RESEARCH -- the COMPLEXITY of LYME - why it's hard to dx

Discussion in 'Fibromyalgia Main Forum' started by victoria, Nov 21, 2005.

  1. victoria

    victoria New Member

    It's no wonder there's so much controversy! Here's 2 recent studies:


    The Lancet 2005; 366:1771

    DOI:10.1016/S0140-6736(05)67721-5 Lyme disease: scratching the surface

    Steven E Phillips a, Nick S Harris a, Richard Horowitz a, Lorraine Johnson a and Raphael B Stricker email address a


    The excellent Comment by Ulrike Munderloh and Timothy Kurtti (Sept 17, p 962)1 describes the complex life cycle of Borrelia burgdorferi, the spirochaetal agent of Lyme disease, as it traffics between tick and mammalian hosts.

    The Comment highlights a growing problem with Lyme disease: while what is known about the basic science of this tick-borne illness becomes more complex, the clinical science remains relatively simplistic and uninformed.2

    This divergence has produced a disconnection between the recognition of B burgdorferi as one of the most invasive and elusive bacteria known to man, and the clinical perception that Lyme disease is "hard to catch and easy to cure".

    The complexity of the Lyme disease spirochaete goes beyond the features described by Munderloh and Kurtti. With more than 1500 gene sequences, B burgdorferi contains at least 132 functioning genes; by comparison, the spirochaetal agent of syphilis, Treponema pallidum, contains only 22 such genes.2

    Furthermore, the Lyme disease spirochaete contains 21 plasmids (nine circular and 12 linear).2 This is by far the largest number of plasmids found in any known bacterium, and the large number of plasmid genes is thought to provide a rapid response system that allows the spirochaete to cycle efficiently between ticks and mammals.3 Gene exchange and plasmid transfers among Borrelia strains can also increase the pathogenicity of the organism.3

    In the mammalian milieu, B burgdorferi uses the host fibrinolytic system to penetrate the blood-brain barrier and gain access to the central nervous system. The Lyme disease spirochaete contains a secretory mechanism for porin, adhesin, and haemolysin proteins, and these secreted products can contribute to the invasive properties of the organism.4 The spirochaete can enter cells such as fibroblasts, synovial cells, endothelial cells, and macrophages. In these cells, it becomes functionally resistant to treatment, partly due to "camouflage" proteins produced by itself or adsorbed from the cell, and partly due to altered morphology as the spirochaete assumes a non-replicating cyst form.2

    The immune evasion strategy used by B burgdorferi is similar to strategies used by the mycobacterial agents that cause chronic infections such as tuberculosis or leprosy.2 These organisms also exist as non-replicating cyst forms that can be "resuscitated" by autocrine cytokine-like factors after lying dormant for months. B burgdorferi has been shown to use luxS, an autoinducer gene used by other bacteria, to regulate replication.5 It is the first time that this autoinducer gene has been identified in a spirochaete. Thus the combination of genetic complexity, intracellular localisation, immune evasion, and autoregulation makes the Lyme disease spirochaete a formidable infectious agent.2

    By contrast with the complex basic science of B burgdorferi outlined above, a popular clinical notion is that Lyme disease can be cured with 2-4 weeks of antibiotics. Although this might be true of promptly treated acute B burgdorferi infection, chronic infection that allows the spirochaete's complex pathophysiological mechanisms to unfold can result in tenacious tissue invasion that is extremely difficult to eradicate. Understanding the pathophysiological complexity of this organism should help to improve our clinical approach to Lyme disease.2

    We declare that we have no conflict of interest.

    References
    1. Munderloh UG, Kurtti TJ. The ABCs of Lyme disease spirochaetes in ticks. Lancet 2005; 366: 962-964.

    2. Stricker RB, Lautin A, Burrascano JJ. Lyme disease: point/counterpoint. Expert Rev Anti Infect Ther 2005; 3: 155-165.

    3. Qiu WG, Schutzer SE, Bruno JF, et al. Genetic exchange and plasmid transfers in Borrelia burgdorferi sensu stricto revealed by three-way genome comparisons and multilocus sequence typing. Proc Natl Acad Sci USA 2004; 101: 14150-14155.

    4. Cluss RG, Silverman DA, Stafford TR. Extracellular secretion of the Borrelia burgdorferi Oms28 porin and Bgp, a glycosaminoglycan binding protein. Infect Immun 2004; 72: 6279-6286.

    5. Stevenson B, von Lackum K, Wattier RL, McAlister JD, Miller JC, Babb K. Quorum sensing by the Lyme disease spirochete. Microbes Infect
    2003; 5: 991-997.


    Affiliations a International Lyme and Associated Diseases Society, PO Box 341461, Bethesda, MD 20827, USA
    *****

    ---
    In lymeinfo@yahoo
    InfoTrac Web: Health Reference Center-Academic

    Source: The Lancet, Sept 17, 2005 v366 i9490 p962(3). Title: The ABCs of Lyme disease spirochaetes in ticks.(Comment) Author: Ulrike G. Munderloh and Timothy J. Kurtti Subjects: Spirochetes - Research Ticks - Physiological aspects Ticks - Research Lyme disease - Research

    Locations: Minnesota Electronic Collection: A136563058 RN: A136563058

    Full Text COPYRIGHT 2005 The Lancet Publishing Group, a division of Elsevier Science Ltd.

    Late last year, Utpal Pal and colleagues (1) described a receptor displayed on the lumenal side of the gut of black-legged ticks, Ixodes scapularis. Borrelia burgdorferi, the causative agent of Lyme disease, grabs this molecule like bus riders holding onto hand straps. Lyme spirochaetes grip the receptor with an outer-coat protein called OspA, hence the name that has been coined for the receptor--TROSPA, tick receptor for OspA.

    Attachment to TROSPA allows B burgdorferi to persist in the gut and avoid elimination from the time they were ingested by the tick through the subsequent molt, so that they can be injected into a new host at the next blood meal. Pal and others (2) have started to unravel the complex molecular requirements for spirochaetal infection, and colonisation of 13 burgdorferi with its environment is mediated by the bacterial cell wall which incorporates several lipoproteins.

    Three of these outer surface proteins (Osp: OspA, OspB, and OspC) are differentially expressed during the bacterial life-cycle. (3,4) The ospA and ospB genes are arranged in tandem on a large linear plasmid, Ip54, whereas ospC is situated on a circular (supercoiled) plasmid, cp26.

    Why is what happens in a tick relevant to human disease? We think the answer lies in the complexity of the life-cycle of a tick-borne pathogen. Disease agents that infect only mammals are highly specialised to live in just those hosts, which requires little if any changes in their life-style.

    By contrast, hopping from ticks to vertebrates and back on a routine basis requires adaptive mechanisms that allow the pathogens to survive and multiply in the different animals.
    (5) With the drastic biological differences between a warm-blooded mammal and a tick as hosts for bacteria, the required changes are dramatic and significant.

    Temperature, tick factors, and blood induce several changes in spirochaetes that facilitate their transmission while the tick feeds. (6,7) In-vivo and in-vitro studies reveal a negative correlation between production of OspA and OspC in B burgdorferi as long as the tick is inactive and has not yet found a warm-blooded host.

    OspA production dominates and the spirochaetes remain adherent to the gut wall, presumably binding to TROSPA. Once the tick starts to suck blood, the spirochaetes downregulate OspA production within 2-3 days, and upregulate OspC, causing them to detach from TROSPA, penetrate the gut, and invade the salivary glands, from where they are delivered with saliva into the host's skin. OspC is necessary for tick salivary-gland invasion and infection of the vertebrate.

    This scenario teaches us that disruption of the tick phase of the spirochaetes' life by preventing the microbes from attaching to the inner gut lining could potentially derail the entire transmission cycle.

    Previous efforts towards an immunological solution have focused on the spirochaetes' coat protein, OspA, (8) which is thought to engage TROSPA. The resulting vaccine was controversial, because of concerns that it could trigger arthritis in susceptible individuals, (9) and did not remain on the market long.

    It seems reasonable to approach the problem from the other side and modify the inner lining of the gut lumen in such a way that TROSPA is not expressed. Presumably, if the borrelial surface coat does not find a receptor to latch onto, B burgdorferi will not find safe footing in the tick midgut, and not be able to persist through the molt either, resulting in the cancellation of its ticket for transfer back to the vertebrate host.

    Pal and colleagues show that this is indeed the case, and is probably a worthy project to pursue. However, experience with the OspA vaccine has taught us to assume nothing and to proceed with extreme caution when it comes to ticks and tick-borne pathogens. Pal's data indicate that blockage or downregulation of TROSPA expression is not 100% effective in preventing colonisation of ticks by B burgdorferi and subsequent transmission and infection of the mammalian host.

    Apparently, B burgdorferi can use alternative pathways to persist in ticks (10) and is probably able to engage receptors other than TROSPA, possibly via OspB. Together, these facts support the notion that Lyme disease spirochaetes are able to rapidly adapt to changes in their environment, and come out ahead.

    We expect nothing less from a tick-borne pathogen that has evolved to make the best of the roller-coaster life that constitutes the tick-mammal transmission cycle.

    A separate issue is what kind of response repeated exposure to a tick antigen might evoke in vaccinees. Whilst it is assumed that salivary-gland components induce the hypersensitivity reaction which causes the itching at the tick-bite site, we cannot rule out that tick-gut antigens do not have the capacity to induce allergic reactions, or worse, shock. (11) Serological reactivity to glycosylated salivary-gland antigens is not species-specific, and may also not be organ-specific.

    The potentially heavily O-glycosylated TROSPA molecule might not be expected to be a potent antigen, but the mammalian immune reaction to tick glycosylation patterns could be difficult to predict, and be more prone to induce hypersensitivity, as salivary-gland antigens do. The function of TROSPA in the tick is unknown and needs to be determined before selection as a target for vaccine strategies for Lyme disease control.

    We declare we have no conflict of interest.

    (1) Pal U, Li X, Wang T, et al. TROSPA, an Ixodes scapularis receptor for Barrelia burgdorferi. Cell 2004; 119:457-68.

    (2) Singh SK, Girschick HJ. Molecular survival strategies of the Lyme disease spirochaete Borrelia burgdorferi. Lancet Infect Dis 2004; 4: 575-83.

    (3) Yang XF, Pal U, Alani SM, et al. Essential role for OspA/B in the life cycle of the Lyme disease spirochete. J Exp Med 2004; 199:641-48.

    (4) Pal U, Yang X, Chen M, et al. OspC facilitates Borrelia burgdorferi invasion of Ixodes scapularis salivary glands. J Clin Invest 2004; 113:220-30.

    (5) Munderloh, UG, Jauron, S, Kurtti TJ. The tick: a different kind of host for human pathogens. In: Goodman J, Dennis D, Sonenshine D, eds. Tick-borne diseases of humans. Washington DC: ASM Press, 2005: 37-64.

    (6) Tokarz R, Anderton JM, Katona LI, Benach J. Combined effects of blood and temperature shift on Barrelia burgdorferi gene expression as determined by whole genome DNA array. Infect Immun 2004; 72: 5419-32.

    (7) Obonyo M, Munderloh UG, Fingerle V, Wilske B, Kurtti TJ. Borrelia burgdorferi in tick cell culture modulates expression of outer surface proteins A and C in response to temperature. J Clin Microbial 1999; 37: 2137-41.

    (8) de Silva AM, Telford SR 3rd, Brunet LR, et al. Borrelia burgdorferi OspA is an arthropod-specific transmission-blocking Lyme disease vaccine. J Exp Med 1996;183: 271-75.

    (9) Willett TA, Meyer AL, Brown EL, Huber BT. An effective second-generation outer surface protein A-derived Lyme vaccine that eliminates a potentially autoreactive T cell epitope. Proc Natl Acad Sci USA 2004; 101:1303-08.

    (10) Fikrig E, Pal U, Chen M, et al. OspB antibody prevents Borrelia burgdorferi colonization of Ixodes scapularis. Infect Immun 2004; 72:1755-59.

    (11) Fernandez-Soto P, Davila I, Laffond E, Lorente F, Encinas-Grandes A, Perez-Sanchez R. Tick-bite-induced anaphylaxis in Spain. Ann Trop Med Parasitol 2001; 95: 97-103.

    * Ulrike G Munderloh, Timothy J Kurtti Department of Entomology, University of Minnesota, St Paul, MN 55108, USA


    [This Message was Edited on 11/21/2005]
  2. pepper

    pepper New Member

    This is interesting info. Thanks.

    Pepper
  3. victoria

    victoria New Member