Clostridium novyi

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. It comes in three types, labelled A, B, and a non-pathogenic type C distinguished by the range of toxins they produce. Some authors include Clostridium haemolyticum as Clostridium novyi type D. C novyi is closely related to Clostridium botulinum types C and D as Yoshimasa Sasaki et al. have demonstrated by 16S rDNA sequence analysis.[2]

Clostridium novyi
Scientific classification
Kingdom:
Bacteria
Phylum:
Firmicutes
Class:
Clostridia
Order:
Clostridiales
Family:
Clostridiaceae
Genus:
Clostridium
Species:
C. novyi
Binomial name
Clostridium novyi
(Migula 1894 [sic]) Bergey et al. 1923[1]

Growth in culture proceeds through 3 stages: Initial growth wherein no toxin is produced; vigorous growth wherein toxin is produced; and spore formation wherein endospores are formed and toxin production decreases. It is suggested that type C may be type B that forms spores more readily so does not go through the toxin-production stage.

Isolating and identifying C novyi is difficult due to its extreme anaerobic nature. Commercial kits may not be adequate.[3][4]

It is also fastidious and difficult to culture, requiring the presence of thiols.[5]

Toxins
The toxins are designated by Greek letters. The toxins normally produced by the various types are shown in table 1[6]
Table 1
C novyi type Toxins
A alpha, gamma, delta, epsilon
B alpha, beta, zeta
C gamma

The alpha-toxin of Clostridium botulinum types C and D, is similar to the C novyi beta-toxin. The A and B toxins of Clostridium difficile show homology with the alpha-toxin of C novyi as does the lethal toxin of clostridium sordellii.[7]

Alpha toxin

The alpha-toxin is characterised as lethal and necrotizing.

The type A alpha-toxin is oedematising.[8] It acts by causing morphological changes to all cell types especially endothelial cells by inhibition of signal transduction pathways,[9] resulting in the breakdown of cytoskeletal structures.[10] The cells of the microvascular system become spherical and the attachments to neighbouring cells are reduced to thin strings. This results in leakage from the capillaries, leading to oedema. The threshold concentration for this action to occur is 5 ng/ml (5 parts per billion) with 50% of cells rounded at 50 ng/ml.

The duodenum is particularly sensitive to the toxin. Injection into dogs resulted in extreme oedema of the submucosal tissues of the duodenum while leaving the stomach uninjured. Injection into the eye resulted in lesions similar to flame haemorrhages found in diabetic retinopathy.[8]
The toxin is a large 250-kDa protein the active part of which is the NH2-terminal 551 amino acid fragment.[11] Alpha-toxins are glycosyltransferases, modifying and thereby inactivating different members of the Rho and Ras subfamily of small GTP-binding proteins.[12][13][14] C novyi type A alpha-toxin is unique in using UDP-N-acetylglucosamine rather than UDP-glucose as a substrate.[15]

Beta-Toxin

The beta-toxin is characterised as haemolytic, necrotizing lecithinase.

Gamma-Toxin

The gamma-toxin is characterised as haemolytic, lecithinase.

Delta-Toxin

The delta-toxin is characterised as oxygen labile haemolysin.

Epsilon-Toxin

The epsilon-toxin is characterised as lecithino-vitelin and thought to be responsible for the pearly layer found in cultures.

Zeta-Toxin

The zeta-toxin is characterised as haemolysin.

Human diseases

The type and severity of the disease caused depends on penetration of the tissues. The epithelium of the alimentary tract, in general, provides an effective barrier to penetration. However, spores may escape from the gut and lodge in any part of the body and result in spontaneous infection should local anaerobic conditions occur.

Tissue penetration

Wound infection by C novyi and many other clostridium species cause gas gangrene[16] Spontaneous infection is mostly associated with predisposing factors of hematologic or colorectal malignancies and with diabetes mellitus,[17] although Gram-negative organisms, including Escherichia coli, may lead to a gas gangrene-like syndrome in diabetic patients. This presents with cellulitis and crepitus, and may be mistaken for gas gangrene.[18] Spontaneous, nontraumatic, or intrinsic infections from a bowel source have been increasingly reported recently.[19]

C novyi has been implicated in mortality among injecting illegal drug users.[20][21]

Epithelial infections

Symptoms are often non-specific including, colitis, oedematous duodenitis, and fever with somnolence.

Testing is problematical with figures presented by McLauchlin and Brazier [cited above] suggesting a false negative rate of about 40% under ideal conditions. Only positive results may be regarded as reliable. In the absence of a positive test, C. novyi type A may be inferred from characterisation by clinical observation, table 2.

Table 2
Observation Comment
Oedema Especially if extreme with rapid onset. In view of the sensitivity of the duodenum to the alpha-toxin, oedematous duodenum is always suspect.
Anaerobic Infection occurs at an anaerobic site such as the gut or salivary gland. It may also occur at a site temporarily made anaerobic by occlusion and maintained in this state by oedema.
Gram positive If penicillin causes remission of oedema then a Gram positive organism is the causative agent.

Chronic infection leading to leaky capillaries may also cause retinal haemorrhages and oedema in the lower extremities leading to necrosis and gangrene. Leaky nephrons may compromise the ability of kidneys to concentrate urine leading to frequent urination and dehydration.

Animal diseases

Gas gangrene: Infectious necrotic hepatitis (Black disease)[22]

Further reading
  • Mengesha, Asferd; Dubois, Ludwig; Paesmans, Kim; Wouters, Brad; Lambin, Philippe; Theys, Jan (2009). "Clostridia in Anti-tumour Therapy". In Brüggemann, Holger; Gottschalk, Gerhard (eds.). Clostridia: Molecular Biology in the Post-genomic Era. Norfolk, England: Caister Academic Press. pp. 199–214. ISBN 978-1-904455-38-7.
  • Bettegowda C, Dang LH, Abrams R, et al. (December 2003). "Overcoming the hypoxic barrier to radiation therapy with anaerobic bacteria". Proceedings of the National Academy of Sciences of the United States of America. 100 (25): 15083–8. doi:10.1073/pnas.2036598100. PMC 299912. PMID 14657371.
  • Groot AJ, Mengesha A, van der Wall E, van Diest PJ, Theys J, Vooijs M (December 2007). "Functional antibodies produced by oncolytic clostridia". Biochemical and Biophysical Research Communications. 364 (4): 985–9. doi:10.1016/j.bbrc.2007.10.126. PMID 17971292.
  • Dang LH, Bettegowda C, Huso DL, Kinzler KW, Vogelstein B (December 2001). "Combination bacteriolytic therapy for the treatment of experimental tumors". Proceedings of the National Academy of Sciences of the United States of America. 98 (26): 15155–60. doi:10.1073/pnas.251543698. PMC 64999. PMID 11724950.
  • St Jean AT, Zhang M, Forbes NS (October 2008). "Bacterial Therapies: Completing the Cancer Treatment Toolbox". Current Opinion in Biotechnology. 19 (5): 511–7. doi:10.1016/j.copbio.2008.08.004. PMC 2600537. PMID 18760353.
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References
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  2. Sasaki Y, Takikawa N, Kojima A, Norimatsu M, Suzuki S, Tamura Y (May 2001). "Phylogenetic positions of Clostridium novyi and Clostridium haemolyticum based on 16S rDNA sequences". International Journal of Systematic and Evolutionary Microbiology. 51 (Pt 3): 901–4. doi:10.1099/00207713-51-3-901. PMID 11411712.
  3. Brazier JS, Duerden BI, Hall V, et al. (November 2002). "Isolation and identification of Clostridium spp. from infections associated with the injection of drugs: experiences of a microbiological investigation team". Journal of Medical Microbiology. 51 (11): 985–9. doi:10.1099/0022-1317-51-11-985. PMID 12448683.
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  7. Hofmann F, Herrmann A, Habermann E, von Eichel-Streiber C (June 1995). "Sequencing and analysis of the gene encoding the alpha-toxin of Clostridium novyi proves its homology to toxins A and B of Clostridium difficile". Molecular & General Genetics. 247 (6): 670–9. doi:10.1007/BF00290398. PMID 7616958.
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  9. Schmidt M, Rümenapp U, Bienek C, Keller J, von Eichel-Streiber C, Jakobs KH (February 1996). "Inhibition of receptor signaling to phospholipase D by Clostridium difficile toxin B. Role of Rho proteins". The Journal of Biological Chemistry. 271 (5): 2422–6. doi:10.1074/jbc.271.5.2422. PMID 8576201.
  10. Müller H, von Eichel-Streiber C, Habermann E (July 1992). "Morphological changes of cultured endothelial cells after microinjection of toxins that act on the cytoskeleton". Infection and Immunity. 60 (7): 3007–10. PMC 257268. PMID 1612768.
  11. Busch C, Schömig K, Hofmann F, Aktories K (November 2000). "Characterization of the Catalytic Domain of Clostridium novyi Alpha-Toxin". Infection and Immunity. 68 (11): 6378–83. doi:10.1128/IAI.68.11.6378-6383.2000. PMC 97722. PMID 11035748.
  12. Just I, Selzer J, Hofmann F, Green GA, Aktories K (April 1996). "Inactivation of Ras by Clostridium sordellii lethal toxin-catalyzed glucosylation". The Journal of Biological Chemistry. 271 (17): 10149–53. doi:10.1074/jbc.271.17.10149. PMID 8626575.
  13. Just I, Selzer J, Wilm M, von Eichel-Streiber C, Mann M, Aktories K (June 1995). "Glucosylation of Rho proteins by Clostridium difficile toxin B". Nature. 375 (6531): 500–3. doi:10.1038/375500a0. PMID 7777059.
  14. Just I, Wilm M, Selzer J, et al. (June 1995). "The enterotoxin from Clostridium difficile (ToxA) monoglucosylates the Rho proteins". The Journal of Biological Chemistry. 270 (23): 13932–6. doi:10.1074/jbc.270.23.13932. PMID 7775453.
  15. Selzer J, Hofmann F, Rex G, et al. (October 1996). "Clostridium novyi alpha-toxin-catalyzed incorporation of GlcNAc into Rho subfamily proteins". The Journal of Biological Chemistry. 271 (41): 25173–7. doi:10.1074/jbc.271.41.25173. PMID 8810274.
  16. Hatheway CL (January 1990). "Toxigenic clostridia". Clinical Microbiology Reviews. 3 (1): 66–98. doi:10.1128/CMR.3.1.66. PMC 358141. PMID 2404569.
  17. Nagano N, Isomine S, Kato H, et al. (April 2008). "Human Fulminant Gas Gangrene Caused by Clostridium chauvoei". Journal of Clinical Microbiology. 46 (4): 1545–7. doi:10.1128/JCM.01895-07. PMC 2292918. PMID 18256217.
  18. "Necrotising infections". The British Society for Antimicrobial Chemotherapy. Archived from the original on 2003-11-26. Retrieved 2009-08-04.
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  20. Finn SP, Leen E, English L, O'Briain DS (November 2003). "Autopsy findings in an outbreak of severe systemic illness in heroin users following injection site inflammation: an effect of Clostridium novyi exotoxin?". Archives of Pathology & Laboratory Medicine. 127 (11): 1465–70. doi:10.1043/1543-2165(2003)127<1465:AFIAOO>2.0.CO;2. PMID 14567722.
  21. McLauchlin J, Salmon JE, Ahmed S, et al. (November 2002). "Amplified fragment length polymorphism (AFLP) analysis of Clostridium novyi, C. perfringens and Bacillus cereus isolated from injecting drug users during 2000". Journal of Medical Microbiology. 51 (11): 990–1000. doi:10.1099/0022-1317-51-11-990. PMID 12448684.
  22. Kahn, Cynthia M., ed. (2005). "Infectious Necrotic Hepatitis (Black disease)". The Merck Veterinary Manual (9th ed.). Whitehouse Station, New Jersey: Merck & Co. ISBN 978-0-911910-50-6. OCLC 57355058.
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