Corynebacterium granulosum
1. Classification
a. Higher order taxa
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2. Introduction
Corynebacterium granulosum (which is synonymous with Cutibacterium granulosum and Propionibacterium granulosum [1]) is a member of the Cornybacterium genus. It is anaerobic tolerant, Gram-positive and is also generally catalase-positive [2]. The bacterium is ubiquitous in skin flora, especially around sebaceous glands, which, in conjunction with Propionibacterium granulosum, has been shown to contribute to the pathogenesis of acne [3]. However, there have been cases where C. granulosum has been isolated in patients with endocarditis [4] and septicemia [5]. In the 1970s and 1990s, there was much research on the potential immunomodulating properties of C. granulosum [6]. In particular, fractionated p40 derived from C. granulosum significantly improved the efficacy of some chemotherapies in murine tumors [7]. A particulate fraction like p40 is obtained by agitating a solution of bacterial cells with detergent, centrifuging, and precipitating the desired protein products [15]. There have been few clinical trials investigating the immunomodulating properties of C. granulosum in humans that have run to completion.
3. Organism
Metabolism and Cell Genome Structure
C. granulosum’s genome sequenced with Illumina High Sequencing revealed to be exactly 2.14036 Mb long and consists of double stranded, linear DNA. A total of 1821 genes have been recognized, from which 1653 proteins are expressed [1]. Most of the proteins that were identified are involved in replication, transcription or translation mechanisms. Many others serve in metabolic pathways to allow the bacteria to draw nutrients from the environment. However, many proteins have not yet been studied and are classified as “hypothetical” [1]. Like most Corynebacrteria species, C. granuslosum is chemoorganotrophic, nonmotile, Gram-positive, and there is evidence that C.granulosum can perform fermentative metabolism of maltose and sucrose [2][5]. C. granuslosum is aerobic, perhaps anaerobic tolerant, as it usually grows on oxidative environments, such as on the human skin, and since it is positive for catalase synthesis (enzyme that turns hydrogen peroxide into water and oxygen). The species does not digest indole and does not liquefy gelatin, suggesting its inability to digest the amino acid tryptophan and the lack of gelatinase enzyme [3]. Experimental evidence suggests that Corynebacterium granulosum should be incubated for 24-48 hours at 37C and in a 5% carbon dioxide-enriched atmosphere to obtain optimal growth.
Ecology and Habitat
Species from the Corynebacterium family can be found in different environments, such as on the surface of animals, in water or on synthetic products. They are often found to be living in with other organisms, including humans, as mutualistic symbionts or pathogens. C. granulosum has been found as part of many animals and plants’ flora, as well as on different parts of the human skin, predominantly in the oily sections of the skin, such as the scalp, forehead, ear and alae nasi [3][5].
Pathogensis
C. granulosum have generally being considered as non pathogenic for human. However, a case was reported where a patient acquires septicemia, a type of blood infection, from C. granulosum through undergoing a hepatic puncture procedure [5]. C. granulosum thus have shown to act as an opportunistic pathogen that causes systemic infection [5]. It has been observed (table 1) that C. granulosum is susceptible to most antimicrobial agents [11].
Anti-Tumor Activity
Species from the Corynebacterium genus exhibit immunostimulation (stimulation of an immune response). When tumor infected mice were injected with small C. granulosum, the experimental mice showed an observable regression in the size as well as infiltration of lymphocytes in tumor cells [12]. C. granulosum culture intralesional injected (delivery of microbe into skin lesion or immediately below the skin) into mice prior to tumor cell (melanotic melanoma) transplant have found to have the effect of regressing the size and limiting the spread of tumor cells [13]. Histological examination of melanoma cells after the experimental period showed dense infiltration of neutrophils and lymphocytes [13]. It remains unclear, however, how C. granulosum actually stimulates the immune system in responses to tumor cells. C. granulosum have been found to associate with macrophage, activating them to destroy tumor cells in vitro, in which neither macrophage nor C.granulosum can be functional when acting alone [14]. C. granulosum activated macrophage have no effect in non-tumor cells [14].
Immunopotentiation
Multiple mice-based experiments support the hypothesis that C. granulosum may improve the immune response of the host to mitogens (mitotic inducers) and to skin transplantations or allografts [9] [10]. Moreover, injection of the bacterium into ALS (anti-mouse lymphocyte serum) mice infected with HSV2 (Herpes Simplex Virus 2) resulted in partial recovery of the immune system and a smaller percentage of deaths [10].
4. Future Work
No current research on C. granulosum is present in the literature. However, all the literature concerning the ability of the bacterium to conduct anti-cancer activity and immunopotentiation does not give any specific information on how these processes are achieved. Therefore, this could be a plausible starting point for future research on C. granulosum [9] [10].
5. References
[1]https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=33011&lvl=3&lin=f&keep=1&srchmode=1&unlock https://www.ncbi.nlm.nih.gov/genome/proteins/13083?genome_assembly_id=174249
[2] Bernard, Kathryn. 2012. “The Genus Corynebacterium and Other Medically Relevant Coryneform-Like Bacteria” Journal of Clinical MIcrobiology. 50 (10):3152.
[3] McGinley, K.J., Webster, G.F., Leyden, J.J. 1978. “Regional variations of cutaneous propionibacteria” Applied and Environmental Microbiology. 35 (1):62-66.
[4] Armstrong RW, Wuerflein RD. 1996. Endocarditis due to Propionibacterium granulosum. Clin Infect Dis. 23 (5): 1178-1179
[5] Branger, C., Bruneaeu, B., Goullet, P. 1987. “Septicemia Caused by Propionibacterium granulosum in a Compromised Patient” American Society for Microbiology. 25 (12): 2405-2406.
[6] Bizzini. B., Carlotti, M., German, F. G. 1992. “Anti-infectious effect of C. granulosum-derived P40 immunomodulator given by aerosolization and intranasal instillation.” Biomed & Pharmacother. 46 (1992): 491-494.
[7] Milas, L., Hunter, N., Basic, I., Mason, K., Grdina, D.J., Withers, H.R. 1975. “Nonspecific Immunotherapy of Murine solid tumors With Cornyebacterium granulosum” Journal of the National Cancer Institute. 54 (4):895-902.
[9] Milas, Luka, Ivan Basic, H. D. Kogelnik, and Rodney Withers. "Effects of Corynebacterium Granulosum on Weight and Histology of Lymphoid Organs, Response to Mitogens, Skin Allografts, and a Syngeneic Fibrosarcoma in Mice." Cancer Research 35 (1975): 2365-374. Print.
[10]Gabrielson, David A., and James J. Kelleher. "Effect of Corynebacterium Granulosum Immunopotentiation on the Pathogenesis of Herpes Simplex Virus Type 2 in BALB/c Mice." N.p., Dec. 1980. Web.
[11]Hoeffler, U., H. L. Ko, and G. Pulverer. 1976. Antimicrobial susceptibility of Propionibacterium acnes and related microbial species. Antimicrob. Agents Chemother. 10:387-394.
[12]Milas, Luke, Nancy Hunter, and Rodney Withers. "Complete Regressions of an Established Murine Fibrosarcoma Induced by Systemic Application of Corynebaclerium Granulosum." Cancer Research 34 (1974): 2470-475.
[13]Paslin, David, Nikolay Dimitrov, and Charles Heaton. "Brief Communication: Regression of a Transplantable Hamster Melanoma by Intralesional Injections of Corynebacterium Granulosum." Oxford Journals. Journal of the National Cancer Institute, 1 Feb. 1974.
[14]Basic, Ivan, Luka Milas, and David Grdina. "In Vitro Destruction of Tumor Cells by Macrophages From Mice Treated With Corynebacterium Granulosum." Oxford Journals. Journal of the National Cancer Institute, 1 Sept. 1975.
