receptor-mediated endocytosis of PA63. Via the drop of pH caused by the endosomal acidification, the prepore converts to a pore, and EF and LF are translocated with at least a partial unfolding to reach their cytosolic targets [67]. The enzymatic activity of EF has been shown to be an adenylate cyclase that is highly homologous to Bordetella pertussis adenylate cyclase. The specific activity of EF is 1000-fold higher than that of the mammalian calmodulin-activated adenylate cyclase. In contrast, the enzy matic activity of LF was a longstanding mystery until it was realized that LF cleaves all known mitogen-activated protein kinase kinases (Mek1 to Mek7) with the exception of Mek5. As a consequence of the cleavage, the Meks are unable to dock with their substrate, mitogen-activated protein kinase (MAPK) [68]. How these two toxins bring about the observed symptoms is not understood at all. The edema and death caused by these toxins have been known for decades, but the mechanisms how these physiological effects arise are still subject to debate.

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