Lyme Disease Microbiology - Mechanisms of Persistence

Mechanisms of Persistence

While B. burgdorferi is susceptible to a number of antibiotics in vitro, there are contradictory reports as to the efficacy of antibiotics in vivo. B. burgdorferi may persist in humans and animals for months or years. Some studies have suggested persistence of infection despite antibiotic therapy, although others suggested antibiotics rapidly end infections.

Various survival strategies of B. burgdorferi have been posited to explain how the pathogen can persist in its host. including the following:

• Physical sequestration of B. burgdorferi in sites less accessible to the immune system and antibiotics, such as the brain and central nervous system. New evidence suggests that B. burgdorferi may use the host's fibrinolytic system to penetrate the blood–brain barrier.

• Intracellular invasion

B. burgdorferi can invade a variety of cultured cells, including endothelium, fibroblasts, lymphocytes, macrophages, keratinocytes, synovium, and most recently neuronal and glial cells. By 'hiding' inside these cells during human infection, B. burgdorferi may be able to evade the immune system and be protected to varying degrees against some antibiotics, sometimes allowing the infection to persist. However it remains unknown whether the in vitro observations made with cultured cells are relevant to persistent infection in Lyme disease patients as there have been few reports of intracellular B. burgdorferi in vivo.

• Altered morphological forms, i.e. round bodies (cysts, granules, spheroplasts)

The formation of rounded forms of B. burgdorferi cells, sometimes called spheroplasts, which either lack a cell wall or have a damaged cell wall, has been observed in vitro, in vivo, and in an ex vivo model. The finding that energy is required for the spiral bacterium to convert to this form suggests that these altered forms have a survival function, and are not merely end stage degeneration products. Some data suggest these rounded cells are virulent and infectious, are able to survive under adverse environmental conditions, and may revert to the spiral form in vitro, once conditions are more favorable. However, rounded cell types triggered by an antibody binding to the OspB surface protein are damaged and dying forms of the bacteria and do not represent a separate form of the organism.

Compared to the spiral form, spheroplasts of B. burgdorferi have reduced surface area exposed to immune surveillance. They also express some different surface proteins from spirochetes. B. burgdorferi spheroplasts have shown sensitivity in vitro to antiparasitic drugs, such as metronidazole, tinidazole, and hydroxychloroquine to which the spiral form of B. burgdorferi is not sensitive.

• Antigenic variation and gene expression

Like the Borrelia that causes relapsing fever, B. burgdorferi has the ability to vary its surface proteins in response to immune attack. This ability is related to the genomic complexity of B. burgdorferi, and is another way B. burgdorferi evades the immune system to establish a chronic infection.

• Immune system suppression.

Complement inhibition, induction of anti-inflammatory cytokines such as IL-10, and the formation of immune complexes have all been documented in B. burgdorferi infection. Furthermore, the existence of immune complexes may be involved in seronegative acute-phase disease (i.e. false-negative antibody tests of blood and cerebrospinal fluid). One study shows some acute-phase seronegative Lyme patients have antibodies bound up in these complexes.