Exotoxins bacterial

Exotoxins. Bacterial toxins which, in contrast to en-dotoxins, are secreted by living, mostly Gram-positive bacteria (Staphylococcus aureus E. Comyebacterium diphtheriae see diphtheria toxin Clostridium botuli-num see botulism toxin Clostridium tetani). E. are... 

Bacterial Toxins. Table 1 Intracellular acting exotoxins... 

Damage to the host may arise in two ways. First, multiplication of the microorganisms may cause mechanical damage to the tissue cells through interference with the normal cell metabolism, as seen in viral and some bacterial infections. Second, a toxin associated with the microorganism may adversely affect the tissues or organs of the host. Two types of toxins, called exotoxins and endotoxins, are associated with bacteria. 

Diphtheria is a bacterial respiratory infection characterized by membranous pharyngitis. The membrane may cover the pharynx, tonsillar areas, soft palate, and uvula. Diphtheria may also cause anal, cutaneous, vaginal, and conjunctival infections. The impact of diphtheria is not from the causative bacteria, Corynebacterium diphtheriae, but rather from complications attributed to its exotoxin, such as myocarditis and peripheral... 

Generally, there are three major types of bacterial exotoxins that differ with respect to their structure and principle mode of action. First, there are toxins that attack the cell membrane and thereby damage eukaryotic... 

Classical bacterial exotoxins, such as diphtheria toxin, cholera toxin, clostridial neurotoxins, and the anthrax toxins are enzymes that modify their substrates within the cytosol of mammalian cells. To reach the cytosol, these toxins must first bind to different cell-surface receptors and become subsequently internalized by the cells. To this end, many bacterial exotoxins contain two functionally different domains. The binding (B-) domain binds to a cellular receptor and mediates uptake of the enzymatically active (A-) domain into the cytosol, where the A-domain modifies its specific substrate (see Figure 1). Thus, three important properties characterize the mode of action for any AB-type toxin selectivity, specificity, and potency. Because of their selectivity toward certain cell types and their specificity for cellular substrate molecules, most of the individual exotoxins are associated with a distinct disease. Because of their enzymatic nature, placement of very few A-domain molecules in the cytosol will normally cause a cytopathic effect. Therefore, bacterial AB-type exotoxins which include the potent neurotoxins from Clostridium tetani and C. botulinum are the most toxic substances known today. However, the individual AB-type toxins can greatly vary in terms of subunit composition and enzyme activity (see Table 2). 

Figure 1 The mode of action for bacterial AB-type exotoxins. AB-toxins are enzymes that modify specific substrate molecules in the cytosol of eukaryotic cells. Besides the enzyme domain (A-domain), AB-toxins have a binding/translocation domain (B-domain) that specifically interacts with a cell-surface receptor and facilitates internalization of the toxin into cellular transport vesicles, such as endosomes. In many cases, the B-domain mediates translocation of the A-domain into the cytosol by pore formation in cellular membranes. By following receptor-mediated endocytosis, AB-type toxins exploit normal vesicle traffic pathways into cells. One type of toxin escapes from early acidified endosomes (EE) into the cytosol, thus they are referred to as short-trip-toxins . In contrast, the long-trip-toxins take a retrograde route from early endosomes (EE) through late endosomes (LE), trans-Golgi network (TGN), and Golgi apparatus into the endoplasmic reticulum (ER) from where the A-domains translocate into the cytosol to modify specific substrates.

Endotoxin. A heat-stable bacterial toxin not freely liberated into the surrounding medium. Endotoxins are released only when the integrity of the cell wall is disturbed, are less potent than most exotoxins, are less specific, and do not form toxoids. When injected in large quantities, endotoxins produce hemorrhagic shock and severe diarrhea. Smaller amounts cause fever, altered resistance to bacterial infections, leukopenia followed by leukocytosis, and numerous other biological effects. 

In AD increased S. aureus colonization plays a fundamental role therefore, antistaphylococcal therapy is part of a successful management of the disease. Epidermal lipid deficiencies and barrier dysfunction contribute to enhanced S. aureus attachment to the skin and mediate immunological and inflammatory effects including the release of superantigens, additional exotoxins, and exoenzymes, and perhaps bacterial DNA-triggered mechanisms. Therapeutic possibilities include the use of topical antiseptics in cases of microbial-laden atopic eczema, corticosteroids, and specific antibiotic-antiseptic combinations in cases of localized superinfected atopic eczema and systemic antibiotics in cases of generalized superinfected atopic eczema.48... 

The ribosomal elongation Factor 11 is the acceptor protein for the ADP-ribosyltransferase activity of diphtheria toxin and P. aeruginosa exotoxin A, as well as a mammalian cytosolic ADP-ribosyltransferase. ADP-ribosylation results in loss of activity. The uncontrolled action of the bacterial toxins causes the cessation ofprotein synthesis andhence cell death. The more regulated action of the endogenous ADP-ribosyltransferase is part of the normal regulation of protein synthesis. 

Fig. 3.3 shows the principle behind the design of immunotoxins. A number of protein toxins of bacterial and plant origin are useful for the production of immunotoxins. These include the diphtheria toxin and pseudomonas exotoxin from bacteria, and ricin, arbin, pokeweed antiviral proteins, saporin, and gelonin from plants (Pastan et al, 1986 Pastan and FitzGerald, 1991). All of these toxins kill cells by entering the cells, and enzymatically inactivating the translational machinery of the cells. Some, such as diphtheria toxin, arbin, and ricin, are composed of two protein chains, A and B. The B chains bind to the cell-surface... 

For many years S. aureus exotoxins have been considered the cause of associated conditions snch as blepharo-keratoconjunctivitis. It has been determined that all Staphylococcus species produce exotoxins, and becanse these species are foimd on the Uds of both normal and blepharitis patients, they are most likely not primarily responsible for the findings. More recent evidence suggests that an abnormal blink mechanism or destabilization of the tear film due to bacterial Upolytic enzyme pathways and increased hydrolysis of phosphoUpids may be the canse. It has also been shown that a delayed hypersensitivity to these toxins can prodnce the marginal keratitis seen in many patients. 

If a significant inflammatory component or a response to bacterial exotoxin hypersensitivity in the fiarm of marginal corneal infiltrates or phlyctenules is present, treatment may require concurrent topical steroid therapy. When chronic dacryocystitis is involved, treatment should include irrigation of the lacrimal system with trimethoprim-polymyxin B or gentamicin. Adjunctive systemic antibiotic therapy may also be required (see Chapter 24). 

Examination typically reveals diffuse SPK erosions and also may disclose punctate epithelial keratopathy that is visible as small grayish opacities in the epithelium. The location and pattern of this keratitis can be helpful in determining the etiology (Box 26-1) and in distinguishing the condition from bacterial-related causes. SPK from blepharitis usually is more severe in the inferior one-third of the cornea where it contacts the staphylococcal exotoxins from infection of the lower lid. In cases of SPK caused by bacterial conjunctivitis, the entire cornea may be involved. 

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