The bacterium Borrelia burgdorferi (Bb) is the causative agent of Lyme disease, a tick-borne illness that can lead to persistent, multi-systemic symptoms in humans. Despite the host’s ability to mount a strong immune response, the spiral-shaped spirochete can survive and persist for months or even years. This persistence is due to a sophisticated suite of evasion tactics developed by the bacterium. These mechanisms allow Bb to bypass the host’s defense systems, including both the immediate innate response and the targeted adaptive response.
Rapid Changes in Surface Proteins
The most sophisticated mechanism Bb uses to evade the adaptive immune system is a genetic process called antigenic variation, which constantly alters its outer surface proteins (OSPs). The bacterium achieves this through a unique genetic system centered on the variable major protein-like sequence, known as VlsE. This surface-exposed lipoprotein is the primary target for the host’s antibody production, which typically labels a pathogen for destruction.
The vls locus consists of a single expression site, vlsE, and a series of 15 or more silent DNA cassettes. During infection, Bb uses a process of non-reciprocal recombination, or gene conversion, to shuffle small segments of DNA from these silent cassettes into the active vlsE expression site. This genetic rearrangement occurs at a high frequency, continuously generating thousands of new VlsE variants within the host.
Each new VlsE variant presents a distinct surface structure, or epitope, to the host immune system. As the body successfully produces antibodies to target the current version of VlsE, the spirochete population rapidly changes its coat, rendering the existing antibodies useless. The immune system is thus forced into an endless cycle of “catching up,” delaying effective clearance and allowing the infection to become chronic. The constant change in VlsE expression is a powerful tool against the humoral response.
Neutralizing the Complement Cascade
In addition to evading the adaptive immune system, Borrelia burgdorferi must also neutralize the immediate innate defense known as the complement cascade. This system is a collection of blood proteins designed to tag bacteria for engulfment (opsonization) or directly destroy them by punching holes in their membrane. Bb evades this attack by recruiting host-specific regulatory proteins directly to its surface.
The spirochete expresses a family of outer surface proteins collectively called Complement Regulator-Acquiring Surface Proteins, or CRASPs. These CRASPs, which include proteins like CspA, CspZ, and OspE, function by binding to human Factor H (FH), a key negative regulator of the complement pathway. Factor H is a protein the host uses to protect its own cells from accidental complement attack.
By coating itself with host Factor H, the bacterium effectively cloaks itself in a host-like identity, signaling to the immune system that it is “self” rather than an invader. This binding causes the inactivation of C3b, a protein that initiates the destruction process, preventing the formation of the Membrane Attack Complex (MAC). Some CRASPs, such as CspA, also directly inhibit the terminal complement pathway by binding to components like C7 and C9, blocking the assembly of the MAC pore structure.
Disrupting Immune Cell Function
The spirochete actively interferes with the function of phagocytes, such as macrophages and dendritic cells, which are responsible for initiating the inflammatory response and engulfing pathogens. Bb achieves this by manipulating the chemical signaling environment to suppress the host’s defense reactions. A primary tactic is to enhance the production of the anti-inflammatory cytokine Interleukin-10 (IL-10) by these immune cells.
High levels of IL-10 create a localized immunosuppressive environment that dampens inflammation. This cytokine actively suppresses the secretion of pro-inflammatory messengers, such as TNF-α and various interleukins, which are necessary to recruit other immune cells to the site of infection. The resulting low-inflammation state allows the bacteria to multiply and spread without triggering a full-scale immune mobilization.
Furthermore, the presence of Bb-elicited IL-10 directly diminishes the ability of macrophages to perform phagocytosis. IL-10 also suppresses the upregulation of co-stimulatory molecules on the surface of antigen-presenting cells. This interference hinders the step of presenting bacterial antigens to T-cells, which is necessary for establishing a robust and targeted adaptive immune response.
Hiding in Immune-Protected Tissues
As a final strategy, Borrelia burgdorferi retreats from the bloodstream, where immune defenses are most concentrated, into immunologically sheltered tissues. The bacterium exhibits tropism for sites like joints, the central nervous system (CNS), and the eyes, which are less accessible to high concentrations of antibodies and T-cells. This physical seclusion is a major factor in the persistence of the infection.
The spirochete’s corkscrew shape and motility aid its deep tissue penetration, allowing it to navigate through dense tissue matrices. Bb preferentially colonizes the extracellular matrix, particularly in areas rich in collagen and decorin. The bacterium uses adhesin proteins to bind to these structural components, establishing a protected microenvironment.
Once embedded within this connective tissue, the bacteria can persist in a physical refuge, shielded from the full force of the host’s immune attack. This sequestration contributes significantly to the persistent and chronic symptoms of Lyme disease, as the combination of molecular cloaking, complement evasion, cellular suppression, and physical hiding creates an environment where the infection is nearly impossible to fully clear.