Lyme disease microbiology

Borrelia burgdorferi the causative agent of Lyme disease (borreliosis). Magnified 400 times.

Lyme disease, or borreliosis, is caused by spirochetal bacteria from the genus Borrelia,[1] 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 microaerophilic 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.[2] The strains differ in clinical symptoms and/or presentation as well as geographic distribution.[3]

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.[4]

Species and strains

Until recently, only three genospecies were thought to cause 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). Totally 10 complete genomes of B. burgdorferi sensu stricto, B. afzelii and B. garinii strains are available on NCBI Genome server at Feb 2013. B. burgdorferi strain B31 was derived by limited dilutional cloning from the original Lyme-disease tick isolate derived by Alan Barbour.

Thirteen distinct genomic classifications of Lyme disease bacteria have been identified worldwide. These include but are not limited to B. burgdorferi sensu stricto, B. afzelii, B. garinii, B. valaisana, B. Lusitaniae, B. andersoni, 25015, DN127, CA55, 25015, HK501, B. Miyamotoi, and B. Japonica.[5] Many of these genomic groups are country or continent specific. For example, without migration, B. Japonica is only prevalent in the eastern hemisphere.[5]

The genomic variations have direct implications on the clinical symptoms of tick borne Lyme disease. For example, B. burgdorferi senso stricto’s tick borne Lyme disease may manifest itself into arthritis-like symptoms.[5] In contrast, B. garinii’s tick borne Lyme disease may manifest itself into an infection of the central nervous system.[5]

Emerging genospecies

Newly discovered genospecies have also been found to cause disease in humans:

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 Ixodes ricinus ticks in Sweden and I. scapularis ticks in the U.S.[14][15][16]

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.[17] B. lonestari is suspected of causing southern tick-associated rash illness (STARI), also known as Masters disease in honor of its discoverer, Edwin Masters. The illness follows a lone star tick bite, and clinically resembles Lyme disease, but sufferers usually test negative for Lyme.[18] Currently, no diagnostic test is available for STARI/Masters, and no official treatment protocol exists, though antibiotics are generally prescribed.

Epidemiology

Lyme disease is most endemic in Northern Hemisphere temperate regions,[19][20] but sporadic cases have been described in other areas of the world.

The number of reported cases of the borreliosis have been increasing, as are endemic regions in North America. Of cases reported to the United States Centers for Disease Control and Prevention (CDC), the rate of Lyme disease infection is 7.9 cases for every 100,000 persons. In the 10 states where Lyme disease is most common, the average was 31.6 cases per 100,000 persons for 2005.[21] Although Lyme disease has now been reported in 49 of 50 states in the U.S (all but Hawaii), 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).[22]

In Europe, cases of B. burgdorferi sensu lato-infected ticks are found predominantly in Norway, the 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 burgdorferi sensu lato-infested ticks are being found more frequently in Japan, as well as in northwest China and far eastern Russia.[23][24] Borrelia has been isolated in Mongolia as well.[25]

In South America, tick-borne disease recognition and occurrence is rising. Ticks carrying B. burgdorferi sensu lato, as well as canine and human tick-borne diseases, have been reported widely in Brazil, but the subspecies of Borrelia has not yet been defined.[26] The first reported case of Lyme disease in Brazil was made in 1993 in Sao Paulo.[27] B. burgdorferi sensu stricto antigens in patients have been identified in Colombia and in Bolivia.

In Northern Africa, B. burgdorferi sensu stricto has been identified in Morocco, Algeria, Egypt, and Tunisia.[28][29][30]

In western and sub-Saharan Africa, tick-borne relapsing fever has been recognized for over a century, since it was first isolated by the British physicians Joseph Everett Dutton and John Lancelot Todd in 1905. Borrelia in the manifestation of Lyme disease in this region is presently unknown, but evidence indicates 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.[31] In East Africa two cases of Lyme disease have been reported in Kenya.[32]

In Australia, no definitive evidence exists 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.[33] Cases of neuroborreliosis have been documented in Australia, but are often ascribed to travel to other continents. The existence of Lyme disease in Australia is controversial.[34]

Lifecycle

Further information: Tick § Lifecycle

The lifecycle of B. burgdorferi is complex, requiring ticks, and species that are competent reservoirs, often small rodents. Mice are the primary reservoir for the bacteria.

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 stage to hatch from 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 lifecycle of the backlogged tick, commonly called the deer tick (Ixodes scapularis)' comprises three growth stages: the larva, nymph and adult.

The lifecycle 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 spheroplast-like forms, straight uncoiled 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 lifecycle.[35][36]

Whereas B. burgdorferi is most associated with deer ticks and the white footed mouse,[37] B. afzelli is most frequently detected in rodent-feeding vector ticks, and B. garinii and B. valaisiana appear to be associated with birds. Both rodents and birds are competent reservoir hosts for B. burgdorferi sensu stricto. The resistance of a genospecies of Lyme disease spirochetes to the bacteriolytic activities of the alternative immune complement system of various host species may determine its reservoir host association.

Genomic characteristics

The genome of B. burgdorferi (B31 strain) was the third microbial genome ever to be sequenced, following the sequencing of both H. influenzae and M. genitalium in 1995, and its chromosome contains 910,725 base pairs and 853 genes.[38] One of the most striking features of B. burgdorferi as compared with other bacteria is its unusual genome, which is far more complex than that of its spirochetal cousin Treponema pallidum, the agent of syphilis.[39] In addition to a linear chromosome, the genome of B. burgdorferi strain B31 includes 21 plasmids (12 linear and 9 circular) – by far the largest number of plasmids found in any known bacterium.[40] Genetic exchange, including plasmid transfers, contributes to the pathogenicity of the organism.[41] 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 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.[42]

Structure and growth

B. burgdorferi is a highly specialized, motile, two-membrane, flat-waved spirochete, ranging from about 9 to 32 micrometers in length.[43] Because of its double-membrane envelope, it is often mistakenly described as Gram negative,[44] though it stains weakly in Gram stain. The bacterial membranes in at least the B31, NL303 and N40 strains of B. burgdorferi do not contain lipopolysaccharide, which is extremely atypical for Gram negative bacteria; instead, the membranes contain glycolipids.[45] However, the membranes in the B31 strain have been found to contain a lipopolysaccharide-like component.[46] B. burgdorferi is a microaerophilic organism, requiring little oxygen to survive. Unlike most bacteria, B. burgdorferi does not use iron, hence avoiding the difficulty of acquiring iron during infection.[47] It lives primarily as an extracellular pathogen, although in vitro it can also hide intracellularly (see Mechanisms of persistence section).

Like other spirochetes, such as Treponema 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.

B. burgdorferi is very slow growing, with a doubling time of 12–18 hours[48] (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.

Outer surface proteins

The outer membrane of B. burgdorferi is composed of various unique outer surface proteins (Osp) that have been characterized (OspA through OspF). The Osp proteins are lipoproteins anchored by N-terminally attached fatty acid molecules to the membrane.[49] They are presumed to play a role in virulence, transmission, or survival in the tick.

OspA, OspB, and OspD are expressed by B. burgdorferi residing in the gut of unfed ticks, suggesting they promote the persistence of the spirochete in ticks between blood meals.[50][51] During transmission to the mammalian 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 surfaces. Simultaneous with the disappearance of OspA, the spirochete population in the midgut begins to express an OspC and migrates to the salivary gland. Upregulation of OspC begins during the first day of feeding and peaks 48 hours after attachment.[52]

The OspA and OspB genes encode the major outer membrane proteins of B. burgdorferi. The two Osp proteins show a high degree of sequence similarity, indicating a recent duplication event.[53] Virtually all spirochetes in the midgut of an unfed nymph tick express OspA. OspA promotes the attachment of B. burgdorferi to the tick protein TROSPA, present on tick gut epithelial cells.[54] OspB also has an essential role in the adherence of B. burgdorferi to the tick gut.[55] Although OspD has been shown to bind to tick gut extracts in vitro, as well as OspA and OspB, it is not essential for the attachment and colonization of the tick gut, and it is not required for human infections.[51]

OspC is a strong antigen; detection of its presence by the host organism stimulates an immune response. While each individual bacterial cell contains just one copy of the ospC gene, the gene sequence of ospC among different strains within each of the three major Lyme disease species is highly variable.[56] OspC plays an essential role during the early stage of mammalian infection.[57] In infected ticks feeding on a mammalian host, OspC may also be necessary to allow B. burgdorferi to invade and attach to the salivary gland after leaving the gut, although not all studies agree on such a role for the protein.[58][59] OspC attaches to the tick salivary protein Salp15, which protects the spirochete from complement and impairs the function of dendritic cells.[60][61][62]

OspE and OspF were initially identified in B. burgdorferi strain N40.[63] The ospE and ospF genes are structurally arranged in tandem as one transcriptional unit under the control of a common promoter.[63] Individual strains of B. burgdorferi carry multiple related copies of the ospEF locus, which are now collectively referred to as Erp (Osp'E'/F-like 'r'elated 'p'rotein) genes. In B. burgdoreri strains B31 and 297, most of the Erp loci occupy the same position on the multiple copies of the cp32 plasmid present in these strains.[64] Each locus consists of one or two Erp genes. When two genes are present, they are transcribed as one operon, although in some cases, an internal promoter in the first gene may also transcribe the second gene.[65] The presence of multiple Erp proteins was proposed to be important in allowing B. burgdorferi to evade killing by the alternative complement pathway of a broad range of potential animal hosts, as individual Erp proteins exhibited different binding patterns to the complement regulator factor H from different animals.[66] However, the presence of factor H was recently demonstrated to not be necessary to enable B. burgdorferi to infect mice, suggesting the Erp proteins have an additional function.[67]

Mechanisms of persistence

While B. burgdorferi is susceptible to a number of antibiotics in vitro, reports are contradictory 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,[68][69][70] although others suggested antibiotics rapidly end infections.[71][72]

Various survival strategies of B. burgdorferi have been posited to explain how the pathogen can persist in its host.[73] including the following:

B. burgdorferi can invade a variety of cultured cells, including endothelium,[76] fibroblasts,[77] lymphocytes,[78] macrophages,[79] keratinocytes,[80] synovium,[81][82] and most recently neuronal and glial cells.[83] 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,[84][85] 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.[73]

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,[86][87][88][89] in vivo,[82][90] and in an ex vivo model.[91] The finding that energy is required for the spiral bacterium to convert to this form[86] suggests 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.[92][93] 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.[94]

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,[95] tinidazole,[96] and hydroxychloroquine [97] to which the spiral form of B. burgdorferi is not sensitive.

Like the Borrelia that causes relapsing fever, B. burgdorferi has the ability to vary its surface proteins in response to immune attack.[73][98] 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.[99]

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.[73] 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.[100]

Advancing immunology research

The role of T cells in Borrelia was first made in 1984,[101] the role of cellular immunity in active Lyme disease was made in 1986,[102] and long-term persistence of T cell lymphocyte responses to B. burgdorferi as an "immunological scar syndrome" was hypothesized in 1990.[103] The role of Th1 and interferon-gamma (IFN-gamma) in Borrelia was first described in 1995.[104] The cytokine pattern of Lyme disease, and the role of Th1 with down-regulation of interleukin-10 (IL-10) was first proposed in 1997.[105]

Recent studies in both acute and antibiotic refractory, or chronic, Lyme disease have shown a distinct proinflammatory immune process. This proinflammatory process is a cell-mediated immunity and results in Th1 up-regulation. These studies have shown a significant decrease in cytokine output of (IL-10), an up-regulation of interleukin-6 and interleukin-12 and interferon-gamma and dysregulation in TNF-alpha,` predominantly.

New research has also found chronic Lyme patients have higher amounts of Borrelia-specific FoxP3 than healthy controls, indicating regulatory T cells might also play a role, by immunosuppression, in the development of chronic Lyme disease. FoxP3 is a specific marker of regulatory T cells.[106] The signaling pathway P38 mitogen-activated protein kinases (p38 MAP kinase) has also been identified as promoting expression of proinflammatory cytokines from borrelia.[107][108]

The culmination of these new and ongoing immunological studies suggests 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.[109]

Vaccines

A vaccine based on the surface protein OspA (LYMErix; SmithKline Beecham) was licensed for use in adults. However, the manufacturer voluntarily removed the vaccine from the market in 2002. The current focus is on vaccine candidates that require fewer boosts and provide long-term protection.[110] Interest is developing in vaccines that specifically target the tick vectors of Lyme disease, specifically components of tick saliva that coat the bacteria. This approach offers the advantage of protecting against multiple pathogens with one vaccine.[111] While an effective Lyme disease vaccine seems likely to be developed, earlier experiences with the LYMErix vaccine suggest bringing such a vaccine to market will be a challenge.[110]

A vaccine made by Pfizer, known as LymeVax, is currently available for use in dogs. It is a two-strain, multiantigen vaccine which induces an antibody response to bacterial proteins OspA and OspC.[112]

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