Pathogenesis of Lyme disease caused by Borrelia burgdorferi
Lyme disease is caused by the spirochete B. burgdorferi, which is transmitted by the bite of a small tick of the genus Ixodes.
Humans are “accidental” hosts for B. burgdorferi because spirochetes from infected people are not transmitted to other hosts.
While in the midgut of the Ixodes tick between feeding periods, the spirochetes of B. burgdorferi are in a dormant, non-replicating state attached to epithelial cells.
There they express a plasmid-encoded, major outer surface protein (OspA), which plays a critical role in protection of B. burgdorferi from antibodies present in the blood meal from immune hosts and may also promote tick midgut colonization by binding to tick midgut cell receptors.
Outer surface protein A (OspA) is expressed on the surface of B. burgdorferi residing in the midgut of unfed ticks and binds specifically to gut proteins.
Upon feeding, expression of this protein is repressed, allowing the spirochete to migrate to the salivary glands, and outer surface protein C (OspC) expression, which appears critical for transmission from ticks to mammals, is up-regulated.
In humans, the bite of the infected tick is required for introduction of the pathogen through healthy skin.
This extracellular pathogen starts in the dermal tissue where it begins to adapt to life in the mammalian host by changing the expression of its surface glycoproteins.
The change in the gene expression profile of the spirochetes in response to tick feeding, typified by the switch from OspA to OspC, is essential.
The ability of B. burgdorferi to multiply and establish infection in the skin of the mammalian host is reflected in one of the characteristic signs of localized infection or stage 1 Lyme disease in humans, the erythema migrans (EM) rash which reflects infiltration of lymphocytes and macrophages.
The spirochetes are highly motile and probably coated with the host protease plasmin.
After certain period, they are able to spread through the skin, resulting in expansion of the rash, leaving a blanched central area, and a bull’s-eye appearance.
B. burgdorferi expresses outer surface proteins that selectively interact with endothelial cells, platelets, chondrocytes, and extracellular matrix via specific interactions with integrins, glycosaminoglycans, fibronectin, and collagen.
These interactions are important in homing to and colonization of tissues, including the skin, joint, and heart and the bacterium also activates proteases and other induced host cell molecules to allow for dissemination through the blood and into other tissues.
Disseminated infection (stage 2) includes transient colonization of the bloodstream.
At this stage some degree of vascular damage, including mild vasculitis or hypercellular vascular occlusion, may be seen in multiple sites, suggesting that the spirochetes colonize the vessel wall. This stage is known as early disseminated infection or stage 2 Lyme disease.
Later, in late stage or stage 3 Lyme disease, the rate of bacterial multiplication appears to be significantly reduced or is kept in check by the host defenses, resulting in the very low number of bacteria present in tissues.
The host response to B. burgdorferi plays a key role in disease pathogenesis.
B. burgdorferi does not produce toxins or proteases that are directly responsible for tissue damage upon colonization.
In contrast, the bacterium produces multiple molecules that activate host responses and can lead to localized and generalized inflammatory pathogenic responses.
Most of these host responses normally function to contain or clear infections and are components of the innate defense and/or inflammatory response.
These bacteria, however, are not eradicated by the host immune response.
Once human infection is established, the spirochete can survive for years, despite the development of a vigorous host immune response.
B. burgdorferi is able to bind mammalian complement regulatory factors, which may provide resistance to complement-mediated lysis and opsonization during persistent infection of host tissues.
Clinical Manifestations of Borrelia burgdorferi
Lyme disease is characterized by three stages.
The first stage, erythema migrans (EM), is the characteristic red, ring shaped skin lesion with a central clearing that first appears at the site of the tick bite but may develop at distant sites as well.
The clinical manifestations include headache, fever, muscle and joint pain, and malaise during this stage.
The second stage, beginning weeks to months after infection, may include arthritis, but the most important features are neurologic disorders which include meningitis, neurologic deficits and carditis.
This is a result of the hematogenous spread of spirochetes to organs and tissues.
In addition, neurologic symptoms and infection may occur in the meninges, spinal cord, peripheral nerves, and brain.
The third stage is usually characterized by chronic arthritis or acrodermatitis chronica atrophicans (ACA), a diffuse skin rash, and may continue for years.