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Chapter 58 : Histotoxic Clostridia

Authors: Dennis L. Stevens, Julian I. Rood
Content Type: Reference
Publication Year: 2006

Category: Bacterial Pathogenesis

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Abstract:

Histotoxic clostridial infection is a general term coined over a century ago that referred to gas gangrene and malignant edema in humans and blackleg in cattle. Histotoxic infections are rapidly progressive, are associated with gas in tissue, and manifest impressive tissue destruction, shock, and frequently death. Although the histotoxic clostridia are classified as grampositive, spore-forming, anaerobic bacilli, not all of them are definitely so. The main habitats of all of the histotoxic clostridia are soils and the intestinal contents of humans and animals. is the most widespread of the histotoxic clostridia, with the quantity of organisms in soil being proportional to the degree and duration of animal husbandry in the region. The major extracellular toxins implicated in gas gangrene are alpha-toxin and theta-toxin. Two independent studies have shown that the alpha-toxin is an essential toxin in the disease process. First, vaccination with a purified recombinant protein consisting of the C-terminal alpha-toxin domain (amino acids 247 to 370) has been shown to protect mice from experimental infection. Second, an alpha-toxin (plc) mutant constructed by allelic exchange has been shown to be avirulent in a mouse myonecrosis model. Toxin production has been documented in vivo by demonstrating the progressive appearance of both theta- and alpha-toxins at the site of the experimental infection by 4 h. Immunization with the C-domain of alpha-toxin is a viable strategy for the prevention of gas gangrene caused by .

Citation: Stevens D, Rood J. 2006. Histotoxic Clostridia, p 715-725. In Fischetti V, Novick R, Ferretti J, Portnoy D, Rood J (ed), Gram-Positive Pathogens, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816513.ch58
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Histotoxic Clostridia
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Citation: Stevens D, Rood J. 2006. Histotoxic Clostridia, p 715-725. In Fischetti V, Novick R, Ferretti J, Portnoy D, Rood J (ed), Gram-Positive Pathogens, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816513.ch58
/content/10.1128/9781555816513.chap58.fig58-1
FIGURE 1

Effects of clostridial exotoxins on mean arterial pressure. Rabbits with stable vital signs were given intravenous infusions of normal saline, crude toxin preparation, or recombinant alpha-toxin or theta-toxin. Mean arterial pressures were measured continuously via a catheter placed in the carotid arterty. Each data point represents the mean arterial pressure (± standard error) determined by using six animals, with triplicate determinations for each time point. Asterisks indicate values significantly different from control values ( 0.05) using Student's test. Circles, control (normal saline); squares, recombinant alpha-toxin; triangles, recombinant theta-toxin; inverted triangles, crude toxin. (Reprinted, with permission, from reference .)

10.1128/9781555816513/fig58-1_thmb.gif
10.1128/9781555816513/fig58-1.gif
Image of FIGURE 1
FIGURE 1

Effects of clostridial exotoxins on mean arterial pressure. Rabbits with stable vital signs were given intravenous infusions of normal saline, crude toxin preparation, or recombinant alpha-toxin or theta-toxin. Mean arterial pressures were measured continuously via a catheter placed in the carotid arterty. Each data point represents the mean arterial pressure (± standard error) determined by using six animals, with triplicate determinations for each time point. Asterisks indicate values significantly different from control values ( 0.05) using Student's test. Circles, control (normal saline); squares, recombinant alpha-toxin; triangles, recombinant theta-toxin; inverted triangles, crude toxin. (Reprinted, with permission, from reference .)

Citation: Stevens D, Rood J. 2006. Histotoxic Clostridia, p 715-725. In Fischetti V, Novick R, Ferretti J, Portnoy D, Rood J (ed), Gram-Positive Pathogens, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816513.ch58
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FIGURE 2

Effects of clostridial exotoxins on cardiac index. Rabbits with stable vital signs were given an intravenous infusion of normal saline, crude toxin preparation, or recombinant alpha-toxin or theta-toxin. Cardiac index was measured over a 3-h period using a thermodilution technique. Each data point represents the mean cardiac index (± standard error) determined by using six animals, with triplicate determinations for each time point. Asterisks indicate values significantly different from control values ( < 0.05). Circles, control (normal saline); squares, recombinant alpha-toxin; triangles, recombinant theta-toxin; inverted triangles, crude toxin. (Reprinted, with permission, from reference .)

10.1128/9781555816513/fig58-2_thmb.gif
10.1128/9781555816513/fig58-2.gif
Image of FIGURE 2
FIGURE 2

Effects of clostridial exotoxins on cardiac index. Rabbits with stable vital signs were given an intravenous infusion of normal saline, crude toxin preparation, or recombinant alpha-toxin or theta-toxin. Cardiac index was measured over a 3-h period using a thermodilution technique. Each data point represents the mean cardiac index (± standard error) determined by using six animals, with triplicate determinations for each time point. Asterisks indicate values significantly different from control values ( < 0.05). Circles, control (normal saline); squares, recombinant alpha-toxin; triangles, recombinant theta-toxin; inverted triangles, crude toxin. (Reprinted, with permission, from reference .)

Citation: Stevens D, Rood J. 2006. Histotoxic Clostridia, p 715-725. In Fischetti V, Novick R, Ferretti J, Portnoy D, Rood J (ed), Gram-Positive Pathogens, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816513.ch58
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FIGURE 3

In vivo TNF-α production is induced by alpha-toxin. Serum samples were obtained from rabbits infused with recombinant alpha-toxin. TNF-α was measured by enzyme-linked immunosorbent assay. Each data point represents the mean TNF-α production (± standard error) of duplicate serum samples run in triplicate. (Reprinted, with permission, from reference .)

10.1128/9781555816513/fig58-3_thmb.gif
10.1128/9781555816513/fig58-3.gif
Image of FIGURE 3
FIGURE 3

In vivo TNF-α production is induced by alpha-toxin. Serum samples were obtained from rabbits infused with recombinant alpha-toxin. TNF-α was measured by enzyme-linked immunosorbent assay. Each data point represents the mean TNF-α production (± standard error) of duplicate serum samples run in triplicate. (Reprinted, with permission, from reference .)

Citation: Stevens D, Rood J. 2006. Histotoxic Clostridia, p 715-725. In Fischetti V, Novick R, Ferretti J, Portnoy D, Rood J (ed), Gram-Positive Pathogens, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816513.ch58
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FIGURE 4

Alpha-toxin-induced TNF-α production by human mononuclear cells. TNF-α was measured in supernatant from 106 human mononuclear cells stimulated with recombinant alpha-toxin. Each data point represents the mean TNF-α production (± standard error) on samples collected at 24 h and assayed in duplicate using a commercial enzyme-linked immunosorbent assay. (Reprinted, with permission, from reference 43.)

10.1128/9781555816513/fig58-4_thmb.gif
10.1128/9781555816513/fig58-4.gif
Image of FIGURE 4
FIGURE 4

Alpha-toxin-induced TNF-α production by human mononuclear cells. TNF-α was measured in supernatant from 106 human mononuclear cells stimulated with recombinant alpha-toxin. Each data point represents the mean TNF-α production (± standard error) on samples collected at 24 h and assayed in duplicate using a commercial enzyme-linked immunosorbent assay. (Reprinted, with permission, from reference 43.)

Citation: Stevens D, Rood J. 2006. Histotoxic Clostridia, p 715-725. In Fischetti V, Novick R, Ferretti J, Portnoy D, Rood J (ed), Gram-Positive Pathogens, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816513.ch58
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Tables

Histotoxic Clostridia
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Citation: Stevens D, Rood J. 2006. Histotoxic Clostridia, p 715-725. In Fischetti V, Novick R, Ferretti J, Portnoy D, Rood J (ed), Gram-Positive Pathogens, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816513.ch58
/content/10.1128/9781555816513.chap58.tab58-1
TABLE 1

Histotoxic clostridial infections

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TABLE 1

Histotoxic clostridial infections

Citation: Stevens D, Rood J. 2006. Histotoxic Clostridia, p 715-725. In Fischetti V, Novick R, Ferretti J, Portnoy D, Rood J (ed), Gram-Positive Pathogens, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816513.ch58
/content/10.1128/9781555816513.chap58.tab58-2
TABLE 2

Major virulence factors of the histotoxic clostridia

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10.1128/9781555816513/tab58-2.gif
Generic image for table
TABLE 2

Major virulence factors of the histotoxic clostridia

Citation: Stevens D, Rood J. 2006. Histotoxic Clostridia, p 715-725. In Fischetti V, Novick R, Ferretti J, Portnoy D, Rood J (ed), Gram-Positive Pathogens, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816513.ch58
/content/10.1128/9781555816513.chap58.tab58-3
TABLE 3

Anti-inflammatory effects of alpha- and theta-toxins

Adapted from reference .

10.1128/9781555816513/tab58-3_thmb.gif
10.1128/9781555816513/tab58-3.gif
Generic image for table
TABLE 3

Anti-inflammatory effects of alpha- and theta-toxins

Adapted from reference .

Citation: Stevens D, Rood J. 2006. Histotoxic Clostridia, p 715-725. In Fischetti V, Novick R, Ferretti J, Portnoy D, Rood J (ed), Gram-Positive Pathogens, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816513.ch58

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