Clostridium septicum

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Clostridium septicum
Clostridium septicum.tif
Scientific classification OOjs UI icon edit-ltr.svg
Domain: Bacteria
Phylum: Bacillota
Class: Clostridia
Order: Eubacteriales
Family: Lachnospiraceae
Genus: Clostridium
Species:
C. septicum
Binomial name
Clostridium septicum
(Macé 1889) Ford 1927

Clostridium septicum [1] is a gram positive, spore forming, obligate anaerobic bacterium.

Contents

Clostridium septicum can cause gas gangrene, but unlike other Clostridium species like Clostridium perfringens , no trauma is necessary at the site of the infection. It is thought that the infection is established by hematogenous spread from the gastrointestinal tract. Gas gangrene caused by Clostridium septicum is associated with colorectal cancer and other defects of the bowel. [2]

Clostridium septicum causes myonecrosis through the release of exotoxins such as the alpha toxin, lethal toxin, and hemolytic toxin [3]

General and morphological information

Clostridium septicum is a large, gram-positive, rod-shaped bacterium that is a member of the normal gut flora in humans as well as other animals. [4] C. septicum are spore formers, with a terminal spore that gives them their drumstick-like shape. [5] They are also motile bacteria, using peritrichous flagellae to navigate from one environment to the next. [6] C. septicum are fermentative anaerobes and therefore can live off of a variety of substrates like sugars, amino acids and other organic compounds, generating molecular hydrogen gas and carbon dioxide as byproducts of cellular respiration. [7]

Clostridium septicum can cause infection quickly if the gut tissue becomes necrotic or inflamed. [4] C. septicum produces four toxins; alpha, beta, gamma and delta, with alpha toxin being necrotic and lethal. [5] Their anaerobic nature creates susceptibility in areas of decreased blood flow. [4] Although rare, C. septicum infections are often found in individuals with a recent history of trauma, surgery, peripheral vascular disease, diabetes, colon cancer, skin infections or burns and septic abortions. [4]

Ecology and habitat

Clostridium septicum is a resident bacterium of the human microflora, however it can be found in almost any anoxic habitat in which exists organic compounds. [4] Under unfavorable conditions, C. septicum forms endospores allowing it to survive under harsh conditions such as extreme temperature, dry land, and nutrient-deficient habitats. [4] [6]

Pathogenesis

Patient with right leg gas gangrene. The right leg is edematous and discolored with fluid-filled bullae. Gas gangrene.jpg
Patient with right leg gas gangrene. The right leg is edematous and discolored with fluid-filled bullae.

As of 2006, between 1000 and 3000 cases of clostridial myonecrosis were reported in the United States each year, typically accompanied by another pre-existing medical condition. C. septicum is one of several bacteria responsible for myonecrosis, otherwise known as gas gangrene. [4] Infection by C. septicum was once thought to be extremely rare, however anaerobic laboratory techniques allowed for the discovery of the true potential of this infectious microbe. [8] Infections are typically seen in settings of immunodeficiency, trauma, surgery, malignancy, skin infections/burns, and septic abortions. [4] Sites prone to infection are those with poor vascular supply, although because of pH, electrolyte and osmotic differences, the colon may promote the growth of C. septicum better than most other anatomical regions. [5] One of the more aggressive progenitors of gas gangrene, C. septicum infection progresses very rapidly, with a mortality rate of approximately 79% in adults, typically occurring within 48 hours of infection. [5] The greatest survival rates are typically seen in patients without pre-existing medical conditions, and with infection localized to the extremities. [4] Gas gangrene proceeds via disruption of blood flow to the infected site, resulting in diminished levels of oxygen and nutrients ultimately causing premature cell death and tissue necrosis. [9] Four toxins have been isolated from C. septicum: the lethal alpha toxin, DNase beta-toxin, hyaluronidase gamma toxin, and the thiol-activated (or septicolysin) delta toxin. [10] Alpha toxin causes intravascular hemolysis and tissue necrosis and is well known as the main virulent factor in C. septicum. [9] Symptoms of infection include pain, described as a heaviness or pressure that is disproportionate to physical findings, tachycardia, and hypotension. [4] Tissue necrosis then causes edema and ischemia resulting in metabolic acidosis, fever, and kidney failure. [4] The carbon dioxide and hydrogen produced during cellular respiration move through tissue planes, causing their separation, producing features characteristic of palpable emphysema. [4] This also results in a magenta-bronze skin discoloration and bulla filled with a foul-smelling serosanguinous fluid. [4]

Association with malignancy

Clostridium septicum derived gas gangrene has shown strong correlations with increased levels of malignancy. Generally, patients with C. septicum infections present colonic carcinoma or a tumor that has metastasized to the colon. [10] One particular study by Alpern and Dowell noted 85% comorbidity with malignancy, while another study by Koransky et al. noted 71% comorbidity. [5] [8] [11] This relationship suggests the opportunistic nature of this pathogen raising the possibility that immunosuppression plays a key role in the ability of C. septicum to cause infection. [8] It seems likely that either the treatment or the malignancy itself impairs the immune function of the gastrointestinal mucosa allowing C. septicum to gain access to the circulatory system. [8]

Alpha toxin

The alpha toxin produced by C. septicum is the underlying cause of gas gangrene, otherwise known as myonecrosis; a disease characterized by extensive tissue destruction, edema, thrombosis, and fluid-filled bullae. [9] Alpha toxin is a pore-forming toxin exotoxin that is secreted as a protoxin that requires proteolytic cleavage of a 5kDa peptide from its carboxy-terminal in order to become active. [12] Cleavage is typically initiated by the cell surface protease furin. [13] Once activated, the toxin can oligomerize and form ion-permeable pores through the cell membrane. [12] Pores formed by alpha toxin are approximately 1.5 nm in diameter, allowing the release of potassium ions from erythrocytes, thus disrupting the ionic equilibrium within the cell. [12] Alpha toxin binds GPI-anchored cell surface receptors including the human folate receptor (hFR) as well as the neuronal molecules contactin and Thy-1 (CD90). [13] Alpha toxin can activate the immune sensor NLRP3 in mammalian cells, causing the cells to die and release inflammatory molecules. [14]

ModelofAerolysin.jpg
Solved crystal structure of aerolysin. Green=D1, Purple=D2, Cyan=D3, Yellow=D4, Orange=TMD, and Red=Propeptide
ModelofAT.jpg
Proposed crystal structure of Alpha-toxin based on the structure of aerolysin. Purple=D1, Cyan=D2, Yellow=D3, Orange=TMD, Red=Propeptide

Alpha-toxin and aerolysin

Quite surprisingly, the alpha toxin of C. septicum is not related to the alpha toxin of C. perfringens (another bacterium implicated in the pathogenesis of gas gangrene). [10] C. septicum alpha toxin does, however, exhibit similarities to aerolysin, another beta-pore forming toxin. Alpha toxin and aerolysin share approximately 72% sequence similarity and have numerous functional similarities as well. [13] Both proteins require cleavage by furin, or a furin-like protease, and then oligomerize to form transmembrane pores. [13] [15] Similarities between the two toxins have also been discovered through analysis of the crystal structure of aerolysin. Aerolysin is a bilobar protein consisting of four domains (D1-D4). [15] The smallest lobe of aerolysin is missing in the alpha toxin of C. septicum, implying that the alpha toxin is monolobar with three domains, similar to domains D2-D4 in aerolysin. [15] Further research has led to the conclusions that the D1 domain is involved in receptor-binding and the D3 domain functions to prevent premature oligomerization of alpha toxin. [13]

Diagnosis and treatment

If left untreated, the mortality rate for C. septicum infection nears 100%. [10] A study by Cline and Turnbull offers that diagnosis be based on findings of pain disproportionate to clinical findings or injury, marked tachycardia, discolored or edematous skin, and a gram-stain of bullous drainage showing gram-positive bacilli without spores and few leukocytes. [16] Physical manifestations of infection include pain caused by infiltration of the infected muscle with edema and gas, tachycardia, muscle and skin discoloration, and the presence of a brown, watery discharge with a foul smell within the wounds. [17] Treatment for C. septicum infection includes antibiotic administration, surgical intervention, and hyperbaric oxygen therapy (HBOT). [4] For antibiotic selection, usual anaerobic coverage can include penicillin, metronidazole or clindamycin. There are no CLSI standards for susceptibility testing so antibiotic selection is often made based on local patterns of resistance. In a Canadian survey from 2000 to 2006, 19 isolates were tested and 9 (47%) were resistant to clindamycin and 1 (5%) was resistant to both metronidazole and clindamycin. None had reduced susceptibility to penicillin. [18] The Infectious Diseases Society of America (IDSA) recommends that for gas gangrene where clostridium has been identified as the cause that both penicillin and clindamycin be used. [19] Often in severe cases amputation becomes the only viable option remaining to clear the infection.[ citation needed ]

Other animals

In sheep, C. septicum causes a disease known as braxy; affected animals are generally found dead. [20]

See also

Related Research Articles

<span class="mw-page-title-main">Gangrene</span> Type of tissue death by a lack of blood supply

Gangrene is a type of tissue death caused by a lack of blood supply. Symptoms may include a change in skin color to red or black, numbness, swelling, pain, skin breakdown, and coolness. The feet and hands are most commonly affected. If the gangrene is caused by an infectious agent, it may present with a fever or sepsis.

<span class="mw-page-title-main">Necrotizing fasciitis</span> Infection that results in the death of the bodys soft tissue

Necrotizing fasciitis (NF), also known as flesh-eating disease, is a bacterial infection that results in the death of parts of the body's soft tissue. It is a severe disease of sudden onset that spreads rapidly. Symptoms usually include red or purple skin in the affected area, severe pain, fever, and vomiting. The most commonly affected areas are the limbs and perineum.

<i>Clostridium</i> Genus of Gram-positive bacteria, which includes several significant human pathogens

Clostridium is a genus of anaerobic, Gram-positive bacteria. Species of Clostridium inhabit soils and the intestinal tract of animals, including humans. This genus includes several significant human pathogens, including the causative agents of botulism and tetanus. It also formerly included an important cause of diarrhea, Clostridioides difficile, which was reclassified into the Clostridioides genus in 2016.

<i>Clostridium perfringens</i> Species of bacterium

Clostridium perfringens is a Gram-positive, bacillus (rod-shaped), anaerobic, spore-forming pathogenic bacterium of the genus Clostridium. C. perfringens is ever-present in nature and can be found as a normal component of decaying vegetation, marine sediment, the intestinal tract of humans and other vertebrates, insects, and soil. It has the shortest reported generation time of any organism at 6.3 minutes in thioglycolate medium.

<span class="mw-page-title-main">Exotoxin</span> Toxin from bacteria that destroys or disrupts cells

An exotoxin is a toxin secreted by bacteria. An exotoxin can cause damage to the host by destroying cells or disrupting normal cellular metabolism. They are highly potent and can cause major damage to the host. Exotoxins may be secreted, or, similar to endotoxins, may be released during lysis of the cell. Gram negative pathogens may secrete outer membrane vesicles containing lipopolysaccharide endotoxin and some virulence proteins in the bounding membrane along with some other toxins as intra-vesicular contents, thus adding a previously unforeseen dimension to the well-known eukaryote process of membrane vesicle trafficking, which is quite active at the host–pathogen interface.

<span class="mw-page-title-main">Gas gangrene</span> Human bacterial infection

Gas gangrene is a bacterial infection that produces tissue gas in gangrene. This deadly form of gangrene usually is caused by Clostridium perfringens bacteria. About 1,000 cases of gas gangrene are reported yearly in the United States.

<span class="mw-page-title-main">Blackleg (disease)</span> Bacterial disease of animals

Blackleg, black quarter, quarter evil, or quarter ill is an infectious bacterial disease most commonly caused by Clostridium chauvoei, a Gram-positive bacterial species. It is seen in livestock all over the world, usually affecting cattle, sheep, and goats. It has been seen occasionally in farmed bison and deer. The acute nature of the disease makes successful treatment difficult, and the efficacy of the commonly used vaccine is disputed.

Paeniclostridium sordellii is a rare anaerobic, gram-positive, spore-forming rod with peritrichous flagella that is capable of causing pneumonia, endocarditis, arthritis, peritonitis, and myonecrosis. C. sordellii bacteremia and sepsis occur rarely. Most cases of sepsis from C. sordellii occur in patients with underlying conditions. Severe toxic shock syndrome among previously healthy persons has been described in a small number of C. sordellii cases, most often associated with gynecologic infections in women and infection of the umbilical stump in newborns. It has also been described in post-partum females, medically induced abortions, injection drug users and trauma cases. So far, all documented post-partum females who contracted C. sordellii septicaemia have died, and all but one woman who contracted the bacterium post-abortion have died.

Alpha toxin or alpha-toxin refers to several different protein toxins produced by bacteria, including:

<span class="mw-page-title-main">Fournier gangrene</span> Medical condition

Fournier gangrene is a type of necrotizing fasciitis or gangrene affecting the external genitalia or perineum. It commonly occurs in older men, but it can also occur in women and children. It is more likely to occur in people with diabetes or alcoholism or those who are immunocompromised.

<i>Clostridium perfringens</i> alpha toxin Toxin produced by the bacterium Clostridium perfringens

Clostridium perfringens alpha toxin is a toxin produced by the bacterium Clostridium perfringens and is responsible for gas gangrene and myonecrosis in infected tissues. The toxin also possesses hemolytic activity.

<span class="mw-page-title-main">Pore-forming toxin</span> Protein-produced toxins that create pores in cell membrane

Pore-forming proteins are usually produced by bacteria, and include a number of protein exotoxins but may also be produced by other organisms such as apple snails that produce perivitellin-2 or earthworms, who produce lysenin. They are frequently cytotoxic, as they create unregulated pores in the membrane of targeted cells.

<span class="mw-page-title-main">Clostridium enterotoxin</span>

Clostridium enterotoxins are toxins produced by Clostridium species. Clostridial species are one of the major causes of food poisoning/gastrointestinal illnesses. They are anaerobic, gram-positive, spore-forming rods that occur naturally in the soil. Among the family are: Clostridium botulinum, which produces one of the most potent toxins in existence; Clostridium tetani, causative agent of tetanus; and Clostridium perfringens, commonly found in wound infections and diarrhea cases.

Clostridium novyi (oedematiens) a Gram-positive, endospore- forming, obligate anaerobic bacteria of the class Clostridia. It is ubiquitous, being found in the soil and faeces. It is pathogenic, causing a wide variety of diseases in man and animals.

Clostridium perfringens beta toxin is one of the four major lethal protein toxins produced by Clostridium perfringens Type B and Type C strains. It is a necrotizing agent and it induces hypertension by release of catecholamine. It has been shown to cause necrotic enteritis in mammals and induces necrotizing intestinal lesions in the rabbit ileal loop model. C. perfringens beta toxin is susceptible to breakdown by proteolytic enzymes, particularly trypsin. Beta toxin is therefore highly lethal to infant mammals because of trypsin inhibitors present in the colostrum.

Hathewaya histolytica is a species of bacteria found in feces and the soil. It is a motile, gram-positive, aerotolerant anaerobe. H. histolytica is pathogenic in many species, including guinea pigs, mice, and rabbits, and humans. H. histolytica has been shown to cause gas gangrene, often in association with other bacteria species.

Clostridium cadaveris is an enteric, gas-forming, motile, strictly anaerobic gram-positive bacterium of the genus Clostridium. First described by Klein in 1899, it was noted to be the most prominent bacteria during human decomposition; historically it was described as "putrefying flora".

Anaerobic infections are caused by anaerobic bacteria. Obligately anaerobic bacteria do not grow on solid media in room air ; facultatively anaerobic bacteria can grow in the presence or absence of air. Microaerophilic bacteria do not grow at all aerobically or grow poorly, but grow better under 10% carbon dioxide or anaerobically. Anaerobic bacteria can be divided into strict anaerobes that can not grow in the presence of more than 0.5% oxygen and moderate anaerobic bacteria that are able of growing between 2 and 8% oxygen. Anaerobic bacteria usually do not possess catalase, but some can generate superoxide dismutase which protects them from oxygen.

The thiol-activated Cholesterol-dependent Cytolysin(CDC) family is a member of the MACPF superfamily. Cholesterol dependent cytolysins are a family of β-barrel pore-forming exotoxins that are secreted by gram-positive bacteria. CDCs are secreted as water-soluble monomers of 50-70 kDa, that when bound to the target cell, form a circular homo-oligomeric complex containing as many as 40 monomers. Through multiple conformational changes, the β-barrel transmembrane structure is formed and inserted into the target cell membrane. The presence of cholesterol in the target membrane is required for pore formation, though the presence of cholesterol is not required by all CDCs for binding. For example, intermedilysin secreted by Streptococcus intermedius will bind only to target membranes containing a specific protein receptor, independent of the presence of cholesterol, but cholesterol is required by intermedilysin for pore formation. While the lipid environment of cholesterol in the membrane can affect toxin binding, the exact molecular mechanism that cholesterol regulates the cytolytic activity of the CDC is not fully understood.

<i>Clostridium tertium</i> Species of bacterium

Clostridium tertium is an anaerobic, motile, gram-positive bacterium. Although it can be considered an uncommon pathogen in humans, there has been substantial evidence of septic episodes in human beings. C. tertium is easily decolorized in Gram-stained smears and can be mistaken for a Gram-negative organism. However, C.tertium does not grow on selective media for Gram-negative organisms.

References

  1. ↑ lpsn.dsmz.de, list of prokaryotic names with standing nomenclature.
  2. ↑ Larson, CM; Bubrick, MP; Jacobs, DM; Malignancy, West MA. (Oct 1995). "Clostridium septicum infection". Surgery. 118 (4): 592–8. doi:10.1016/s0039-6060(05)80023-6. PMID   7570310.
  3. ↑
    • Mahon, Connie R.; Manuselis, George. (2000). Textbook of Diagnostic Microbiology, 2nd edition. Saunders. ISBN   0-7216-7917-X.
  4. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Smith-Slatas CL, Bourque M and Salazar JC (2006). Clostridium septicum infections in children: a case report and review of the literature. Pediatrics 117(4): e796-e805.
  5. 1 2 3 4 5 Koransky, JR; Stargel, MD; Dowell, VR (1979). "Clostridium septicum bacteremia". The American Journal of Medicine. 66 (1): 63–66. doi:10.1016/0002-9343(79)90483-2. PMID   420252.
  6. 1 2 Liechti, ME; Schob, O; Kacl, GM; Caduff, B (2003). "Clostridium septicum aortitis in a patient with colon carcinoma" (PDF). Eur J Clin Microbiol Infect Dis. 22 (10): 632–634. doi:10.1007/s10096-003-1009-0. PMID   14513404. S2CID   39242542.
  7. ↑ Gabay, EL; Rolfe, RD; Finegold, SM (1981). "Susceptibility of clostridium septicum to 23 antimicrobial agents". Antimicrobial Agents and Chemotherapy. 20 (6): 852–853. doi:10.1128/aac.20.6.852. PMC   181814 . PMID   7325648.
  8. 1 2 3 4 Katlic, MR; Derkac, WM; Coleman, WS (1981). "Clostridium septicum infection and malignancy". Ann. Surg. 193 (3): 361–364. doi:10.1097/00000658-198103000-00020. PMC   1345077 . PMID   7212798.
  9. 1 2 3 Hickey, MJ; Kwan, RYQ; Awad, MM; Kennedy, CL; Young, LF; Hall, P; Cordner, LM; Lyras, D; Emmins, JJ; Rood, JI (2008). "Molecular and cellular basis of microvascular perfusion deficits induced by clostridium perfringens and clostridium septicum". PLOS Pathogens. 4 (4): 1–9. doi: 10.1371/journal.ppat.1000045 . PMC   2275794 . PMID   18404211.
  10. 1 2 3 4 Ballard, J; Bryant, A; Stevens, D; Tweten, RK (1992). "Purification and characterization of the lethal toxin (alpha-toxin) of clostridium septicum". Infection and Immunity. 60 (3): 784–790. doi:10.1128/IAI.60.3.784-790.1992. PMC   257555 . PMID   1541552.
  11. ↑ Alpern, RJ; Dowell, VR (1969). "Clostridium septicum infections and malignancy". JAMA. 209 (3): 385–388. doi:10.1001/jama.209.3.385. PMID   5819436.
  12. 1 2 3 Ballard, J; Crabtree, J; Roe, BA; Tweten, RK (1995). "The primary structure of clostridium septicum alpha-toxin exhibits similarity with that of aeromonas hydrophila aerolysin". Infection and Immunity. 63 (1): 340–344. doi:10.1128/IAI.63.1.340-344.1995. PMC   172997 . PMID   7806374.
  13. 1 2 3 4 5 Melton-Witt, JA; Bensten, LM; Tweten, RK (2006). "Identification of functional domains of clostridium septicum alpha toxin". Biochemistry. 45 (48): 14347–14354. doi:10.1021/bi061334p. PMC   2561313 . PMID   17128973.
  14. ↑ Jing, Weidong; Pilato, Jordan Lo; Kay, Callum; Feng, Shouya; Tuipulotu, Daniel Enosi; Mathur, Anukriti; Shen, Cheng; Ngo, Chinh; Zhao, Anyang; Miosge, Lisa A.; Ali, Sidra A.; Gardiner, Elizabeth E.; Awad, Milena M.; Lyras, Dena; Robertson, Avril A. B.; Kaakoush, Nadeem O.; Man, Si Ming (2022). "Clostridium septicum α-toxin activates the NLRP3 inflammasome by engaging GPI-anchored proteins". Science Immunology. 7 (71): eabm1803. doi: 10.1126/sciimmunol.abm1803 . PMID   35594341. S2CID   248921445.
  15. 1 2 3 Melton, JA; Parker, MW; Rossjohn, J; Buckley, JT; Tweten, RK (2004). "The identification and structure of the membrane-spanning domain of the clostridium septicum alpha toxin". The Journal of Biological Chemistry. 279 (14): 14315–14322. doi: 10.1074/jbc.m313758200 . PMID   14715670.
  16. ↑ Turnbull, TL; Cline, KS (1985). "Spontaneous clostridial myonecrosis". The Journal of Emergency Medicine. 3 (5): 353–360. doi:10.1016/0736-4679(85)90319-1. PMID   3914999.
  17. ↑ Altemeier, WA; Fullen, WD (1971). "Prevention and treatment of gas gangrene". JAMA. 217 (6): 806–813. doi:10.1001/jama.217.6.806. PMID   5109333.
  18. ↑ Leal, J; Gregson, DB; Ross, T; Church, DL; Laupland, KB (2008-06-19). "Epidemiology of Clostridium species bacteremia in Calgary, Canada, 2000-2006". J Infect. 57 (3): 198–203. doi:10.1016/j.jinf.2008.06.018. PMID   18672296.
  19. ↑ Stevens, DL; Bisno, AL; Chambers, HF; Dellinger, EP; Goldstein, EJ; Gorbach, SL; Hirschmann, JV; Kaplan, SL; Montoya, JG; Wade, JC (2014-06-18). "Practice Guidelines for the Diagnosis and Management of Skin and Soft Tissue Infections: 2014 Update by the Infectious Diseases Society of America". Clin Infect Dis. 59 (2): 147–59. doi: 10.1093/cid/ciu296 . PMID   24947530.
  20. ↑ Scott, PR (2015). "Digestive system: Braxy". Sheep medicine (2nd ed.). CRC Press. p. 137. ISBN   9781498700153.
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