Info

— Superantigen

MHC II protein

ifif

Antigen-presenting cell (macrophage)

Figure 19.13 Superantigens These exotoxins override the specificity of the T-cell response, causing systemic toxic effects due to the massive release of cytokines by an inordinate number of effectorT cells.The superantigens effectively short-circuit the normal control mechanisms inherent in antigen processing and presentation by binding simultaneously to the outer portion of the MHC class II molecule and the T-cell receptor.

inordinate number of effector T cells. They include toxic shock syndrome toxin (TSST) as well as several other toxins produced by Staphylococcus aureus and Streptococcus pyogenes.

Superantigens effectively short-circuit the normal control mechanisms inherent in antigen processing and presentation. They do this by binding simultaneously to the outer portion of the major histocompatibility (MHC) class II molecule on antigen-presenting cells and the T-cell receptor (figure 19.13). Whereas most antigens stimulate about one in 10,000 T cells, superantigens can stimulate as many as one in five T cells. The resulting release of cytokines by an inordinate number of T cells leads to symptoms including fever, nausea, vomiting, and diarrhea. Shock may occur, with failure of many organ systems, circulatory collapse, and even death. In addition, the immune response is suppressed because many T cells undergo apoptosis following the excessive stimulation. Superantigens are also suspected of contributing to autoimmune diseases; by overriding the control mechanisms that normally characterize adaptive immunity, they may induce the proliferation of those few T cells that respond to healthy "self."

The family of related exotoxins produced by Staphylo-coccus aureus strains that cause foodborne intoxication are superantigens. Although they causes nausea and vomiting and are therefore referred to as enterotoxins, the manner in which they

19.8 Damage to the Host 475

function and the symptoms that they cause are distinct from those of the enterotoxins of Vibrio cholerae and certain E. coli strains. The spectrum of symptoms associated with the ingestion of a staphylococcal enterotoxin is also different from that of other superantigens. The precise mechanism by which they induce vomiting is poorly understood, but they seem to affect inflammatory functions of subepithelial macrophages and cause a change in local vascular permeability. Unlike most other exotoxins, the enterotox-ins produced by Staphylococcus aureus are heat-stable. Even thorough cooking of foods that have been contaminated with these toxins will not prevent illness. ■ Staphylococcus aureus food poisoning, p. 812

Other Toxic Proteins

Various proteins that are not A-B toxins, superantigens, or membrane-damaging toxins can have detrimental effects. An important example is the exfoliating toxin produced by certain strains of Staphylococcus aureus. This toxin, exfoliatin, destroys material that binds together the layers of skin, causing the outer layer to separate (see figure 22.4). The organism may be growing in a small, localized lesion but the toxin can spread systemically.

Various hydrolytic enzymes including proteases, lipases, and collagenases can break down tissue components. Along with destroying tissues, some of these enzymes facilitate the spread of the organism.

Endotoxin and Other Bacterial Cell Wall Components

The host defenses are primed to respond to various bacterial cell wall components, including lipopolysaccharide and peptidogly-can, in order to contain an infection. A systemic response to these compounds, however, can overwhelm the system and cause toxic effects.

Endotoxin

Endotoxin is lipopolysaccharide (LPS), the molecule that makes up the outer leaflet of the outer membrane of Gram-negative bacteria (figure 19.14). Thus, endotoxin is a fundamental part of Gram-negative organisms. The nomenclature is somewhat unfortunate, because it implies that endotoxin is "inside the cell" and exotoxins are "outside the cell"; in fact, endotoxin is an integral part of the outer membrane, whereas exotoxins are proteins produced by a bacterium that may or may not be secreted. Unlike most exotoxins, endotoxin cannot be converted to an effective toxoid for immunization. Table 19.3 summarizes some of the other differences between exotoxins and endotoxin. ■ lipopolysaccharide molecule, p. 59

Recall from chapter 3 that the lipopolysaccharide molecule is composed of two medically important parts—lipid A and the O-specific polysaccharide side chain. The lipid A component is responsible for the toxic properties of LPS. Unlike the situation with most exotoxins, however, the symptoms associated with endotoxin are due to a vigorous innate immune response. When lipid A is present in a localized region, the magnitude of the response helps clear an infection. It is a different situation entirely, however, when the infection is systemic, such as septicemia. Imagine a state in which inflammation occurs throughout the body—extensive leakage of fluids from permeable blood vessels and widespread activation of the coagulation cascade. The overwhelming response in such bloodstream infections has

profound effects, causing fever, a dramatic drop in blood pressure and disseminated intravascular coagulation. This array of symptoms associated with systemic bacterial infection is called septic shock; because it is caused by endotoxin, it may also be called endotoxic shock.

Lipid A is embedded in the outer membrane and does not evoke a response unless it is released. This occurs primarily when the bacterium lyses, which can happen as a result of phagocytosis, formation of a membrane attack complex by complement components, and treatment with certain types of antibiotics.

Once released from a cell, the LPS molecules can activate the innate and adaptive host defenses by a variety of mechanisms. Monocytes, macrophages, and other cells have toll-like receptors that detect liberated LPS, inducing the cells to produce pro-inflammatory cytokines. LPS also functions as a T-independent antigen; at high concentrations it activates a variety of different B cells, regardless of the specificity of their B-cell receptor. ■ toll-like receptors, p. 381 ■ T-independent antigens, p. 406

Endotoxin is heat-stable; it is not destroyed by autoclav-ing. Consequently, solutions intended for intravenous administration must not only be sterile, but free of endotoxin as well. Disastrous results including death have resulted from administering intravenous fluids contaminated with minute amounts of endotoxin. To verify that fluids are not contaminated with endotoxin, a very sensitive test known as the Limulus amoebo-

cyte lysate (LAL) assay is used. This test employs proteins extracted from blood of the horseshoe crab Limulus polyphemus that form a gel-like clot in the presence of endotoxin; as little as 10 to 20 picograms (1 picogram = 10:12 grams) of endotoxin per milliliter can be detected using the LAL. Horseshoe crabs are one of this planet's more unique and ancient life forms. The critical role they play in this test has led to an increased awareness of the importance of their habitat, and a non-lethal system of capture, blood sampling, and release has been developed.

Other Bacterial Cell Wall Components

Peptidoglycan and other bacterial cell wall components can elicit symptoms similar to those that characterize the response to endotoxin. The systemic response leads to septic shock.

Damaging Effects of the Immune Response

Although the intent of the immune response is to eliminate the invading microbe, the tissues of the host can inadvertently be damaged as well. Note that the reactions to endotoxin and other cell wall components can be viewed as damaging effects of the immune response, but are typically considered a toxic effect of the bacterium because the reactions may be immediate and overwhelming. The damaging responses discussed next generally manifest themselves more slowly.

1 Nester-Anderson-Roberts: Microbiology, A Human Perspective, Fourth Edition

1 III. Microorganisms and 1 19. Host-Microbe Humans Interactions

1 1 © The McGraw-Hill 1 Companies, 2003

19.9 Mechanisms of Viral Pathogenesis

Table 19.3 Comparison of Exotoxins and Endotoxin

Property

Exotoxins

Endotoxin

Bacterial source

Gram-positive and Gram-negative species

Gram-negative species only

Location in the bacterium

Synthesized in the cytoplasm; may or may not be secreted

Component of the outer membrane

Chemical nature

Protein

Lipopolysaccharide (the lipid A component)

Ability to form a toxoid

Generally

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