Borrelia burgdorferi Keeps Moving and Carries on: A Review of Borrelial Dissemination and Invasion

Abstract

Borrelia burgdorferi is the etiological agent of Lyme disease, a multisystemic, multistage, inflammatory infection resulting in patients experiencing cardiac, neurological, and arthritic complications when not treated with antibiotics shortly after exposure. The spirochetal bacterium transmits through the Ixodes vector colonizing the dermis of a mammalian host prior to hematogenous dissemination and invasion of distal tissues all the while combating the immune response as it traverses through its pathogenic lifecycle. The innate immune response controls the borrelial burden in the dermis, but is unable to clear the infection and thereby prevent progression of disease. Dissemination in the mammalian host requires temporal regulation of virulence determinants to allow for vascular interactions, invasion, and colonization of distal tissues. Virulence determinants and/or adhesins are highly heterogenetic among environmental B. burgdorferi strains with particular genotypes being associated with the ability to disseminate to specific tissues and the severity of disease, but fail to generate cross-protective immunity between borrelial strains. The unique motility of B. burgdorferi rendered by the endoflagella serves a vital function for dissemination and protection from immune recognition. Progress has been made toward understanding the chemotactic regulation coordinating the activity of the two polar localized flagellar motors and their role in borrelial virulence, but this regulation is not yet fully understood. Distinct states of motility allow for dynamic interactions between several B. burgdorferi adhesins and host targets that play roles in transendothelial migration. Transmigration across endothelial and blood-brain barriers allows for the invasion of tissues and elicits localized immune responses. The invasive nature of B. burgdorferi is lacking in proactive mechanisms to modulate disease, such as secretion systems and toxins, but recent work has shown degradation of host extracellular matrices by B. burgdorferi contributes to the invasive capabilities of the pathogen. Additionally, B. burgdorferi may use invasion of eukaryotic cells for immune evasion and protection against environmental stresses. This review provides an overview of B. burgdorferi mechanisms for dissemination and invasion in the mammalian host, which are essential for pathogenesis and the development of persistent infection.

Keywords: Borrelia burgdorferi; Lyme disease; chemotaxis; dissemination; invasion; motility; protease; vascular interaction.

Figure 1

Borrelia burgdorferi motility and associated regulation. Motility of B. burgdorferi is driven by multiple flagellum in the periplasmic space that are comprised of an inner membrane anchored basal body, hook, and filament. Coordinated rotation of the flagellar motors drive the direction of swimming or causes flexing of the spirochete. A two component regulatory system controls the motility in response to chemoattractant signals through the membrane-bound chemoreceptor and methyl-accepting chemotaxis protein (MCP). A complex is formed between MCP, linker protein CheW, and histidine kinase CheA with the latter able to autophosphorylate and transfer the phosphate to response regulators CheY1, CheY2, and CheY3 resulting in distinct outcomes. Levels of CheY-P can be reduced by the phosphatase CheX that forms a complex with CheD and increases its activity. The borrelial proteins designated in gray are chemotaxis homologs that have not been characterized to date. BB0569 localizes to the poles of the cell near flagellar motors and influences motility, but its specific function is unknown. CheR and CheB are potential methyltransferase and methylesterase proteins, respectively, which may modify MCP. Modification of Xu et al. (54).

Figure 2

Borrelia burgdorferi vascular interactions and transmigration. B. burgdorferi forms three types of vascular interactions: transient/tethering, dragging, and stationary adhesion. Decorin-binding protein A (DbpA) promotes transient/tethering with endothelial cells. Fibronectin-binding protein (BBK32) is involved in all three types of interactions. Stationary interaction through BBK32 may be through direct interaction with the endothelial surface or through a fibronectin bridge (Fn) to a host integrin. P66 also interacts with integrins and is important for transmigration of B. burgdorferi. Figure is a modification of Moriarty et al. (86).

Figure 3

Proteolytic activity may promote Borrelia burgdorferi invasion of the extracellular matrix. B. burgdorferi (Bb) protease BbHtrA cleaves the family of hyalectin proteoglycans that includes hyalectin family of chondroitin sulfate proteoglycans, including aggrecan, brevican, neurocan, and versican. Specifically, BbHtrA protease activity degrades aggrecan (green lines) as indicated by dotted green line. This activity may contribute to ECM degradation and allow invasion of the pathogen. The presence of B. burgdorferi induces host matrix metalloproteases (MMP) from endothelial cells, chondrocytes, neutrophils, lymphoblast, and keratinocytes. Collagen (red lines) is degraded (dotted red line) by MMP-1 that is transcriptionally regulated along with MMP-3 through the JNK, mitogen-activated protein kinase, and JAK/STAT pathways.