Fig. 9.2 ). LPS is composed of a long-chain fatty acid anchor, termed lipid A, connected to a core sugar chain, both of which are very similar in all gram-negative bacteria. Attached to the core sugar is a variable carbohydrate chain (O antigen), which is used to serotype strains of bacteria to aid in diagnosis. Lipid A binds to CD14 on the surface of host leukocytes, and the complex then binds to Toll-like receptor 4, a pattern recognition receptor of the innate immune system that transmits signals to promote cell activation and inflammatory responses. Responses to LPS can be both beneficial and harmful to the host. The response is beneficial in that LPS activates protective immunity through induction of important cytokines and chemoattractants (chemokines), as well as increased expression of costimulatory molecules, which enhance T-lymphocyte activation. However, high levels of LPS play an important role in septic shock, disseminated intravascular coagulation, and acute respiratory distress syndrome, mainly through induction of excessive levels of cytokines such as tumor necrosis factor (Chapter 4).
Exotoxins are secreted proteins that cause cellular injury and disease. They can be classified into broad categories by their mechanism and site of action.
Enzymes. Bacteria secrete enzymes (proteases, hyaluronidases, coagulases, fibrinolysins) that act on their respective substrates in vitro, but their role in disease is understood in only a few cases. For example, exfoliative toxins are proteases produced by S. aureus that cleave proteins known to hold keratinocytes together, causing the epidermis to detach from the deeper skin.
A-B toxins: Toxins that alter intracellular signaling or regulatory pathways. The two-component toxins have an active (A) component with enzymatic activity and a binding (B) component that binds cell surface receptors and delivers the A protein into the cell cytoplasm. The effect of these toxins depends on the binding specificity of the B domain and the cellular pathways affected by the A domain. A-B toxins are made by many bacteria including Bacillus anthracis, V. cholerae, and Corynebacterium diphtheriae. The mechanism of action of the A-B anthrax toxin is well understood (
Fig. 9.8 ). Anthrax toxin has two alternate A components, edema factor (EF) and lethal factor (LF), which enter cells following binding to the B component, and each A component mediates specific pathologic effects.
Superantigens stimulate very large numbers of T lymphocytes by binding to conserved portions of the T cell receptor, leading to massive T lymphocyte proliferation and cytokine release. The high levels of cytokines lead to capillary leak and the systemic inflammatory response syndrome (Chapter 4). Superantigens made by S. aureus and S. pyogenes cause toxic shock syndrome.
Neurotoxins produced by Clostridium botulinum and Clostridium tetani inhibit release of neurotransmitters, resulting in paralysis. These toxins do not kill neurons; instead, the A domains cleave proteins involved in secretion of neurotransmitters at the synaptic junction. Tetanus and botulism can result in death from respiratory failure due to paralysis of the chest and diaphragm muscles.
Enterotoxins affect the gastrointestinal tract causing varied effects, including nausea and vomiting (S. aureus), voluminous watery diarrhea (V. cholerae), and bloody diarrhea (C. difficile).
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