Some investigators mistakenly use the term “cyst” to describe what are properly termed L-forms or “cell-wall deficient” variants of bacteria. Such variants are present in senescent cultures as amounts of essential nutrients become limiting, and most often appear after exposure to antibiotics that influence cell wall formation and/or protein synthesis (1). There are of two types that differ mainly in the amount of residual cell wall material they possess: spheroplasts, which contain some remnants of the original cell wall material; and, protoplasts that lack residual cell wall material (2).
Saunder’s “Dictionary and Encyclopdeia of Laboratory Medicine and Technology”, lists two definitions for the term “cyst”. The first is used to describe any closed cavity or sac — both normal and abnormal — that is lined by epithelial cells; in some locations, this cavity may be lined by connective tissue or bone. The second definition is used to describe a stage in the life cycle of certain parasites (e.g., Echinococcus granulosus) during which they are enclosed within a protective sac called a hydatid cyst. Neither definition applies to Borrrelia since they do not form such structures. Two genera of soil dwelling bacteria (Azotobacter and Myxobacteria) form a distinctive outer cyst-like structure called an “exine”, surrounding the “intine” or vegetative cell (3). Although both of these structures have been isolated and characterized for Azotobacter, neither is formed by Borrelia. Some bacteria (Bacillus and Clostridia species) form protective heat-resistant structures called spores; however, Borrelia burgdorferi does not make spores. In view of these considerations, use of the term “cyst” with reference to B. burgdorferi is incorrect. In most cases, the term is used to convey the false impression that, by forming “cysts”, Borrelia are somehow able to evade destruction by recommended antibiotic therapy and host immune defense mechanisms, thereby enabling them to establish a long-term, antibiotic-refractory, persistent infection that some associate with the poorly defined phenomenon of “chronic Lyme disease”. Some even advocate additional treatment with metronidazole and other compounds called “cyst busters” to eliminate these variant forms (4); however, this is likely to be a fruitless effort since there is no evidence to confirm that that these morphologic variants are present, let alone cause disease.
Protoplasts and spheroplasts may be stable or unstable, respectively, depending on their capacity to revert to the original parental cell type when placed in an antibiotic- free environment that then permits normal metabolism and/or protein synthesis. If reversion does occur, it happens relatively early after antibiotic treatment, i.e., when the levels of antibiotic first begin to decline (2). Since neither spheroplasts nor protoplasts are surrounded by a “cyst-like” protective structure, there is no reason to believe that they are any less permeable or susceptible to antibiotics than the original parental cell type. In the cases of B. burgdorferi, these variants have not been fully characterized and then only with regard to their general morphology. More important, no well-controlled functional or physiological studies have been conducted to demonstrate that they indeed are relevant to human disease. Two studies show that such residual structures may exist in mice after treatment for B. burgdorferi infection; however, they were found to be not cultivable, not virulent, and eventually eliminated by host defense mechanisms without causing disease (5, 6, and 7).
A systematic review was made as to determine whether B. burgdorferi morphologic variants play a role in “chronic Lyme disease” (7). In the context of the broader medical literature, it is not possible to ascribe a pathogenic role to any morphologic variants of B. burgdorferi in either typical manifestations of Lyme disease or in other disease states, such as “chronic Lyme disease”. There is no clinical literature to justify specific treatment to eliminate B. burgdorferi morphologic variants (7).
References
1. Brorson, O, and Brorson, SH. An in vitro study of the susceptibility of mobile cystic forms of Borreli burgdorferi to metronidazole. APMIS 107: 566-576, 1999.
2. Allan, EJ, Hoischen, D, and Gumpert, Bacterial L-forms. J. Advan. Applied Microbiol. 68: 2-39, 2009.
3. Wyss, O, Neuman, MG, and Socolofsky, MD. Development and germination of the Azotobacter cyst. J. Biophys. Biochem. Cytology 10: 555-565, 1961,
4. Hodzic, E, Feng, S, Holden, K, et al. Persistence of Borrelia burgdorferi following antibiotic treatment in mice. Antimicrob. Agents Chemother. 52: 1728-1736, 2008.
5. Bockenstedt, LK, Mao, J, Hodzic, E, et al. Detection of attenuated. Non-infectious spirochetes in Borrelia-burgdorferi- infected mice after antibiotic treatment. J. Infect. Dis. 186: 1430-1437, 2002.
6. Wormser, GP, and Schwartz, I. Antibiotic treatment of animals infected with Borrelia burgdorferi. Clin. Microbiol. Rev. 22: 387-395, 2009.
7. Lantos, PM, Auwaerter, PG, and Wormser, GP. A systematic review of Borrelia burgdorferi morphologic variants does not support a role in chronic Lyme disease. Clin. Infect. Dis. 58: 663-671, 2014.