Lyme disease microbiology
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Lyme disease, or borreliosisis, is caused by Gram negative spirochetal bacteria from the genus Borrelia, which has at least 37 known species, 12 of which are Lyme related, and an unknown number of genomic strains. Borrelia species known to cause Lyme disease are collectively known as Borrelia burgdorferi sensu lato.
Borrelia are microaerophillic and slow-growing—the primary reason for the long delays when diagnosing Lyme disease—and have been found to have greater strain diversity than previously estimated.[1] The strains differ in clinical symptoms and/or presentation as well as geographic distribution.[1]
Except for Borrelia recurrentis (which causes louse-borne relapsing fever and is transmitted by the human body louse), all known species are believed to be transmitted by ticks.[1]
Species and Strains
Until recently it was thought that only three genospecies caused Lyme disease (borreliosis): B. burgdorferi sensu stricto ( the predominant species in North America, but also present in Europe); B. afzelii; and B. garinii (both predominant in Eurasia). To date the complete genome of B. burgdorferi sensu stricto strain B31, B. afzelii strain PKo and B. garinii strain PBi is known. B. burgdorferi strain B31 was derived by limited dilutional cloning from the original Lyme-disease tick isolate derived by Alan Barbour. There are over 300 species or strains of Borrelia world wide with apx 100 in the U.S. and it is unknown how many cause lyme like sickness, but many of them may.
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.
Emerging Genospecies
- B. valaisiana was identified as a genomic species from Strain VS116, and named B. valaisiana in 1997.[1] It was later detected by Polymerase chain reaction (PCR) in human cerebral spinal fluid (CSF) in Greece.[1] B. valaisiana has been isolated throughout Europe, as well east Asia.[1]
Newly discovered genospecies have also been found to cause disease in humans:
- B. lusitaniae [1] in Europe (especially Portugal), North Africa and Asia.
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.
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.[1][1]
B. lonestari
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.[1] B. lonestari is suspected of causing STARI (Southern Tick-Associated Rash Illness), also known as Masters disease in honor of its discoverer Ed Masters. The illness follows a Lone Star tick bite and clinically resembles Lyme disease, but sufferers usually test negative for Lyme.[1]There is currently no diagnostic test available for STARI/Masters, and no official treatment protocol, though antibiotics are generally prescribed.
Epidemiology
The number of reported cases of the Lyme disease (borreliosis) have been increasing, as are endemic regions in North America. Of cases reported to the United States Center for Disease Control (CDC), the ratio of Lyme disease infection is 7.9 cases for every 100,000 persons. In the ten states where Lyme disease is most common, the average was 31.6 cases for every 100,000 persons for the year 2005.[1] Although Lyme disease has now been reported in 49 of 50 states in the U.S, about 99% of all reported cases are confined to just five geographic areas (New England, Mid-Atlantic, East-North Central, South Atlantic, and West North-Central).[1]
In Europe, cases of B. burgdorferi sensu lato infected ticks are found predominantly in Norway, Netherlands, Germany, France, Italy, Slovenia and Poland, but have been isolated in almost every country on the continent. Lyme disease statistics for Europe can be found at Eurosurveillance website.
Borrelia burgdoferi sensu lato infested ticks are being found more frequently in Japan, as well as in Northwest China and far eastern Russia.[1][1] Borrelia has been isolated in Mongolia as well.[1]
In South America tick borne disease recognition and occurrence is rising. Ticks carrying Borrelia burgdoferi sensu lato, as well as canine and human tick-borne disease, has been reported widely in Brazil, but the subspecies of borrelia has not yet been defined.[1] The first reported case of Lyme Disease in Brazil was made in 1993 in Sao Paulo.[1] Borrelia burgdorferi sensu stricto antigens in patients have been identified in Colombia and in Bolivia.
In Northern Africa Borrelia burgdoferi sensu lato has been identified in Morroco, Algeria, Egypt and Tunisia.[1][1][1]
In Western and Sub-Saharan Africa, tick-borne relapsing fever has been recognized for over a century, first isolated by the British physicians Joseph Dutton and John Todd in 1905. Borrelia in the manifestation of Lyme disease in this region is presently unknown but evidence indicates that the disease may occur in humans in sub-Saharan Africa. The abundance of hosts and tick vectors would favor the establishment of the infection in Africa.[1]In East Africa two cases of Lyme disease have been reported in Kenya.[1]
In Australia there is no definitive evidence for the existence of B. burgdorferi or for any other tick-borne spirochete that may be responsible for a local syndrome being reported as Lyme disease.[1] Cases of neuroborreliois have been documented in Australia but are often ascribed to travel to other continents. The existence of Lyme disease in Australia is controversial.
To date data shows that Northern hemisphere temperate regions are most endemic for Lyme disease.[1][1]
Life cycle
- Further information: Tick#Life cycle
The life-cycle of B. burgdorferi is complex, requiring ticks, rodents, and deer at various points. Mice are the primary reservoir for the bacteria; Ixodes ticks then transmit the B. burgdorferi infection to deer.
Hard ticks have a variety of life histories with respect to optimizing their chance of contact with an appropriate host to ensure survival. The life stages of soft ticks are not readily distinguishable. The first life stage to come out of the egg, a six legged larva, takes a blood meal from a host, and molts to the first nymphal stage. Unlike hard ticks, many soft ticks go through multiple nymphal stages, gradually increasing in size until the final molt to the adult stage.
The life cycle of the deer tick comprises three growth stages: the larva, nymph and adult.
The life-cycle concept encompassing reservoirs and infections in multiple hosts has recently been expanded to encompass forms of the spirochete which differ from the motile corkscrew form, and these include cystic forms spheroplast-like, straighted non-coiled bacillary forms which are immotile due to flagellin mutations and granular forms coccoid in profile. The model of Plasmodium species Malaria with multiple parasitic profiles demonstrable in various host insects and mammals is a hypothesized model for a similarly complex proposed Borrelia spirochete life cycle. [1] [1]
Whereas B. burgdoferi is most associated with deer tick and the white footed mouse,[1] B. afzelii is most frequently detected in rodent-feeding vector ticks, B.garinii and B. valaisiana appear to be associated with birds. Both rodents and birds are competent reservoir hosts for Borrelia burgdorferi sensu stricto. The resistance of a genospecies of Lyme disease spirochetes to the bacteriolytic activities of the alternative immune complement pathway of various host species may determine its reservoir host association.
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.[1] 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.[1] Genetic exchange, including plasmid transfers, contributes to the pathogenicity of the organism.[1] 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.
Chemical analysis of the external membrane of B. burgdorferi revealed the presence of 46% proteins, 51% lipids and 3% carbohydrates.[1]
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 lipopolysaccharide (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 12-18 hours[1] (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.
Outer surface proteins
The outer membrane of Borrelia burgdorferi is composed of various unique outer surface proteins (Osp) that have been characterized (OspA through OspF). They are presumed to play a role in virulence.
OspA and OspB are by far the most abundant outer surface proteins.
The OspA and OspB genes encode the major outer membrane proteins of the B burgdorferi. The two Osp proteins show a high degree of sequence similarity, indicating a recent evolutionary event. Molecular analysis and sequence comparison of OspA and OspB with other proteins has revealed similarity to the signal peptides of prokaryotic lipoproteins.[1]Virtually all spirochetes in the midgut of an unfed nymph tick express OspA.
OspC is an antigen-detection of its presence by the host organism and can stimulate an immune response. While each individual bacterial cell contains just one copy of the gene encoding OspC, populations of B. burgdorferi have shown high levels of variation among individuals in the gene sequence for OspC.[1] OspC is likely to play a role in transmission from vector to host, since it has been observed that the protein is only expressed in the presence of mammalian blood or tissue.[1]
The functions of OspD are unknown.
OspE and OspF are structurally arranged in tandem as one transcriptional unit under the control of a common promoter.[1]
In transmission to the mammaliam host, when the nymphal tick begins to feed, and the spirochetes in the midgut begin to multiply rapidly, most spirochetes cease expressing OspA on their surface. Simultaneous with the disappearance of OspA, the spirochete population in the midgut begins to express a OspC. Upregulation of OspC begins during the first day of feeding and peaks 48 hours after attachment.[1]
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.[1][1][1]
Various survival strategies of B. burgdorferi have been posited to explain this phenomenon,[1] including the following:
- Physical sequestration of B. burgdorferi in sites that are inaccessible to the immune system and antibiotics, such as the brain[1] and central nervous system. New evidence suggests that B. burgdorferi may use the host's fibrinolytic system to penetrate the blood-brain barrier.[1]
- Intracellular invasion.
B. burgdorferi has been shown to invade a variety of cells, including endothelium,[1] fibroblasts,[1] lymphocytes,[1] macrophages,[1] keratinocytes,[1] synovium,[1][1] and most recently neuronal and glial cells. [1] By 'hiding' inside these cells, B. burgdorferi is able to evade the immune system and is protected to varying degrees against antibiotics,[1][1] allowing the infection to persist in a chronic state.
- Altered morphological forms, i.e. spheroplasts (cysts, granules).
The existence of B. burgdorferi spheroplasts, which lack a cell wall, has been documented in vitro,[1][1][1][1] in vivo,[1][1][1] and in an ex vivo model.[1] The fact that energy is required for the spiral bacterium to convert to the cystic form[1] 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.[1][1]
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, [1] tinidazole, [1] and hydroxychloroquine, [1] to which the spiral form of B. burgdorferi is not sensitive.
- Antigenic variation and gene expression.
Like the Borrelia that cause relapsing fever, B. burgdorferi has the ability to vary its surface proteins in response to immune attack.[1][1] 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.[1]
- 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.[1] 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.[1]
Advancing Immunology Research
- Further information: Lyme Disease#Advancing Immunology Research
The role of T cells in borrelia was first made in 1984,[1] the role of cellular immunity in active Lyme disease was made in 1986,[1] and long term persistence of T cell lymphocyte responses to B. burgdorferi as an "immunological scar syndrome" was hypothesized in 1990.[1] The role Th1 and interferon-gamma (INF-gamma) in borrelia was first described in 1995.[1] The cytokine pattern of Lyme disease, and the role of Th1 with down regulation of interleukin-10 (IL-10) was first proposed in 1997.[1]
Recent studies in both acute and antibiotic refractory, or chronic, Lyme disease have shown a distinct pro-inflammatory immune process. This pro-inflammatory process is a cell-mediated immunity and results in Th1 upregulation. These studies have shown a significant decrease in cytokine output of (IL-10), an upregulation of Interleukin-6 (IL-6) and Interleukin-12 (Il-12) and Interferon-gamma (IFN-gamma) and disregulation in TNF-alpha predominantly.
New research has also found that chronic Lyme patients have higher amounts of Borrelia-specific forkhead box P3 (FoxP3) than healthy controls, indicating that regulatory T cells might also play a role, by immunosuppression, in the development of chronic Lyme disease. FoxP3 are a specific marker of regulatory T cells.[1] The signaling pathway P38 mitogen-activated protein kinases (p38 MAP kinase) has also been identified as promoting expression of proinflammatory cytokines from borrelia.[1][1]
The culmination of these new and ongoing immunological studies suggest this cell-mediated immune disruption in the Lyme patient amplifies the inflammatory process, often rendering it chronic and self-perpetuating, regardless of whether the borrelia bacterium is still present in the host, or in the absence of the inciting pathogen in an autoimmune pattern.[1]
References
External links
- Atlas of Borrelia (images of spirochetal, spheroplast and granular forms)
- NCBI Taxonomy Browser - Borrelia
- Borrelia burgdoferi B31 Genome Page
- Borrelia Garinii PBi Genome Page
- Borrelia Afzelli PKo Gemonme Page
- CDC - Vector Interactions and Molecular Adaptations of Lyme Disease and Relapsing Fever Spirochetes Associated with Transmission by Ticks
de:Wanderröte nl:Borrelia burgdorferi no:Borreliauk:Borrelia burgdorferi
Acknowledgement and Attribution Regarding Sources of Content
Some of the initial content on this page may be incorporated in part from copyleft sources in the public domain including wikis such as Wikipedia and AskDrWiki. Drug information for patients came from the The National Library of Medicine. Infectious disease information may have come from the Centers for Disease Control (CDC). Differential Diagnoses are drawn from clinicians as well as an amalgamation of 3 sources: 1.The Disease Database; 2. Kahan, Scott, Smith, Ellen G. In A Page: Signs and Symptoms. Malden, Massachusetts: Blackwell Publishing, 2004:3; 3. Sailer, Christian, Wasner, Susanne. Differential Diagnosis Pocket. Hermosa Beach, CA: Borm Bruckmeir Publishing LLC, 2002:7 .
