Clostridium septicum

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A Microbial Biorealm page on the genus Clostridium septicum

Classification

Higher order taxa

Kingdom: Bacteria; Phylum: Firmicutes; Class: Clostridia; Order: Clostridiales; Family: Clostridiaceae; Species: Clostridium septicum

Species

There are around 150 species in this genus. The familiar ones are Clostridium perfringens, Clostridium acetobutylicum, Clostridium difficile, Clostridium novyi, Clostridium septicum, Clostridium tetani, and Clostridium botulinum

Description and significance

Clostridium septicum are found in virtually all anoxic habitats where organic compounds are present, including aquatic sediments, soils, animals and humans guts. Under unfavorable conditions, they form endospores, which allow them to survive in harsh environments, including but not limited to extremes of temperature, drying, or nutrient depletion. Thus, endospores are a dormant stage of the C. septicum life cycle. When conditions are favorable, such as in the presence of organic compounds, the spores germinate. Like C. botulinum, C. septium produces a number of toxins, most notably the alpha toxin. Alpha toxin is a pore-forming toxin responsible for gas gangrene in humans and animals.

Genome structure

The genome for C septicum has not been completed. However, the genome of C. perfringens str 13, C. botulinum E3 str. Alaska E43, C. difficle 630, and C. tetani have been completed. All sequenced clostridia have circular genome. Many others are in progress (check NCBI for complete list.) The genome of C. perfringens, an agent of gas gangrene, contains 3,031,430 nt, with GC content of 28%. There are 2786 genes, of which 2660 are coding for proteins. The genome of C. tetani contains 2,799,251 nt, with GC content of 28%. There are 2445 genes, of which 2373 are protein coding. The genome of C. difficile contains 3,256,683 nt, with GC content of 28%; there are 3017 genes, of which 2876 are protein coding. The genome of C. botulinum contains 3,659,644 nt, with GC content of 27 %; there are 3381 genes, of which 3256 are protein coding. So the sequenced genomes varied widely. The genome of C. septicum could fall between 2 and 4 millions nt.

Cell structure and metabolism

Clostridium septicum are Gram- positive rod and are spore-former. The terminal or sub-terminal spore causes them to appear like drumstick. They have peritrichous flagellae which allow them to move quickly from one environment to the next. They are classical fermentative anaerobes, generating molecular hydrogen gas. They ferment sugars and amino acids, and a few other organic compounds. In all cases, the production of ATP is linked to substrate-level phosphorylations in the glycolytic pathway. Other clostridium, such as C. acetobutylicum, can produce butanol and acetone.

Ecology

Clostridia septicum are ubiquitous in nature. They are found in anoxic soils such as sewage, marine sediments, and the intestinal tracks of both animals and humans. They have the ability to switch from vegetative growth to forming endospores when conditions are not favorable, and endospores could survive in harsh conditions, such as boiling temperature, for an extended period of time. When conditions are favorable, they germinate and become vegetative again.

Pathology

Most clostridia are disease-causing in livestock and wildlife. C. septicum is highly pathogenic in humans because they produce a variety of toxins. One such toxin is the alpha toxin, a potent toxin responsible for non-traumatic gas gangrene. Gas gangrene is a life-threatening syndrome with characteristic patterns of extensive tissue destruction, edema, thrombosis, and restriction of leukocyte infiltration to the infected site. The course of the disease takes less 24 hours with reported dead rate ranging from 67-100%. The pathology of gas gangrene is not fully known, but it is thought to mediate by disruption of blood flow to the infected site. Since blood circulation is essential in nutrients and oxygen delivery, a reduction in perfusion would result in cell death and necrosis. In addition, C. septicum is being associated with malignancy (colon carcinoma, leukemia, and breast carcinoma), pericarditis, and mycotic aneurysm. The precise mechanisms are unknown.

Current Research

One research of interest is to find out how the alpha toxin produced by C. septicum lead to myonecrosis seen in gas gangrene. Using intravital microscopy Hickey et al. (2008) investigated microvascular blood flow in tissue of mice exposed to toxin of C. septicum. They found that the toxin induced severe reduction in capillaries blood flow to the tissues. They speculated that the severe reduction in microperfusion causes myonecrosis seen in gas gangrene, giving the roles of capillaries as an essential in the delivery of oxygen and nutrients.

The second research interest was the use of clostridium for cancer treatment. Solid tumors are anoxic. Thus, it is an ideal place for clostridium spores to germinate. Lemmon et al.(1997) used genetically modified spores from C. oncolyticum (nonpathogenic strain) to inject into the body of mice with tumors. The spores contained an E. coli gene nitroreductase, and this enzyme was used to activate cancer drug. They found that the spores only germinated within the tumors of the mice. And when they injected the nontoxic prodrug, the active form of the drug , being activated by the nitroreductase, was found within the tumors, killing the tumors. Thus, they have found a delivery system of anticancer gene specific to tumors.

Based on the research done by Lemmon et al. (1997), the third research interest was the use of genetically modified C. novyi-NT as an anticancer agent. Agrawal et al. (2004) injected cancerous mice with the spores of C. novyi-NT. They found that the spores only germinated within hypoxic regions of the cancers and destroyed cancer cells through the secretion of enzymes, such as lipases, proteases, and other degradative enzymes. The tissues surrounding the tumors were not affected due to higher level of oxygen. They also found that the immune system was actively attacking the tumors. They speculated that the spores of C. novyi-NT recruited the immune system to the tumors. So acting together, cancer cells are being destroyed at a faster rate, while the surrounding tissues are unaffected.

References

Agrawal, N., Bettegowda, C., Cheong, I., Geschwind, J., Drake, C.G., Hipkiss, E.L., Tatsumi, M., Dang, L.H., Diaz, L.A., Pomper, M., Abusedera, M., Wahl,R.L.,Kinzler, K.W., Zhou,S., Huso,D.L., and Vogelstein, B. 2004. Bacteriolytic therapy can generate a potent immune response against experimental tumors. PNAs, v. 101:42, p.15172-15177.

Brahan, R.B., and Kahler, R.C. 1990. Clostridium septicum as a cause of pericarditis and mycotic aneurysm. Journal of Clinical Microbiology, V. 28:10, p. 2377-2378.

Davies, H.D.2001. Flesh-eating disease: A note on necrotizing fasciitis. Can j infect Dis, v. 12:3, p. 136-140.

Hickey, M.J., Kwan,R.Q., Awad, M.M., Kennedy, C.L., Young, L.F., Hall, P., Cordner, L.M., Lyras, D., Emmins, J.J., and Rood, J.I. 2008. Molecular and cellular basis of microvascular perfusion deficits induced by Clostridium perfringens and Clostridium septicum. Plos Pathogens, v. 4:4, p. 1-9.

Katlic, M.R., Derkac, W.M., and Coleman, W.S. 1980. Clostridium septicum infection and malignancy. Ann.Surg, v. 193:3, p. 362-364.

Lemmon, M.J., Zijl, P.V., Fox, M.E., Mauchline, M.L., Giaccia, A.J., Minton,N.P., and Brown, J.M. 1997. Anaerobic bacteria as a gene delivery system that is controlled by the tumor microenvironment. Gene Therapy, v.4, p.791-796.

Melton-Witt, J.A, Bentsen, L.M., and Tweten, R.K. 2006. Identification of functional domains of Clostridium septic alpha toxin. Biochemistry, v. 45:48, p. 14347-14354.

Prinssen, H.M., Hoekman,K., and Burger, C.W. 1999. Clostridium septicum myonecrosis and ovarian cancer: a case report and review of literature. Gynecologic oncology, v. 72, p. 116-119.

Edited by student of Emily Lilly at University of Massachusetts Dartmouth.