Microbiology of Lyme disease: Difference between revisions
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Lyme disease is caused by spirochetal bacteria from the genus Borrelia, which has well over three hundred known genomic strains. The Borrelia species known to cause Lyme disease are collectively known as Borrelia burgdorferi sensu lato, and have been found to have greater strain diversity than previously estimated.[1] Until recently it was thought that only three genospecies caused Lyme disease: B. burgdorferi sensu stricto (predominant in North America, but also in Europe), B. afzelii, and B. garinii (both predominant in Eurasia). However, newly discovered genospecies have also been found to cause disease in humans: B. lusitaniae[2] in Europe (especially Portugal), North Africa and Asia, B. bissettii[3][4] in the U.S. and Europe, and B. spielmanii[5][6] in Europe. B. valaisiana was detected by PCR in human spinal fluid in Greece,[7] and is present in (Eurasia, especially England, Switzerland and the Netherlands); Additional B. burgdorferi sensu lato genospecies suspected of causing illness, but not confirmed by culture, include B. japonica, B. tanukii and B. turdae (Japan); B. sinica (China); and B. andersonii (U.S.). Some of these species are carried by ticks not currently recognized as carriers of Lyme disease. Note: At present, diagnostic tests are based only on B. burgdorferi sensu stricto (the only species used in the U.S.), B. afzelii and B. garinii.
Apart from this group of closely related genospecies, additional Borrelia species of interest include B. lonestari, a spirochete recently detected in the Amblyomma americanum tick (Lone Star tick) in the U.S.[8] B. lonestari is suspected of causing STARI (Southern Tick-Associated Rash Illness), also known as Masters disease in honor of its discoverer. The illness follows a Lone Star tick bite and clinically resembles Lyme disease, but sufferers usually test negative for Lyme.[9]
There is currently no diagnostic test available for STARI/Masters, and no official treatment protocol, though antibiotics are generally prescribed. The B. miyamotoi spirochete, related to the relapsing fever group of spirochetes, is also suspected of causing illness in Japan. Spirochetes similar to B. miyamotoi have recently been found in both I. ricinus ticks in Sweden and I. scapularis ticks in the U.S.[10][11]
Genomic characteristics
One of the most striking features of B. burgdorferi as compared with other eubacteria is its unusual genome, which is far more complex than that of its spirochetal cousin Treponema pallidum, the agent of syphilis.[12] The genome of B. burgdorferi includes a linear chromosome approximately one megabase in size, with 21 plasmids (12 linear and 9 circular) - by far the largest number of plasmids found in any known bacterium.[13] Genetic exchange, including plasmid transfers, contributes to the pathogenicity of the organism.[14] Long-term culture of B. burgdorferi results in a loss of some plasmids and changes in expressed protein profiles. Associated with the loss of plasmids is a loss in the ability of the organism to infect laboratory animals, suggesting that the plasmids encode key genes involved in virulence.
Structure and growth
B. burgdorferi is a highly specialized, motile, two-membrane, spiral-shaped spirochete ranging from about 9 to 32 micrometers in length. It is often described as gram-negative and has an outer membrane with LPS, though it stains only weakly in the Gram stain. B. burgdorferi is a microaerophilic organism, requiring little oxygen to survive. It lives primarily as an extracellular pathogen, although it can also hide intracellularly (see Mechanisms of persistence section).
Like other spirochetes such as T. pallidum (the agent of syphilis), B. burgdorferi has an axial filament composed of flagella which run lengthways between its cell wall and outer membrane. This structure allows the spirochete to move efficiently in corkscrew fashion through viscous media, such as connective tissue. As a result, B. burgdorferi can disseminate throughout the body within days to weeks of infection, penetrating deeply into tissue where the immune system and antibiotics may not be able to eradicate the infection.
B. burgdorferi is very slow growing, with a doubling time of 12-24 hours (in contrast to pathogens such as Streptococcus and Staphylococcus, which have a doubling time of 20-30 minutes). Since most antibiotics kill bacteria only when they are dividing, this longer doubling time necessitates the use of relatively longer treatment courses for Lyme disease. Antibiotics are most effective during the growth phase, which for B. burgdorferi occurs in four-week cycles. Some clinicians have observed that chronic Lyme patients commonly experience a worsening of symptoms every four weeks; these periodic flare-ups are thought to correspond to the growth phase of B. burgdorferi.[15]
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 despite a robust immune response and standard antibiotic treatment, particularly when treatment is delayed and dissemination widespread. Numerous studies have demonstrated persistence of infection despite antibiotic therapy.[16][17][18][19][20][21][22][23][24]
Various survival strategies of B. burgdorferi have been posited to explain this phenomenon,[25] including the following:
- Physical sequestration of B. burgdorferi in sites that are inaccessible to the immune system and antibiotics, such as the brain[26] and central nervous system. New evidence suggests that B. burgdorferi may use the host's fibrinolytic system to penetrate the blood-brain barrier.[27]
- Intracellular invasion. B. burgdorferi has been shown to invade a variety of cells, including endothelium,[28] fibroblasts,[29] lymphocytes,[30] macrophages,[31] keratinocytes,[32] synovium,[33][34] and most recently neuronal and glial cells. [35] By 'hiding' inside these cells, B. burgdorferi is able to evade the immune system and is protected to varying degrees against antibiotics,[36][37] allowing the infection to persist in a chronic state. Paradoxically, many of these scientific studies were performed and published by critics of persistent Borrelia infection.
- Altered morphological forms, i.e. spheroplasts (cysts, granules).
- The existence of B. burgdorferi spheroplasts, which lack a cell wall, has been well documented in vitro,[38][39][40][41][42][43][44] in vivo,[34][40][45][46] and in an ex vivo model.[47]The fact that energy is required for the spiral bacterium to convert to the cystic form[38] suggests that these altered forms have a survival function, and are not merely end stage degeneration products. The spheroplasts are indeed virulent and infectious, able to survive under adverse environmental conditions, and have been shown to revert back to the spiral form in vitro, once conditions are more favorable.[40][48][49][50][51]
- A number of other factors make B. burgdorferi spheroplasts a key factor in the relapsing, chronic nature of Lyme disease. Compared to the spiral form, spheroplasts have dramatically reduced surface area for immune surveillance. They also express different surface proteins - another reason for seronegative disease (i.e. false-negative antibody tests), as current tests only look for antibodies to surface proteins of the spiral form. In addition, B. burgdorferi spheroplasts are generally not susceptible to the antibiotics traditionally used for Lyme disease. They have instead shown sensitivity in vitro to antiparasitic drugs such as metronidazole,[52] tinidazole,[53] and hydroxychloroquine,[54] to which the spiral form of B. burgdorferi is not sensitive.
- Antigenic variation. Like the Borrelia that cause relapsing fever, B. burgdorferi has the ability to vary its surface proteins in response to immune attack.[25][55] 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.[25] Furthermore, the existence of immune complexes provides another explanation for seronegative disease (i.e. false-negative antibody tests of blood and cerebrospinal fluid), as studies have shown that substantial numbers of seronegative Lyme patients have antibodies bound up in these complexes.[56][57][58]
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