Thursday, 12 November 2009

BRORSON RESEARCH TRANSLATED

Translation: Norwegian » English
Borrelia burgdorferi – en unik bakterie
Ø Brorson
Borrelia burgdorferi - a unique bacterial
E Brorson
Summary
Background. Lyme borreliose is a tick transmitted disease caused by Borrelia burgdorferi. Number of reported cases is rising steadily in both Europe and the United States. Tick as vector for the disease spreading to ever new areas. The disease is now called "the new great imitator disease. The possibility of fault diagnosis and fault management can be significant.

Materials and methods. The overview is based on articles found by searching on the properties of "Borrelia burgdorferi" in PubMed, as well as their own research in the field for the past 20 years.

Results. In recent years, has discovered many new characteristics of Borrelia burgdorferi. It turns out that bacteria can survive even if the host has an intact immune system. The bacterium can be disseminated early in the course of the disease to remote areas, be anaerobic, hiding in the niches, be intracellular and express multi-drug resistance. It can cover itself with the host material, make antigenic changes, manipulate the host's immune system and change to the inactive cyst forms.

There may be clinical treatment failure by any suitable antibiotic. Without appropriate treatment the infection can lead to multi-systemic chronic infection. Erythema migrans is a clinical diagnosis. If chronic illness is the clinical diagnosis is uncertain. Antibody development is slow and negative serological test is frequent, particularly in early disease phase.

Interpretation. Borrelia burgdorferi have many opportunities to escape the host's defense mechanisms and it has the ability to multi-drug resistance. There is a need for better diagnostic methods.

The bacterium Borrelia burgdorferi is named after the zoologist sveitsiskamerikanske Willy Burgdorf (b. 1925). Spirochaete was isolated and recognized as the cause of Lyme borreliose in 1982 (1).

Lyme borreliose has in recent years increased sharply in incidence in both the U.S. and Europe. This is probably due to several factors, both gjengroing of the cultural landscape, increase in hjortedyrbestanden, milder climate and the fact that people spend more time outdoors (2). It can not be excluded that some of the reason for the frequently reported cases is more awareness about the bacteria and better tests.

The purpose of this overview article is to provide an update on the various properties of B. burgdorferi.

Materials and methods
The overview is based on articles about the properties of the bacteria found by searching for "Borrelia burgdorferi" in PubMed, as well as their own research in the field for the past 20 years.

The bacterium Borrelia burgdorferi
B. burgdorferi sensu Lato divided into at least 13 different genospesies. Lyme borreliose typically caused by the four genospesies of B. burgdorferi sensu Lato: B. afzelii, B. garinii, B. burgdorferi sensu stricto and the recently discovered B. spielmanii (3, 4). The bacterium is a gram negative moving spiroket (Fig. 1) which measures 0,18-0,3 x 15-30 microns, are helical and have 7.11 periplasmatiske flag or. Movement related genes occupy more than 6% of the genome of the bacterium. The unique flagellene allows it to move in the viscous fluid and rapidly disseminated (5). The bacterium can be mikroaerofil or anaerobic, depending on genospesies and type. It is also fakultativ intracellular (6-9).

Figure 1 Borrelia burgdorferi grown in BSK-H medium and stained in akridinoransje. UV-microscopy, 2 000 times larger. Photo Øystein Brorson

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One of the most striking features of B. burgdorferi is unusual genome, which consists of a linear chromosome of 910 kilobasepar (KBP) and at least 12 linear and nine circular plasmids that vary in length from 5 to 54 KBP KBP. It is not known other bacteria with as many plasmids per cell. Many of the plasmids can be lost in culture, but the remaining are considered very important for the bacteria and are often called "mini-chromosomes". In all DNA ends of chromosomes are the telomeres that are closed at one end - like a hairpin. It is not known from other prokaryotes. Linear genome is also very unusual among microorganisms. Bacterial genome contains genes for hemolytic and DNA repair and antibiotikaeffluksproteiner. The bacterium contains no genes for cellular biosyntesereaksjon, and it must therefore have a very complex medium for growth. Some plasmids code for proteins that are important virulensfaktorer, including the linear plasmids lp-28, which codes for antigen variation.

Many bacterial genes are encoded to produce more than 100 lipoproteins. This is more than in other known bacteria. These genes are mostly located on plasmids. The proteins are located on the bacterial surface, where they can come in contact with the host. Some of these outer membrane antigens are important for the bacteria - they are called aspen-F protein and 100 (10).

Epidemiology
Lyme borreliose is a vector-transmitted disease. Generally, infected people by infected ticks. In Europe, the Ixodes ricinus is the source of Borrelia infection. In Norway, ticks (Fig. 2) particularly widespread in the coastal areas from Whales to Helgeland, but in recent years of mild winters has now led to a permanent population in some places inland. Lund Lusen Ixodes Uriah can also be carriers of B. garinii. It is therefore possible that infected birds can spread the infection in the Arctic via the grove lice (11). Tick saliva contains proteins that are stupefying, vasodilaterende, immunomodulatory and prevent coagulation (12). This increases infeksiøsiteten. Other insects horsefly and mosquito stick can also be carriers of Spirochaete (13).

Figure 2 Full sucked female that spring has added eggs. The size of the tick is about. 1 cm. Photo Øystein Brorson

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Particularly virulent strains seem constantly increasing in prevalence in both Europe and the USA (14).

Clinical findings
The surest evidence of a Borrelia infection is the expanding red circular rash called erythema migrans, but the characteristic rash may occur and cause problems with the diagnosis of the disease. It may also be delayed development of the rash from the normal (2-30 days) to 100 days (15), which can result in a late treatment. Most often it is skin, muscle, central and peripheral nerves, brain, heart and joints that affect, but the bacteria can be disseminated to all tissues and organs (5, 16).

B. afzelii and B. spelmanii leads often to different hudmanifestasjoner, B. garinii to neurological symptoms and B. burgdorferi sensu stricto to joint problems, but the three genospesies B. afzelii, B. garinii and B. sensu stricto can give all the symptoms (3 , 4). The bacterium is now often called the "the new big sykdomsimitatoren".

Establishment of infection
Two of bacterial lipoproteins (decorinbindende protein A and B) binds to decorin, a proteoglycans that "decorates" collagen fibers (17). The bacterium also has the ability to bind to dermatansulfat, heparin, inte grin and fibronectin. B. burgdorferi increases their ability to invasivitet by degrade soluble and insoluble components of the host's extracellular matrix (18). It is also shown that Lyme Spirochaete use pheromones as an important mechanism for communication, to control the protein production and to coordinate different functions (19).

Special features
B. burgdorferi produces a variety of so-called Erp proteins on its outer membrane that can bind factor H and factor H-like protein (complement inhibitory molecule) and thus circumvent the alternative komplementvei (20). It applies to B. afzelii and B. spielmanii and all or part B. burgdorferi sensu stricto, whereas B. garinii is predominantly sensitive (3, 4). The different Erp proteins have affinity for complement inhibitors in various animal species, and bacteria can therefore withstand komplementmediert murder and fagocytose at any of the potential hosts it infects.

During the antibody can attack B. burgdorferi mutate and make rearrangement of DNA, which can lead to antigenvariasjon. It is particularly OspE undergoing major antigenic variations (21). Modification and lower regulation of other outer surface proteins (aspen, C), so they do not bind to protective antibodies, is also a feature that the bacterium can use to circumvent the host's defense. This is especially important for the bacteria in early infection phase.

Virulensegenskapene leading to infection is considered to be strongly linked to one of the outer surface protein (OspC) (22).

One of the many challenges that the bacterium is exposed to the highly toxic oxygen and nitrogen compounds that are formed in the infected organism in response to bacterial invasion. The bacteria can respond to oxidative stress by activating stress-related genes for the production of enzymes that protect against oxidation (23).

Circulating immune complexes was one of the earliest immunological phenomena that were described by Lyme disease (24). Immune complexes can be found both in serum, cerebrospinal fluid and synovialvæske. When circulating immune complexes are not well-NOK removed by the retikuloendoteliale system, deposited in the tissues and organs and enable komplementer, and this may lead to local inflammatory vevsdestruksjon (25). Immune complexes may also contribute to alter the host's defense mechanisms by defective Fc-receptor, so that opsoniserte B. burgdorferi can not be eliminated by monocytes.

B. burgdorferi is known to produce liposomliknende vesicles (blebs) which repels from the outer membrane. Anti genes aspen, B and D and protein-100 is incorporated into these "blebsene" and its affinity for endothelial cells. In order for bacteria to survive in the circulatory system is probably the removal of surface antigens beneficial. Bacteria "blebser" will be incorporated into the Cytosol and in the nucleus to dendritic cells, lymphocytes and fibroblasts. This leads to the generation of CD8-positive T-cells, which will be able to kill certain cells, and thus stand behind an autoimmune-like state (26). "Blebsene" also contains a mitogen factor for B lymphocytes, which stimulates IgM production. They are also essential penicillin binding proteins.

Much attention has been focused on aspen. This is a special protein that is not found elsewhere in nature. It can, among other things activate nukleærfaktor-kB and induce many cytokines, adhesjonsmolekyler and nitric oxide. Aspen is also a plasminreseptor, and the proteolytic activity on the cell surface can protect against both komplementer and specific antibodies. A marked increase in aspen-reactive CD-positive T-cells are also identified in inflammatory joint with antibiotic resistant patients with Lyme arthritis and in the cerebrospinal fluid in patients with neuroborreliosis.

It is shown that B. burgdorferi isolates from patients can be converted to cyst forms in vivo under the influence of penicillin (27). It has also succeeded in converting cyst forms (Fig. 3) back to moving Spirochaete, both in vitro and in vivo, and cysts have been shown to be infectious for mice (28-30). Cysts have upgraded VlsE (VMP-like sequence, expressed) and aspen-proteins, and they have at least 20 new antigens (31). It is shown that Borrelia can form cysts when exposed to pencillin or doksysyklin in concentrations corresponding to the MIC (minimal inhibitory concentration). It nedreguleres many proteins, including p-66 (an important Porin), and it is expressed more until recently unknown proteins that are important for energy, aminosyresyntese, enzymatic activity and cell division (32). Recently it has been shown by studies in cell culture and in biopsies from the brain tissue of neuroborreliosis patients that Borrelia cysts can be found both extra-and intracellularly and cause apoptosis (33).

Figure 3 Borrelia Burgdorf-cysts from distilled water that is transferred to BSK-H medium and cultivated two weeks at 33 ° C. Cyst forms in the sharing phase (large arrow). It is also seen many normal regular Spirochaete (thin, long arrow) and "blebser" (small, thin arrow). 15 000 times larger. Photo Sverre-Henning Brorson

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Host response to infection
Lipoproteins, Peptidoglycan and circulating immune complexes contribute in large part to the pathogenesis of Lyme borreliose. The bacteria activate different cells to produce betainterleukin-1-beta (IL-1-β), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6) and interleukin-8 (IL-8). When neuroborreliosis is in the spinal fluid demonstrated increased secretion of the Borrelia-specific gamma interferon (INF-γ) and extremely reduced secretion of interleukin-4 (IL-4) (34). This can lead to vevsdestruksjon secondary to the immune response.

B. burgdorferi can induce a four times increase in the number of CD 16-NK-cells (natural kill cells), but also a serious inhibition of NK-cell cytotoxic capacity (35). This is in contrast to other bacteria, which are known to activate NK cells.

Neutrophil granulocytes are important for fagocyttering of promotional organisms, but OspB-production with B. burgdorferi can inhibit the fagocytterende ability of the neutrophil granulocytes and the ability to oxidative killing. Neutrophil granulocytes are the fastest moving fagocytterende cells in the body, but recently it has been shown that B. burgdorferi can move several times faster than them and thus avoid fagocytose (36).

Diagnostics
Serological analysis are important tools to make a clear diagnosis of Lyme borreliose, but sensitivity is low in the early stage of the disease. Medical history and clinical examination is therefore important to be able to make a clear diagnosis.

However, it appears increasingly new and improved methods - eg. "Focus floating microscopy (both horizontal and vertical microscopy) of biopsy material, as the erythema migrans has a sensitivity of 98% and as high specificity of polymerase (PCR). There are also recently shown that by detecting 16S rRNA gene from the serum polymerase will be increased sensitivity. Borrelia antibody specifically bound in circulating immune complexes may contribute to the low diagnostic sensitivity in early course of the disease. Detection of specific immune complexes may therefore be useful where there is clinical suspicion and negative serological test and can possibly say anything about whether there is active infection (37). Validated surveys for the detection of specific immune complexes is not yet available.

The antigenic heterogeneity of the different tribes are great. This can give rise to the low diagnostic sensitivity, since often only one strain of B. burgdorferi sensu Lato is used in ELISA and Western blot tests. It was recently developed an ELISA test in which one uses a synthetic peptide from the conserved part of the OspE (IR6) at Spirochaete. This test has high sensitivity and specificity, but the analysis results are also here depending on the strain causing the infection.

Causes of low antibody production may be that the bacterium actively adheres to, invades and kills the human T-and B-lymphocytes (38), is fakultativ intracellular (6-9, 33) and has the ability to cover himself with the host material (19) .

A study of culture positive spinal fluids showed that there was a large difference in serological and other laboratory markers if the infectious strain was B. garinii or B. afzelii (39). New tests can be useful for spinal fluid is the detection of cytokines CXCL13, which has been shown to be elevated early in the course of neuroborreliosis (40). A new lymfocyttransformasjonstest (LTT-Melis) seems to correlate with Borrelia infection and could possibly say anything about clinical improvement.

Antibiotic resistance mechanisms
Treatment of Lyme borreliose early sykdomsforløper is usually successful if you follow the recommended guidelines, but chronic infection may be difficult to treat.

Mechanisms of bacterial survival is insufficiently understood, but that the bacterium covers himself with the host material, the intracellular localization and lavbiologiske bacteria and cyst forms may be of importance (6-9, 33). Polymorfnukleære leukocyte production of calprotectin, which removes the accessible sink and thereby inhibit cell division, can make bacteria resistant to b-laktamantibiotika (41).

Bacterial antibiotic sensitivity differs from both gram positive and gram negative bacteria. It has natural resistance above aztreonam, teikoplanin, fucidinsyre, fluorokinoloner, aminoglukosider, cefaclor, loracarbef, nalidiksinsyre, trimethoprim-sulfamethoxazole, fosfomycin and rifampicin (42). The strains investigated so far, shows very variable sensitivity to different antibiotics. The minimum concentration of penicillin G to inhibit growth of B. afzelii (MIC) is 100 times higher than that of B. garinii (42).

Efflukssystem bacteria can evolve to include utpumping from the bacterial cell by many different antibiotics, and can thereby contribute to the lack of efficacy and persistent infection (43). New antibiotics that are resistant to bacterial efflukssystem can perhaps be a solution.

It is a controversial question about cysts may be the cause of persistent infection and reactivation of the disease. Hydroxychloroquine and metronidazole, however, has proven to be cyst active in vitro (44, 45). It is also controversial whether persistent symptoms after undergone Lyme borreliose originate from persistent infection or are immunologically related (46), but few studies show that there are effects of repeated and prolonged treatment (47-49).

Vaccination
It developed an aspen-vaccine for B. sensu stricto, but due. bacterial aspen-heterogeneity was not the vaccine is effective against B. afzelii and B. garinii. It also gave more side effects and were withdrawn from the market. Working, however, continued to develop an effective vaccine that can cover the usual genospesies. A new recombinant tetravalent vaccine based on multiple OspC types, which are under development, will cover the sydomsfremkallende genospesies.

Declared conflicts of interest: None
Main message

Borrelia burgdorferi is a unique bacterium that has developed many defense mechanisms
It has the ability to survive all types of antibiotics
The current diagnostic tests are inadequate and are only a supplement in the diagnosis
See also Laboratory Diagnosis of Lyme borreliose See also Borrelia - serological studies to use and trouble
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The manuscript was received 2.7. 2008 and approved 20.8. 2009. Medical Editor Erlend Hem.


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