Introduction
Chronic Lyme disease is a persistent infection involving a variety of clinical signs and symptoms that can include joint pain, neurological manifestations, dysautonomia, limbic irritability, sleep dysfunction, among others. The process in which Lyme disease becomes a chronic infection is something that has been investigated by researchers for years. The research surrounding this topic suggests the involvement of several different mechanisms that work together to ensure the survival of Borrelia burdorferi in its host. Below is a brief description of three of these tactics that seem to be driving the current explanation for the persistence of Lyme.
Immune Evasion
The immune system plays an integral role in the eradication of harmful bacteria. This remains to be true when utilizing antibiotic therapy to kill bacteria. Infections that are successfully treated with antibiotics rely upon the host immune system to manage any bacteria that have persisted despite antibiotic treatment (1). This importance is emphasized when we see the deleterious effects of infection in immunocompromised hosts (1). Borrelia burgdorferi (Bb) has a number of strategies to evade and impair the immune response to avoid eradication even in the face of antibiotic treatment. This includes hiding in the extracellular matrix, suppressing the immune system, impairing the immune system’s inflammatory pathways, and gaining access to primary immune sites (2).
Bb has the ability to disrupt and evade both the innate and humoral immune responses. Bb uses the binding capacity of its surface proteins to dismantle the complement cascade (3) which is responsible for the initial inflammatory response that alerts the body of the incoming antigen and helps mount the first attack. Bb’s surface proteins will also help resist the host’s natural production of antimicrobial peptides (3). In addition, Bb is able to produce anti-inflammatory interleukins that are responsible for down-regulating the immune response and subsequently suppressing phagocytosis (aka killing of the bacteria) by the macrophages (3). Bb is also able to invade the macrophages themselves to hide from the immune system and survive the use of antimicrobial medications (3). Additionally, Bb is able to sabotage the adaptive immune response by infiltrating the lymph nodes and disrupting the formation of memory B cells and therefore potentially inhibiting the ability to clear infection from tissues that IgM cannot get to (3). This may also explain Bb’s ability to become a chronic infection.
Biofilm
Another aspect of the development of chronic infection is the formation of biofilm. Biofilm consists of a bunch of tangled fibers of polysaccharides (2) that are secreted by cells inside the biofilm (4). Biofilm formation is a normal stage of microbial development and is a mechanism that many kinds of bacteria use to develop chronic infection (2). The complex of fibers act as a kind of mesh that prevents neutrophils from getting to the individual bacterial cells and therefore protects them from immune activity, invasion from other bacteria, chemical changes in the environment, and antimicrobial treatments (4). Biofilm structures are incredibly resistant to environmental and therapeutic stressors (2) and are subsequently remarkably difficult to eradicate (4).
Persister cells
Bacteria work hard to adapt to unfavorable conditions and continue to live through stressors such as antimicrobial treatments, nutritional deficiencies, environmental changes to temperature and pH, among others (5). There are many different ways that bacteria can do this, however in further examining how bacteria survive through the exposure of antibiotics, many believe that the presence of persister cells plays a significant role. Persister cells are drug-tolerant, dormant bacterial cells that have the ability to change with the environment (2). Persisters exist in almost all bacteria species, however how persisters form in Bb remains poorly understood (2).
Antibiotic resistance is different from the formation of persister cells. Antibiotic resistance arises from genetic mutations that cause certain bacteria to be resistant to the damaging effects of antibiotics and allows for that bacteria and its offspring to continue to live in spite of antibiotic treatments (4). In the case of antibiotic resistance, the surviving bacteria are still “active” and participate in reproduction to further the infection. Persister cells are “dormant” and do not participate in reproduction which is what allows them to survive through antimicrobial treatments (6). Antimicrobials target various parts of the bacterial cells that are used during reproduction so slow-growing or non-growing cells (like persister cells) can avoid being killed (4). Persisters can remain viable even when exposed to aggressive antibiotic therapy because of this as well as their ability to revert back to viable, motile, and reproducible bacteria once the environmental conditions improve (2).
Persisters have the ability to change size and shape and therefore alter their functionality and ability to respond to hostile environments (2). Bb itself is also pleomorphic which helps with its tolerance of antibiotics (2). It can exist in many different forms including spirochetes, round-bodies (RB), cell wall deficient forms, non-motile atypical forms, and biofilm aggregates (2). The ability to come and go out of these various forms has been observed in other kinds of spirochetes (2) and offers yet another explanation as to how chronic infection can develop.
Conclusion
The combination of immune evasion, biofilm production, and the formation of persister cells offer a reasonable explanation for the development of chronic infections with Bb. While more research needs to be done to further understand these implications and what they mean in a clinical setting, it is clear that Bb has developed a number of strategies to persist despite treatment with antimicrobial agents. A comprehensive understanding of these mechanisms and their clinical applications is necessary to provide patients with a definitive treatment plan for chronic Lyme disease.
Definitions:
Innate immune response – This is the body's first line of defense and is the part of the immune system that reacts right away to a pathogen or foreign substance. This immune action does not adapt based on previous exposure to microorganisms, but rather is the default setting for an initial response.
Surface proteins – These are proteins that exist on the outer part of the cell that allow the cell to interact with its environment.
Complement cascade – This is a term that refers to the activity of multiple different proteins that help the immune system fight pathogens.
Interleukins – proteins that are produced by white blood cells that help regulate the immune response
Phagocytosis – the process of killing cells
Macrophages – a type of white blood cells that perform phagocytosis
Adaptive immune response – This is the part of the immune system that activates after the innate response. It uses antibodies that specifically target the specific pathogens that are responsible for the infection.
Memory B cells – These are immune cells that are designed to remember different pathogens to improve the immune response upon a second exposure
IgM – These are antibodies that are active against acute infections and provide short-term protection
Polysaccharides – These are large macromolecules that consist of long chains of sugar molecules
Neutrophils – a specific kind of white blood cells
Pleomorphic – this term refers to an ability of cells to change shape
Biofilm aggregates – communities of bacteria that group together in a matrix of polysaccharides
References
Sharma B, Brown AV, Matluck NE, Hu LT, Lewis K. Borrelia burgdorferi, the Causative Agent of Lyme Disease, Forms Drug-Tolerant Persister Cells. Antimicrob Agents Chemother. 2015;59(8):4616-4624. doi:10.1128/AAC.00864-15
Rudenko N, Golovchenko M, Kybicova K, Vancova M. Metamorphoses of Lyme disease spirochetes: phenomenon of Borrelia persisters. Parasit Vectors. 2019;12(1):237. Published 2019 May 16. doi:10.1186/s13071-019-3495-7
Anderson C, Brissette CA. The Brilliance of Borrelia: Mechanisms of Host Immune Evasion by Lyme Disease-Causing Spirochetes. Pathogens. 2021;10(3):281. Published 2021 Mar 2. doi:10.3390/pathogens10030281
Yan J, Bassler BL. Surviving as a Community: Antibiotic Tolerance and Persistence in Bacterial Biofilms. Cell Host Microbe. 2019;26(1):15-21. doi:10.1016/j.chom.2019.06.002
Cabello FC, Embers ME, Newman SA, Godfrey HP. Borreliella burgdorferi Antimicrobial-Tolerant Persistence in Lyme Disease and Posttreatment Lyme Disease Syndromes. mBio. 2022;13(3):e0344021. doi:10.1128/mbio.03440-21
Kohanski MA, Dwyer DJ, Collins JJ. How antibiotics kill bacteria: from targets to networks. Nat Rev Microbiol. 2010;8(6):423-435. doi:10.1038/nrmicro2333
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