Pathogenesis and Immunity - Bacillus anthracis

Pathogenesis and Immunity

◗ Virulence factors

Virulence of B. anthracis (Table 28-2) depends on the (a) bacte-rial capsule and (b) anthrax toxin complex.

Bacterial capsule: The poly-D-glutamyl capsule itself isnontoxic. The capsule, however, protects the organism against the bactericidal components of serum and phagocytes, and against phagocytic engulfment.

·           It plays a very important role in the pathogenesis of anthrax.

·           It plays most important role during the establishment of the infection.

·           It plays a less significant role in the terminal phases of the disease, which are mediated by anthrax toxin.

Anthrax toxin complex: Anthrax toxin is an exotoxin anda protein in nature. Anthrax toxin complex comprises three components: (a) protective antigen (PA), (b) edema factor (EF), and (c) lethal factor (LF).

Protective antigen: The PA is an 82.7 kDa protein. It is called PAbecause antibodies against this antigen are protective against the action of anthrax toxin. The PA is the binding (B) domain of anthrax toxin and is necessary for entry of the bacteria into the host cell. The antigen binds to cell receptors within a target tissue. Once bound, a fragment is cleaved free to expose an addi-tional binding site. This additional site can combine with EF to form edema toxin or with LF to form lethal toxin.

Edema factor: Edema factor is an 88.9 kDa protein. It is acomponent of the edema toxin. It is a calmodulin-dependent adenylate cyclase, which acts by converting adenosine triphos-phate (ATP) to cyclic adenosine monophosphate (cAMP). This causes an increase in the cellular cAMP levels, leading to cellular edema within the target tissues. The edema factor also causes inhibition of neutrophil function and lowers the production of tumor necrosis factor (TNF-alpha) and interleukin-6 (IL-6) by monocytes.

Lethal factor: LF is a 90.2 kDa protein. It is a zinc metallopro-tease that inactivates mitogen-activated protein kinase, leading to the inhibition of intracellular signaling. It stimulates the release of TNF-alpha and interleukin-1 (IL-1) by macrophages. This mechanism is thought to contribute to sudden death from toxic effects that occur in animals with high degrees of bacteremia. The local and fatal effects of the infection are due to the toxins produced by B. anthracis.

◗ Pathogenesis of anthrax

Spore is the infective stage of the bacilli. The median lethal inhalational dose for humans—extrapolated from data on experimental infection in monkeys—has been estimated to be 2500–55,000 spores. Spores initiate the disease process in the following ways:

·           The spores, after ingestion by macrophages at the site of entry, germinate to form the vegetative forms of the bacteria.

·           Virulent anthrax bacilli multiply at the site of infection with production of capsule and toxins. Phagocytes migrate to the area but the encapsulated anthrax bacilli resist phago-cytic engulfment; or if engulfed, resist killing and digestion. The anthrax toxin causes further impairment of phagocytic activity and its lethal effect on leukocytes, including phago-cytes, at the site.

·           The activated 83-kDa PA of B. anthracis binds to specific receptors on the host cell surface, thereby creating a secondary binding site for which LF and EF compete and bind, leading to formation of lethal toxin and edema toxin, respectively. The lethal toxin or edema toxin is internalized by endocytosis. Subsequently, following the acidification of the endosome, the lethal toxin or edema toxin crosses the membrane into the cytosol via PA-mediated ion-con-ductive channels. Edema toxin produces the characteris-tic edema of anthrax. Subsequently, the bacteria and their toxins enter the circulation, causing systemic morbidity.

·           The bacteria multiply locally and may invade the blood-stream or other organs (e.g., liver, spleen, and kidneys) via the efferent lymphatics. The presence of anthrax bacilli in the capillaries at the infection site is the characteristic finding in anthrax. The bacilli are found in the capillaries of the invaded organs, such as skin, liver, spleen, or lungs. Dissemination from the organs back into the blood-stream may result in bacteremia. In bacteremic anthrax, hemorrhagic lesions may develop anywhere on the body.

The local and fatal effects of the infection are due to the toxins produced by B. anthracis.

◗ Host immunity

Anthrax is primarily a disease of animals. Herbivores (e.g., cattle, sheep, and horses) are very susceptible to the infection. Rats, chicken, pigs, cats, and dogs are quite resistant to the disease. Birds, buzzards, and vultures are naturally resistant to anthrax but may transmit the spores on their talons and beaks. Humans show intermediate susceptibility to B. anthracis.

Animals surviving naturally acquired anthrax are immune to reinfection. Second attacks are extremely rare. Permanent immunity to anthrax appears to be conferred by specific antibodies (a) to the anthrax toxins and (b) to the capsular polypeptide.

Antibodies against the anthrax toxin, primarily against PA, are protective.