Mis diagnosed as Fibromyalgia, ME/CFS, Musculoskeletal Disease,Poly Myalgia Rheumatica - significantly improved when treated for Lyme Disease.
Perhaps more aptly described as Multi-Systemic Infectious Disease Syndrome - MSIDS.
Lyme Disease and Dementia, Alzheimer, Parkinson, Autism, an Easy Way to Destroy your Brain
DR. JOSE LAPENTA Lapenta JM
Lyme disease or Chronic Erythema Migrans whose first clinical description was made by Afzelius in 1908, and its causative agent the spirochete Borrelia Burgdorferi was discovered 73 years later by Willy Burgorfer in 1981. Lyme disease is spread by a tick bite of the family Ixodidae, Ixodes scapularis and many others. Among the numerous species described, Borrelia Burgdorferi is disseminated mainly in the United States, Borrelia garinii and Borrelia Afzelii in Europe and Asia. In addition to producing skin lesions in infected people, and multi-organ side effects, the spirochete is able to reach the human brain and could produce dementia, Alzheimer, Parkinson and Autism. In this investigation we will make a chronological description of the events that lead to neuronal involvement. Just as the spirochete of syphilis, Treponema pallidum, produces neurosyphilis in its tertiary stage, also the Borrelia is able to reach the brain, and produce collateral damage, a term called neuroborreliosis, and among its most lethal effects may cause dementia, Alzheimer, Parkinson and Autism and hence the so-called post-treatment syndrome of Lyme disease.
This is an excellent article worth reading in full. It documents the history of Lyme discovery and research with very useful links to published papers.
• Lyme “neuroborreliosis” was not born in the 80s when it began to be mentioned in scientific studies after its causative agent, the Borrelia Burgdorferi was discovered by Willy Burgoderfer in 1981 and its presence in the human brain was later confirmed. He was born in 1922 when the French Garin and Bujadoux described for the first time the meningoradiculitis lymphocytic with its neurological manifestations.
• We demonstrate chronologically and scientifically that Borrelia Burgdorferi and its species can conquer the human brain and produce dementia, Parkinson’s, Alzheimer’s and Autism.
• Unlike Treponema pallidum, which only in the tertiary stage of syphilis is when it produces dementia (neurosyphilis); Borrelia Burgdorferi (Lyme) in its secondary and tertiary stage produces neuropsychiatric manifestations (neuroborreliosis).
• Lyme disease can present as pure neurological forms, without the presence of Erythema Chronicum Migrans (ECM); this fact is what in many cases makes the diagnosis difficult.
• Several highly specific diagnostic tests appeared to detect Borrelia Burgdorferi, even surpassing those proposed by the CDC.
• The World Health Organization(WHO) recognized the code “Lyme Neuroborreliosis”, “Dementia due to Lyme” this year of 2018 in the ICD-11 and the “demyelination of the central nervous system due to Lyme borreliosis”
• Clinical diseases not recognized: “Alzheimer due to Lyme”, “Parkinson due to Lyme”, but assuming that “dementia” is a common symptom of Alzheimer’s, its tacit recognition is understood; like the case of Parkinson’s, because the demyelination of the central nervous system and the chronic infection of the brain by Borrelia species can cause symptoms of Parkinsonism. Also the “Autism due to Lyme” was not recognized but like the previously described, it is supposed to be included in the term “neuroborreliosis due to Lyme”
• The Post-Treatment Lyme Disease Syndrome (PTLDS), was not recognized by the WHO; it was extensively reviewed in this research and which was described more than 20 years ago, will be the subject of a forthcoming investigation.
• Finally, the Lyme disease, now it is not only a dermatological disease, is a neuropsychiatric illness that can easy destroy your brain, if it is not detected and treated at time.
If we include Alzheimer’s disease, Parkinson’s disease and Autism within the spectrum “Lyme neuroborreliosis” code, only Post-Treatment Lyme Disease Syndrome (PTLDS) will be left out in this investigation.
From Kris Newby Senior Producer of Under our Skin. 'I’m happy to announce that my narrative nonfiction book, “BITTEN: The Secret History of Lyme Disease and Biological Weapons,” can now be pre-ordered from your favorite book retailer:https://www.harpercollins.com/9780062896278/bitten/
About 5 years ago, I received a videotaped interview of Lyme discoverer Willy Burgdorfer saying that the Lyme disease outbreak was caused by a bioweapons experiment gone wrong. It was a stunning confession given his reputation, and I knew I couldn’t walk away from it.
BITTEN takes readers on my investigation of this claim, starting with Willy’s role in weaponizing ticks, fleas, and mosquitoes for the U.S. military’s bioweapons program, and ending with evidence supporting the theory that this epidemic began around Long Island Sound in 1968 as fallout from a secret bioweapons release.'
The epilogue of BITTEN:
“I believe that history will judge the tick-borne disease outbreak that began in 1968 to be one of the worst public health failures of the last century … The myopic focus on only one of the tick diseases, Lyme disease, has led to treatment delays and fatalities in patients who have serious mixed infections. Physicians urgently need rapid screening tests and the freedom to use clinical judgement in treating these complex patient cases — without the real and present danger of losing their medical licenses.”
If you want to join Kris in this campaign to educate a worldwide audience on the importance of increasing funding and treatment options for tick-borne diseases, here’s how you can help:
Preorder the book *now* if you think you’ll eventually want to read it: TV, radio and podcasters are currently using these tallies to prioritize and schedule author interviews for May, Lyme awareness month.
Word-of-mouth makes a difference: Forward this email to your Lyme-community lists.
Please send Kris any media or celebrity connections that might be helpful in this campaign.
Do you have conferences, Lyme groups, or indie bookstores where you’d like Kris to give a talk? HarperCollins will be sending me on a book tour May through the summer and I’ll add these to my list.
The chronicity of some of the manifestations of Lyme disease, such as the oligoarticular arthritis and meningoradiculitis, suggests that the host cannot effectively rid itself of the infecting agent. Alternatively, the host’s immune response to the spirochete may actually induce or accentuate the pathological lesions associated with this disorder. Thus, knowledge of the balance struck between the host’s immune system and the spirochete during chronic infection may be a key to understanding the pathogenesis of Lyme disease. Johnson, Kodner, Russell In vitro and in vivo susceptibility of Lyme disease spirochete, B burgdorferi, to four antimicrobial agents Antimicrob Agents Chemother 1987: https://www.ncbi.nlm.nih.gov/pubmed/3566246
These observations are particularly important, since the chronic forms of Lyme disease and related disorders appear to be due to the persistence of B. burgdorferi in the affected sites (4,17,19,26,27). Johnson, Russell - US Patent 4,721,617 - Vaccine against Lyme disease January 26, 1998:
...The chronic forms of the disease such as arthritis (joint involvement), acrodermatitis chronica atrophicans (skin involvement), and Bannwart’s [sic] syndrome (neurological involvement) may last for months to years are are associated with the persistence of the spirochete...
The infection may be treated at any time with antibiotics such as penicillin, erythromycin, tetracycline, and ceftriaxone. Once infection has occurred, however. the drugs may not purge the host of the spirochete but may only act to control the chronic forms of the disease. Complications such as arthritis and fatigue may continue for several years after diagnosis and treatment.
Dattwyler, Volkman, Halperin, Luft, Thomas, Golightly. Specific immune responses in Lyme borreliosis: Characterization of T and B cell responses to Borrelia burgdorferi Ann NY Acad Sci 1988: https://www.ncbi.nlm.nih.gov/pubmed/3263829
Lyme borreliosis, B burgdorferi infection, is a chronic progressive infection involving multiple organ systems including the skin, the central and peripheral nervous systems, the heart, liver, and kidney, and the musculoskeletal system (1-3). As in other chronic infectious diseases, host responses to this infecting microorganism play a major role in shaping the clinical expression of this persistent spirochetosis.
As with any infection, the immune response plays a pivotal role in the containment of the invading microorganism. In any chronic infection, the microbe must evolve strategies to avoid eradication by the host. Such strategies include suppression of the host’s defenses; evasion of host defenses through antigenic mimicry or antigenic variation; or invasion of immunologically privileged sites...
Erythema chronicum migrans (ECM) has classically been the best marker of Lyme borreliosis.
Bergstrom (Sweden) Bundoc Barbour (U TX San Antonio), Molecular analysis of linear plasmid-encoded major surface proteins, OspA and OspB, of the Lyme disease spirochaete Borrelia burgdorferi Molecular Microbiology 1989: https://www.ncbi.nlm.nih.gov/pubmed/2761388
“In many patients the infection of some tissues, particularly the brain and joints, persists for years and can be severely disabling. These forms of chronic Lyme borreliosis are a consequence of the host’s inability to rid itself of the infecting agent and are perhaps also caused by the development of an autoimmune immunological reaction (Steere et al, 1979).” Aberer, Brunner, Suchanek, Klade, Barbour (UT San Antonio), Stanek, Lassmann (Univ Vienna) Molecular mimicry and Lyme borreliosis: A shared antigenic determinant between Borrelia burgdorferi and human tissue Ann Neuro 1989: https://www.ncbi.nlm.nih.gov/pubmed/2481425
By testing monoclonal antibodies directed against various borrelia antigens, we found an antigenic determinant shared by the 41 kDa flagella protein and human tissue, especially prominent on myelinated fibers of human peripheral nerve, on nerve cells and axons of the central nervous system, as well as on certain epithelial cells (including joint synovia) and on heart muscle cells. Immune reactions against such a shared antigen could play a pathogenic role in chronic organ manifestations of Lyme borreliosis.
... Besides the various neurological diseases and Lyme arthritis, fatal respiratory distress syndrome (6), hepatitis (5), endomyopericarditis (7) and interstitial nephritis (4) have been described. However, if autoimmune reactions are important for these alterations, additional factors, such as local antigen presentation and histocompatibility antigen expression, must also be involved because the chronic manifestations in Lyme borreliosis are so variable.
Abstract ...Clinical studies have documented the efficacy of antibiotics, but therapy has failed in as many as 50% of cases of chronic infection..
Persistent B burgdorferi infection can produce various insidious and chronic dermatologic, neurologic, and rheumatologic manifestations [3-15]. The pathophysiologic mechanisms involved in the chronic phase of this illness remain incompletely defined, It has not been determined whether persistent symptoms are secondary to some immunologic process or whether anything short of total eradication of B burgdorferi is sufficient for ultimate cure and resolution of symptoms.
As in any chronic infectious disease, host responses are thought to play a major role in shaping the clinical expression of this illness. These responses include and early and vigorous T cell response to the presence of the Lyme spirochete and a more slowly evolving B cell response (16,17).
The failure of early antimicrobial therapy to completely eradicate the infection and the subsequent development of a chronic illness make this disease especially difficult to diagnose in patients who do not develop a mature antibody response. However, specific T cell and/or local humoral responses may be demonstrable in patients who lack diagnostic levels of circulating antibodies to B burgdorferi (17,24-26).
It is now recognized that only by understanding the different lines of investigation in Europe and the US can we achieve a true appreciation of the multiplicity of acute and chronic disease manifestations due to B burgdorferi infection.
If not effectively treated during the local or the acute disseminated phase of infection, a chronic phase of infection can develop. Clinical manifestations observed during this chronic phase include chronic meningitis, meningoradiculitis, encephalitis, peripheral neuropathy, lymphocytoma, ACA and arthritis
It is now well recognized that late neurological disorders are common in B burgdorferi infection, that CNS infection can be documented by demonstrating intrathecal anti- B burgdorferi antibody production, and that CNS infection is frequently associated with chronic headache and a profound sense of fatigue which may indicate a chronic encephalopathic state. Duray Histopathology of clinical phases of human Lyme disease Rheum Dis Clin North Am 1989: https://www.ncbi.nlm.nih.gov/pubmed/2685926
Lyme borreliosis in humans can be divided into acute, subacute and chronic states of inflammation with variable degrees of dysfunction. (15, 31-34). Multisystem involvement appears to be random and unpredictable, with chronic states of persistence in some cases.
Chronic Lyme borreliosis A subset of patients go on to chronic, persistent disease in the presence of continuing spirochetes in selected sites with continuing inflammation and humoral immunologic reactions. These manifestations are not inevitable because the disease process may be completed at the end of each prior phase of the inflammatory illness, and not progress any further. However, chronic Lyme borrelial disease occurs worldwide predilecting for the skin and central and peripheral nervous systems in Europe, (6,9) and in the muscular skeletal system, particularly the joints and synovium, in North America (29, 53). This target organ selectivity in either hemisphere in chronic disease is a phenomenon not well understood but may relate to minor differences in the North American versus the European strains of B burgdorferi.
Chronic Cutaneous Involvement The skin is involved in chronic disease as a consequence of the continuing presence of the spirochete in deep dermal and subcutaneous tissues. This may take place over a period ranging from many months to several years.
Acrodermatitis Chronica Atrophicans (ACA) ACA is a peculiar, chronic, long-term Lyme dermatosis defined clinically as a purple, red-rubor discoloration of the skin, generally of the acral limbs, hands, wrists, forearms, elbows, or ankles and lower legs...
Speculation of the Histopathogenesis ...With continuing infection, demyelination is thought to occur in some humans. Demyelination may result from immunologic cross reactivity directed against variable major protein in a given infection. Regardless, demyelination does seem to be fundamental to many of the neurologic manifestations in chronic Lyme neural infections.
Lyme disease, a tick-borne infection caused by the spirochete Borrelia burgdorferi, is a chronic disorder characterized by dermatologic, rheumatologic, cardiac, and neurological manifestations.
...While differences between these infections and between their causative organisms undoubtedly exists, it is plausible that B burgdorferi and T pallidum share some parasitic strategies and that common host immune mechanisms are operative in the containment of both chronic diseases.
Wallich Moter Simon Ebnet Heiberger Kramer The Borrelia burgdorferi flagellum- associated 41-kilodalton antigen (flagellin): Molecular cloning, expression and amplification of the gene Infect Immun 1990: https://www.ncbi.nlm.nih.gov/pubmed/2341173
In humans Lyme disease appears as a chronic progressive disease that involves multiple organs, including the heart, the liver, the kidneys, the musculoskeletal system, the skin, and the central and peripheral nervous systems.
The demonstration of Bb within endothelial cells suggests that intracellular localization may be a potential mechanism by which the organism escapes from the immune response of the host and may contribute to persistence of the organism during the later stages of Lyme disease.
...This multisystemic and chronic tick-borne spirochetosis is of world-wide distribution and has been the subject of various mongraphs (18,66,113,121) and recent reviews (5,47,114)... In this article, we will focus on studies investigating interactions between the spirochetes and the host. In so doing, we will attempt to present current hypotheses of how the disease progresses and to indicate the directions for future investigations into the chronic nature of Lyme disease.
...How do spirochetes evade the immune response? Is the chronic condition in Lyme disease the result of antigenic variability such as is seen in the relapsing fever borrelia (8,9), or is the chronic condition associated with persistent antigen perpetuated by a specific immune response to the spirochete? Does an autoreactive condition arise as a result of molecular mimicry between the bacterium and host. leading to a continuous cycle of injury in the patient?
“Lyme disease is a chronic, multisystem disorder involving the skin, nervous system, joints and heart ”
“The B cell response in Lyme disease is characterized by the early recognition of a limited number of antigens. In the chronic phase of the disease, a much larger repertoire of antigens is recognized (5,6)”
...During Lyme borreliosis, caused by B. burgdorferi, chronic infection is often established. In Lyme borreliosis, this is characterized by an inability of the immune system to clear the infection. Perhaps this is a means by which B. burgdorferi increases its probability of transmission to new hosts...
Infection with the spirochete B burgdorferi causes the acute and chronic manifestations of Lyme borreliosis. Despite considerable work on humoral and cell-mediated responses to infection, which has recently been reviewed, the pathogenic mechanisms that contribute to chronic disease induced by this spirochete remain obscure... However, the persistent infections documented in humans and animal models indicate that immune clearance is either rare or nonexistent (24,25)
Luft Mudri Jiang Dattwyler Gorevic Fischer Munoz Dunn Schubach The 93- kilodalton protein of Borrelia burgdorferi An immunodominant protoplasmic cylinder antigen Infect Immun 1992: https://www.ncbi.nlm.nih.gov/pubmed/1398941
In many untreated cases, the acute infection is self limiting and becomes latent only to recrudesce later in life as a chronic infection involving the joints, heart, nervous system, or skin. The symptoms associated with the chronic infection may be vague and not associated with demonstrable clinical signs of disease. It is unclear whether the vague symptoms of late disease can be attributed to an actual ongoing infection or whether they result from some other pathogenic mechanism.
... patients with evidence of chronic infection have been reported to have negative serum antibody titers (23,35,41,72).
Montgomery Nathanson Malawista The fate of Borrelia burgdorferi, the agent for Lyme disease, in mouse macrophages. Destruction, survival, recovery J Immunol 1993: https://www.ncbi.nlm.nih.gov/pubmed/8423346 Abstract ...Persistence of spirochetes within macrophages provides a possible pathogenetic mechanism for chronic or recurrent Lyme disease in man.
... Although most patients are cured by antibiotic therapy, Lyme disease may sometimes progress or recur despite therapy, perhaps because spirochetes survive in privileged sites away from the immune system or antibiotic, such as the central nervous system or inside cells.
Although spirochetes become more difficult to find as Lyme disease progresses in vivo, there is reason to believe that they are driving the illness throughout its course. Evidence in favor of a reservoir of live spirochetes includes the frequent response of late symptoms to antibiotics, the enlarging antigen specificity of immune sera from patients in later stages of disease, suggesting newly exposed spirochetal epitopes (2), and the occasional identification of spirochetes in affected areas (3,4). Inasmuch as the macrophage acts as a reservoir for numerous other infectious agents, we investigated whether it might serve a similar role in Lyme disease.
Discussion ... Our results show that B burgdorferi can survive via a route that is distinct kinetically from its prominent pathway of degradation, and that such organisms retain the ability to multiply...
Late Lyme disease is not likely to show a clear improvement within the time frame of the therapy, at least not for the standardly recommended period. Not surprisingly, there is controversy about whether the appropriate treatment duration for chronic Lyme disease is measured in weeks or months (5, 68, 78).
When clinical findings are consistent with late or chronic disease (e.g. arthritis) a negative result militates against the diagnosis. Chronic Lyme disease samples are generally positive in high titer )13,46). This may be true even in the case of recently treated patients because titers may remain positive for years despite successful treatment. Nevertheless, there are exception, and negative, low, or decreasing titers, although uncommon in untreated chronic Lyme disease, may occur. (46-48).
“These studies show that some humans chronically infected with B. burgdorferi produce protective antibodies. Our data showing that sera from patients with late- but not early-stage Lyme disease can partly protect mice from infection correlates with our clinical observations. In general, patients with chronic Lyme disease do not develop new episodes of erythema migrans (unpublished data). In contrast, patients with erythema migrans that were treated with antibiotics early in the course of infection appear susceptible to reinfection with B burgdorferi since they can develop erythema migrans after new tick bites. This suggests that patients with chronic Lyme disease may be immune to reinfection with borreliae while patients with early Lyme disease are not, The fact that some patients with chronic disease do not develop OspA or OspB antibodies further suggests that other B. burgdorferi antigens may play a role in protective immunity,”
Determining the precise location of spirochetes within tissues chronically infected with B burgdorferi has been difficult. However, when spirochetes are visualized in such tissue specimens, they appear to be extracellular. Dissemination of B burgdorferi in the blood also occurs in chronically infected immunocompetent mice, despite the presence of B burgdorferi-specific antibodies. Such observations provide the rationale for studying the molecular architecture of the Lyme-disease spirochete within the context of immune evasion.
In contrast to T pallidum, which appears to have no surface lipoproteins, there is overwhelming evidence that borrelial lipoproteins are found on the surface of organisms cultivated in vitro. If these molecules are such accessible immune targets, why are spirochetes not cleared rapidly during natural or experimental infection? This question is even more paradoxical in that sera from chronically infected individuals may be borreliacidal in vitro (49). The answer appears to involve both genetic mechanisms for downregulating the expression of surface lipoproteins at various times during infection and also the slective repression of antibody responses against specific proteins, particularly OspA and OspB (Refs 14,40,50). The ultimate effects of these poorly understood dynamic processes are dramatic reductions in both the immunogenicity of the spirochetal surface and the absolute number of targets for potentially borreliacidal antibodies.
...Late or persistent infection (stage 3) usually begins months to years later and typically consists of intermittent or chronic arthritis (19), chronic neurologic involvement (48-51), or acrodermatitis chronica atrophicans (52).
Bergstrom Barbour Magnarelli, “Background of the invention” section in U.S. patent description for “DNA encoding Borrelia burgdorferi OspA and a method for diagnosing Borrelia burgdorferi infection” 12.10.96 (filed 10.3.94):
“In many patients the infection of some tissues, particularly the brain and joints, persists for years and can be severely disabling. These forms of chronic Lyme disease are a consequence of the host’s inability to rid itself of the infectious agent and perhaps the development of an autoimmune reactiom (7)
7 = Steere et al, Early clinical manifestations of Lyme disease Ann Intern Med 1983, 99:76-72
Humoral immune response against OM proteins during chronic Lyme disease. A poorly understood aspect of Lyme disease concerns the inability of host immune responses to eradicate persistent
spirochetal infection. Although rising antibody titers to Bb and expanding reactivity to spirochetal antigens have been well documented during persistent infection in a variety of mammalian hosts (39), it is not known how much of this antibody response is directed against surface-exposed borrelial proteins (and, therefore, is capable of contributing to bacterial clearance).
...Our finding that these highly abundant immunogens have only limited surface exposure prompts a major revision of current concepts of B burgdorferi ultrastructure and its relationship to immune evasion during chronic Lyme disease.
Norgard Arndt Akins Curetty Harrich Radolf Activation of human monocytic cells by Treponema pallidum and Borrelia burgdorferi and synthetic lipopeptides proceeds via pathway distinct from that of lipopolysaccharide but involves transcriptional activator NF-kB Infect Immun 1996: https://www.ncbi.nlm.nih.gov/pubmed/8751937
Syphillis and Lyme disease are chronic infections caused by the pathogenic spirochetes Treponema pallidum and Borrelia burgdorferi, respectively.
The observation that proinflammatory activity is a “generic” property of spirochetal lipoproteins raises the intriguing possibility that lipoproteins unrelated to OspA or OspB which are expressed exclusively during the course of infection can promote the inflammatory processes that engender clinical manifestations in chronic Lyme disease. This contention can be evaluated by examining the proinflammatory properties of borrelial lipoproteins expressed exclusively during the mammalian phase of the spirochete life cycle.
Wooten Modur McIntyre Weis Borrelia burgdorferi outer membrane protein A induces nuclear translocation of nuclear factor-kappa B and inflammatory activation in human endothelial cells J Immunol 1996: https://www.ncbi.nlm.nih.gov/pubmed/8906837
...OspA expression can reappear late in disease, and this re-expression may contribute to the inflammation associated with chronic Lyme disease (58).
Nanagara, Duray Schumacher Ultrastructural demonstration of spirochetal antigens in synovial fluid and synovial membrane in chronic Lyme disease: Possible factors contributing to persistence of organisms Human Pathology 1996: https://www.ncbi.nlm.nih.gov/pubmed/8892586
Electron microscopy adds further evidence for persistence of spirochetal antigens in the joint in chronic Lyme disease. Locations of spirochetes or spirochetal antigens both intracellulary and extracellulary in deep synovial connective tissue as reported here suggest sites at which spirochaetes may elude host immune response and antibiotic treatment.
In our EM study, there was strong evidence of ongoing vascular injury in acute and also in chronic Lyme synovium. These feature of vasulopathy were not related to the total duration of arthritis. The signs of active vascular injury, found even in long-standing chronic Lyme arthritis (patient 3) may be evidence of repeated microvascular insults, occurring during each episode of arthritis.
If spirochetes are already sequestered in tissue that is inaccessible to antibiotics such as in the fibrinous and collagen tissue or within fibroblasts, high-dose parenteral antibiotics (54), or combination therapies (55, 56) with long duration may be needed to kill the living spirochetes. Failure of antibiotic treatment in chronic Lyme arthritis may also be explained by spirochetal antigens that exist in the joint and perpetuate immune response in genetically predisposed patients.
Bunikis Noppa Östberg Barbour Bergström Surface exposure and species specificity of immunoreactive domain of a 66-kilodalton outer membrane protein (P66) of the Borrelia spp. that cause Lyme disease Infect Immun 1996: https://www.ncbi.nlm.nih.gov/pubmed/8945554
...Later, hematogenous spread of the borreliae may occur causing chronic dermatologic, neurologic, and arthritic complications...
...These proteins may also contribute to the development of chronic Lyme disease by undergoing subtle antigenic changes which give rise to immunoevasive mutants (13,19,20,33).
Norris, Barbour et al, U.S. patent description for “VMP-like sequences of pathogenic Borrelia”, 4.13.04 (filed 2.20.97 -> 8.16.02) Norris, U.S patent description for “VMP-like sequences of pathogenic Borrelia species and strains” 8.25.15 (filed 4.21.14)
“The infection, if untreated, commonly persists for months to years despite the occurrence of host antibody and cellular responses; this observation indicates effective evasion of the immune response. Lyme disease may be disabling (particularly in its chronic form), and thus there is a need for effective therapeutics and prophylactic treatment.”
... although timely administration of appropriate antibiotics is usually curative, long courses of therapy may be required if the infection is allowed to become chronic, and in some patients there is no response to therapy at all.
... it is likely that VlsE plays an important role in some aspect of infection... and that antigenic variation merely permits surface expression of this protein without leading to elimination of the bacteria by the host’s immune response.
Abstract: The discovery of antigenic variation in Borrelia burgdorferi, the bacterium that causes Lyme disease, provides a potential explanation for the chronic nature of infection as well as new insights into the genetic structure of highly recombinogenic loci responsible for combinatorial genetic diversification. ... And now the Lyme disease pathogen, Borrelia burgdorferi can be added to this list; the recent discovery of antigenic variation in this species may explain the chronic nature of Lyme disease.
“Determination of the B burgdorferi genome has opened doors for investigation and closed just as many. By understanding the biosynthetic and transport limitations of B burgdorferi, we may be able to develop a medium in which to grow as-yet uncultivable Borrelia spp. The results encourage study of a more metabolically competent spirochaete, such as the free-living Spirochaeta aurantia, f or a better understanding of how this ancient group of bacteria evolved, and to identify catalytic molecules of industrial importance. But the sequence does not explain the persistence of the disease in some people yet not in others;...”
Phillips Mattman Hulinska Moayad, Proposal for reliable culture of B burgdorferi from patients with chronic Lyme, even those previously extensively treated Infection 1998: https://www.ncbi.nlm.nih.gov/pubmed/9861561
Chronic Lyme disease is a controversial topic. Even after extended antibiotic treatment, persistent infection in chronic Lyme disease has been strongly suggested by the persistence of borrelial antigen, as demonstrated by polymerase chain reaction (3,4)...
...This study proves that chronic Lyme disease is of chronic infectious etiology, and that even antibiotic treatment well in excess of current recommendations is not necessarily curative.
The sequence conservation of the six invariable regions across strain and genospecies barriers indicates that these regions are important in whichever role VlsE may play in the physiology of B burgdorferi. One would therefore expect that such sequences are not antigenic in hosts with a chronic B burgdorferi infection or would be otherwise inaccessible to Ab, either because they are conformationally buried withing the VlsE molecule or are unavailable on the spirochetal surface.
[BUT...] In addition, 35 of 41 human serum samples collected in the Northeast and Midwest of the US from patients with acute or chronic Lyme disease also reacted with the C6 peptide...
... The immunodominance of IR6 was further underscored by the long term persistence of anti-C6 Abs in infected monkeys and in patients with chronic Lyme disease (not shown).
... What then is the role of the antigenicity and immunodominance of IR6? It has been hypothesized that chronic host exposure to immunodominant Ags or epitopes diverts the immune system from responding to less antigenic but functionally important Ags or epitopes, thus serving as a protective strategy for persistent pathogens (30).
Hemmer Gran Zhao Marques Pascal Tzou Kondo Cortese Bielekova Straus McFarland Houghten Simon Pinilla Martin Identification of candidate T-cell epitopes and molecular mimics in chronic Lyme disease Nature Med 1999: https://www.ncbi.nlm.nih.gov/pubmed/10581079
In chronic infectious diseases such as Lyme disease, immune-mediated damage may add to the effects of direct infection by means of molecular mimicry to tissue autoantigens. Here, we describe a new method to effectively identify both microbial epitopes and candidate autoantigens. The approach combines data acquisition by positional scanning peptide combinatorial libraries and biometric data analysis by generation of scoring matrices. In a patient with chronic neuroborreliosis, we show that this strategy leads to the identification of potentially relevant T-cell targets derived from both Borrelia burgdorferi and the host.
In chronic CNS lesions, vasculitis and lymphocytic infiltrates both indicate involvement of cell-mediated autoimmunity, but little is known about the specific B. burgdorferi antigens that may be involved in CNS Lyme disease. Moreover, information is scarce on which CNS antigens may be relevant as target autoantigens in this condition [5,23].
Coburn (NEMC) Chege Magoun Bodary (Genentech) Leong (U Mass Worcester) Characterization of a candidate Borrelia burgdorferi B3-chain integrin ligand identified using a phage display library Mol Microbiol 1999: https://www.ncbi.nlm.nih.gov/pubmed/10594819
...A remarkable aspect of this infection is that, in the absence of appropriate antibiotic therapy, the bacteria are able to establish chronic infection even in the face of an intact immune system...
As is the case in humans, in animals the spirochaete is able to disseminate widely and avoid clearance by the immune system, thereby establishing chronic infection.
Straubinger Straubinger Summers Jacobson Status of Borrelia burgdorferi infection after antibiotic treatment and the effects of corticosteroids: An experimental study J Infect Dis 2000: https://www.ncbi.nlm.nih.gov/pubmed/10720533
... Patients with acute Lyme borreliosis are normally highly responsive to therapy and even chronic cases shows a favorable response to antibiotic treatment (23). However, patients may show relapses weeks to years after antibiotic therapy (24), which raises the question of reinfection or reactivation of the primary infection. It appears that B burgdorferi can survive antibiotic therapy either by residing in privileged sites provided by the host or by using other strategies... In conclusion, the canine model of acute Lyme arthritis has provided further insight into this disease.
We were able to investigate the status of the infection >360 days after antibiotic treatment and to collect data relevant to the chronic course of the disease seen in humans. We demonstrated that chronic silent infection with B burgdorferi can be converted into active disease. Positive PCR results after therapy may reflect low-level persistent infection. Further research is needed to uncover the mechanisms that enable B burgdorferi to gain a permanent foothold in the mammalian host.
Straubinger (College of Veterinary Medicine, Cornell) PCR-based quantification of Borrelia burgdorferi organisms in canine tissues over 500-day postinfection period J Clin Micro 2000: https://www.ncbi.nlm.nih.gov/pubmed/10834975
In this study, q-PCR was used to quantify B burgdorferi populations in skin tissue and blood samples of beagle dogs collected sequentially over a period of more than 500 days. To determine whether the number of borrelia organisms is correlated with clinical disease and whether antibiotic therapy eliminates the organisms in tissues, three groups of four dogs were each treated with different antibiotics for a 30- day period, and data for these animals were compared to those for untreated dogs. This experimental model was used because Lyme borreliosis is very similar to the disease in humans (1,28). Our studies have shown that despite a vigorous immune response of the dog, B burgdorferi is not eliminated and the bacterium establishes a persistent infection, particularly in collagen-rich tissue (10).
In summary, real-time PCR allowed a quantitative insight into the host-bacterium interaction in canine Lyme borreliosis: ... (iii) antibiotic therapy reduced the load of B burgdorferi organisms in the host but failed to eradicate the agent. This technique will benefit future studies designed to solve the exact mechanisms by which B burgdorferi establishes a persistent infection and triggers an inflammatory response in tissue.
Beerman Lochnit Geyer Groscurth Filgueira The lipid component of lipoproteins from B burgdorferi Structural analysis, antigenicity and presentation via human dendritic cells Biochem Biophys Comm 2000: https://www.ncbi.nlm.nih.gov/pubmed/10673388
Borrelia burgdorferi sensu stricto strain LW2 , a tendon isolate of a patient suffering from chronic Lyme disease...
Lyme borreliosis is characterized by chronic manifestations that coexist with a measurable immune response
Abstract: ... These data demonstrate that Lyme neuroborreliosis is a persistent infection, that spirochetal presence is a necessary but not sufficient condition for inflammation, and that antibody measured in serum may not predict the severity of infection.
This manuscript presents for the first time a combined analysis of spirochetal load, immunological response to the spirochete in the CSF and serum, and inflammation in infected tissues in a large group of animals in the NHP [nonhuman primate] model of LNB [Lyme neuroborreliosis]. The work showed that B burgdorferi is widely disseminated throughout the central and peripheral nervous system, a strong host immune response attacks the spirochete but is unable to clear the organism, and there is widespread inflammation in which presence of spirochete is necessary but not sufficient to cause inflammation.
This test is presently hailed as a potential breakthrough for reliable diagnosis of Lyme disease in patients with late or chronic illness.
Martin (NINDS/NIH) Gran Zhao Markovic-Plese Bielekova Marques (NIAID/NIH) Sung Hemmer (NINDS/NIH, Univ Marburg) Simon McFarland Pinilla (Torrey Pines Institute, San Diego) Molecular mimicry and antigen-specific T cell responses in MS and chronic CNS Lyme disease J Autoimmunity 2001:
We already utilized this search strategy for the identification of both B burgdorferi-derived sequences, the causative agent of Lyme disease, and to human proteins, for a clone (CSF-3) that was isolated from the CSF of a patient with chronic CNS Lyme disease (25 = Hemmer et al Nature Med 1999).
Hudson (USDA, Athens, GA) Frye Quinn Gherardini (Univ Georgia, Athens) Increased expression of B burgdorferi vlsE in response to human endothelial cell membranes Mol Microbiol 2001: https://www.ncbi.nlm.nih.gov/pubmed/11454215
As B burgdorferi disseminates to various sites in the body, other cell types and conditions are encountered, which could trigger additional changes in gene expression that are essential for maintaining an infection. Identifying the genes that are involved in establishing and maintaining a chronic infection is essential for understanding the pathogenesis of Lyme disease.
The chronic nature of Lyme disease and the genetic and antigenic diversity of the Lyme disease spirochetes suggest that antigenic variation may play an important role in immune evasion.
Vrethem Hellblom Widlund Ahi Danielsson Emerudh Forsberg Chronic symptoms are common in patients with neuroborreliosis — a questionnaire follow-up study Acta Neurol Scand 2002: https://www.ncbi.nlm.nih.gov/pubmed/12225315
OBJECTIVES: The existence of chronic neuroborreliosis is controversial. The aim of our study was to investigate the existence and kind of persistent symptoms in patients previously treated because of neurological symptoms as a result of neuroborreliosis.
MATERIALS AND METHODS: A total of 106 patients with neuroborreliosis, according to established criteria, and a control group of 123 patients with Borrelia induced erythema migrans diagnosed in a general practitioner office were studied. A questionnaire was sent to patients and controls concerning their health situation. Time from onset of neurological symptoms to the questionnaire send out was 32 months (mean) for the patients with neuroborreliosis and 33 months (mean) for the controls.
Fifty per cent of the individuals in the patient group compared with 16% of the individuals in the control group showed persistent complaints after their Borrelia infection (P < 0.0001). The most significant differences between the groups were the presence of neuropsychiatric symptoms such as headache, attention problems, memory difficulties and depression. Paresthesia, pain and persistent facial palsy was also significantly more common in patients treated because of neuroborreliosis.
CONCLUSION: Our study shows that persisting neurological symptoms are common after a neuroborreliosis infection. The pathological mechanisms that lay behind the development of chronic symptoms, however, are still uncertain.
Widhe Ernerudh (Univ Linkoping, Sweden) Cytokines in Lyme borreliosis Lack of early TNF-alpha and transforming growth factor-beta responses are associated with chronic neuroborreliosis Immunology 2002: https://www.ncbi.nlm.nih.gov/pubmed/12225362
In Europe, neuroborreliosis (NB) is a common manifestation, with the risk of developing into a chronic disease. Several reports suggest the occurrence of persistent or reappearing neurological symptoms in 20-50% of NB patients treated (3-5).
“If left untreated, infection with B burgdorferi sensu lato may lead to chronic Lyme borreliosis. It is still unknown how this pathogen manages to persist in the host in the presence of competent immune cells.” [p.3979]
“If infection with this pathogen is not treated adequately with antibiotics, it may lead to a chronic multisystemic disorder which is difficult to cure.” [p.3979]
“Blood cells from patients sufffering from persistent LB released significantly lower levels of proinflammatory cytokines (i.e. TNF-alpha and gamma interferon) in response to either a Borrelia-specific stimulus or LPS than cells from healthy volunteers (8). [p. 3979]
“Understanding the immunopathology of LB is still a major challenge. Although it induces strong immune activation, e.g. in phases of arthritis, the causative agent of LB persist and leads to a chronic pathology in the immunocompetent host. Of note, the inflammatory episodes associated with LB are typically self- limiting and the site of manifestation often changes, e.g. between different joints. These phenomena suggest counterregulatory anti-inflammatory mechanisms, and the long phases of latency indicate phases of immune evasion. [p. 3984-85]
Abstract: The immuno-pathogenetic mechanisms underlying chronic Lyme neuroborreliosis are mainly unknown. Human Borrelia burgdorferi (Bb) infection is associated with Bb-specific secretion of interferon-gamma (IFN-gamma), which may be important for the elimination of Bb, but this may also cause tissue injury. In order to increase the understanding of the pathogenic mechanisms in chronic neuroborreliosis, we investigated which cell types that secrete IFN-gamma. Blood mononuclear cells from 13 patients with neuroborreliosis and/or acrodermatitis chronicum atrophicans were stimulated with Bb antigen and the phenotypes of the induced IFN-gamma-secreting cells were analyzed with three different approaches. Cells expressing CD8 or TCR gamma delta, which both have cytolytic properties, were the main phenotypes of IFN-gamma-secreting cells, indicating that tissue injury in chronic neuroborreliosis may be mediated by cytotoxic cells.
Although B. burgdorferi can induce a strong bactericidal immune activation, e.g., in phases of arthritis, the causative agent of Lyme borreliosis seems to be able to persist in humans, which probably contributes to a chronic pathology in the immunocompetent host (11). A remitting and episodic course of inflammation has been described, indicating a repetitive confrontation of the immune system with spirochaetal components (43).
Cassiani-Ingoni Cabral Marques Martin B burgdorferi induces TLR1 and TLR2 in human microglia and peripheral blood monocytes but differentially regulates HLA-class II expression J Neuropathol Exp Neurol 2006: https://www.ncbi.nlm.nih.gov/pubmed/16783164
Because nervous system manifestations of Lyme disease occur frequently, besides the chronic involvement of the skin, the heart, and the joints, and because the CNS is considered an immunoprivileged organ, it is important to understand which factors contribute to tissue inflammation in the CNS.
The closely related spirochetal pathogens Borrelia burgdorferi sensu lato and Treponema pallidum are associated with persistent disease and infection of the brain, causing neurological disorders denoted Lyme neuroborreliosis and neurosyphilis, respectively...
...We hypothesized that like Lyme disease and syphilis, certain relapsing fever infections may be persistent in nature, providing a bacterial reservoir for potential infection of naive vectors...
...Intriguingly, B duttonii is far more persistent in the blood than the other species tested, and can cause a quantifiable persistent residual brain infection for at least 270 days. In addition, host immunosuppression enables these bacteria to re-enter the blood and achieve densities similar to those of the initial infection. We also present further evidence of bacterial immune evasion since animals with residual brain infection display a gene expression profile consistent with uninfected controls. Thus, the experiments in this study challenge the current paradigm of relapsing fever as an acute disease to include in some cases silent infection, in which bacteria can persist in an immune privileged site that provides a reservoir for reactivation.
Better knowledge of ... genetic and structural bases for these interactions of Bb with extracellular matrix will be required before understanding of persistence of Bb in tissues and development of chronic infections can be achieved
Bb... causes a chronic extracellular infection }
Here we suggest that these interactions are of great importance in chronic infections with this organism
Interaction of B burgdorferi with ECM is important for chronic infection
Interaction between Bb with the ECM (24), a hydrated complex of fibrous and non-fibrous proteins and proteoglycans, and specifically collagen (or its associated molecules), appears to be essential for persistence and chronic infection.
...ability of this pathogen to produce acute and chronic infections.
Abstract: ... Results indicated that following antibiotic treatment, mice remained infected with nondividing but infectious spirochetes, particularly when antibiotic treatment was commenced during the chronic stage of infection.
The current study further investigated the issue of B burgdorferi persistence following antibiotic therapy by examining mice treated with ceftriaxone during the early stage of infection compared to mice treated during the late stage of infection. A recent study has shown that there are significant shifts into or preferential survival of spirochetes in collagen during chronic infection (7), which may facilitate immune evasion and impact effectiveness of antibiotics.
Within mammals, however, ospA expression is essentially repressed, while vlsE expression is unregulated, especially during chronic infection of immunocompetent hosts (Liang et al, 2004b).
After dissemination, humoral responses greatly upregulate vlsE in all tissues, an event consistent with the critical role of VlsE in immune evasion during chronic infection of immunocompetent hosts ( Bankhead & Chaconas, 2007; Zhang et al, 1997).
... the immune system is needed to fully eliminate the remaining spirochetes. However, therein lies the challenge, since Borrelia burgdorferi has evolved to persistently infect fully immunocompetent hosts. Persistent infection has been shown to be the rule, rather than the norm, in a variety of laboratory animal species, including mice, rats, Peromyscus leucopus, hamsters, gerbils, guinea pigs, rabbits, dogs, and nonhuman primates. Based upon culture and/or PCR, persistent infections have also been documented in humans from both Europe (3,36,43,46,65,67,71,74) and the US (14,19,47). Therefore, the “mop up” phase, which is dependent upon the immune system, is likely to be ineffective against an agent such as B burgdorferi, which is highly effective at evading host clearance. ... At all phases of these events, spirochetes cannot be cultured, and their numbers are very low, suggesting a viable but slowly dividing or nondividing population (27). These features fit the paradigm of multidrug tolerance or “recalcitrance to eradication” by antibiotics that occurs among a variety of persistent bacterial and fungal infections (reviewed in references 30,38, 39).
These results challenge prevailing dogma about effectiveness of antibiotics for eliminating B burgdorferi infection, and therefore further work is critically needed.
Embers Barthold Borda Bowers Doyle Hodzic Jacobs Hasenkampf Martin Narasimhan Phillippi-Falkenstein Purcell Ratterree Philipp Persistence of Borrelia burgdorferi
...These results demonstrate that B. burgdorferi can withstand antibiotic treatment, administered post- dissemination, in a primate host. Though B. burgdorferi is not known to possess resistance mechanisms and is susceptible to the standard antibiotics (doxycycline, ceftriaxone) in vitro, it appears to become tolerant post-dissemination in the primate host. This finding raises important questions about the pathogenicity of antibiotic-tolerant persisters and whether or not they can contribute to symptoms post- treatment.
“Tendons and ligaments are a structurally and topographically ideal retreat for Borrelia. Their involvement is a further factor to indicate a chronic course of the disease. Serological antibody diagnostic techniques proved to be inadequate in cases such as this, possibly because the formation of antibodies is inhibited by the pathogen ””
Abstract A066 (D054) - p.114 Nepereny Vrzal (Bioveta, Czech Republic) Sensitivity of different Borrelia genospecies to dog serum complement
Lyme disease is a chronic multisystem infectious disease that is the most common arthropod-borne infectious disease both in Europe and in the United States.
Abstract A083 (P045) - p. 128 Troy Norris Hu (Tufts, U Texas Houston) Understanding barriers to B burgdorferi dissemination during infection using massively parallel sequencing
B burgdorferi is an invasive spirochetal pathogen that can cause acute and chronic infections in the skin, heart, joints and central nervous system of infected mammalian hosts. Following transmission into a mammalian host through the bite of an Ixodes scapularis tick, the bacteria establish infection at the inoculation site and then quickly disseminate to distal tissues initiating long-term colonization. In this process, B burdorferi encounters multiple potential barriers to infection including adapting to
environmental changes in nutrients, pH and temperature, breaking through tissue barriers to invasion and dissemination, and evading host immune responses.
Abstract B017 (P016) - p.150 Embers Jacobs (Tulane Primate Research Ctr, Covington, LA) Tick-mediated B burgdorferi infection on nonhuman primates for assessment of antibiotic efficacy
... The causative agent, B burgdorferi, can chronically infect humans, causing rash, arthritis, carditis, and neurological dysfunction.
Abstract B029 (D021) - p. 162 Blenk (EuromedClinic, Fuerth, Germany) Straubinger Schuster Ünsal-Kirici Steinhaven Schütt Komorowki (EUROIMMUN AG, Luebeck, Germany) Relevance of quantitative determination of IgG antibodies against VlsE as an activity marker in the monitoring of treated Lyme borreliosis: A retrospective study
Archived (-80C) sera from patients with confirmed or suspected Lyme disease from our Lyme outpatient clinic were used as sample material.
Results: A significant drop in the titer of anti-VlsE antibodies could be detected as early as 6-8 weeks after successful treatment in all active chronic Lyme infections, inc Lyme arthritis, ACA, acute neuroborreliosis and other active chronic stages of Lyme infection. This decrease in anti-VlsE correlated with a reduction in clinical symptoms. The absence of an anti-VlsE titer virtually excludes a florid chronic Lyme infection (control panel of healthy individuals, n=105). Strongly positive anti-vlsE values (>1000 RU/ml) in untreated patients are to 99% an indication of an active chronic Lyme infection.
Conclusion: Quantitative determination of anti-VlsE IgG is suitable - always under consideration of clinical symptoms - for confirmation of diagnosis and as an activity marker for monitoring patients with active chronic Lyme borreliosis before and after treatment.
Abstract B037 (D035) - p.170 Chan Marras Schutzer Parveen Development of a novel nucleic acid-based diagnostic assay for Lyme disease:
The infection with Borrelia burgdorferi can result in acute to chronic Lyme disease... We anticipate that pre-enrichment of the spirochetes present in the blood by culture before conducting the rt-PCR will further improve sensitivity and specificity of the assay such that it can be used as a diagnosis of early to chronic stages of infection by Lyme spirochetes
Abstract B048 (D055) Eshoo Crowder Schutzer Aucott Direct molecular detection of B burgdorferi from whole blood and CSF of patients with acute and chronic Lyme disease (revised)
... Results will also be presented on the analysis of a large set (>200) of CSF specimens collected in Germany from patients with acute and chronic neuroborreliosis.
Abstract B053 Reye Muller (Nat’l Public Health Lab, Luxembourg) From prevalence studies to the development of novel diagnostic tests for Lyme disease
Therefore, antigen-specific B-cells will be isolated and compared on a single cell level between acute, chronic, and resolved patients.
Abstract B076 (D018) - p. 207 Guadulupe Javier Lyme neuroborreliosis is highly prevalent in tertiary care hospitals of Central- southeast Mexico
Results: We studied 650 patients and confirmed Lyme Neuroborreliosis in 132 (20.3%). The acute disseminated stage was documented ion 100 (75.7%) with facial palsy, lymphocytic meningitis, poliradiculopathy 27 cases, and the chronic stage in 32 (24%) of the cases with encephalomyelitis.
Conclusions: This is the first report of Lyme neuroborreliosis in central of Latin-American, and presents as disseminated and a chronic stage.
“Lipopeptides in combination with other antigens from spirochetes facilitates the transition from innate to prolonged adaptive immune responses that contribute to chronic manifestations of spirochetal diseases such as syphilis and Lyme disease (11). “ Hodzic Imai Feng Barthold Resurgence of persisting non-cultivable Borrelia burgdorferi following antibiotic treatment in mice PLoS One 2014: https://www.ncbi.nlm.nih.gov/pubmed/24466286
Abstract: The agent of Lyme borreliosis, Borrelia burgdorferi, evades host immunity and establishes persistent infections in its varied mammalian hosts. This persistent biology may pose challenges to effective antibiotic treatment. Experimental studies in dogs, mice, and non-human primates have found persistence of B. burgdorferi DNA following treatment with a variety of antibiotics, but persisting spirochetes are non-cultivable. Persistence of B. burgdorferi DNA has been documented in humans following treatment, but the significance remains unknown...
Experimental animal studies have shown that Borrelia burgdorferi, the agent of Lyme borreliosis, consistently establishes persistent infections in a variety of immunocompetent hosts, including laboratory mice (1), white-footed mice (Peromyscus leucopus) (2,3,4), rats (5), hamsters (6), guinea pigs (7), gerbils (8), dogs (9), and nonhuman primates, including rhesus macaques (Macaca mulatta) (10) and baboons (Papio spp.) (11). Clinical evidence extends this paradigm to humans (12). Persistence is an essential strategy for a complex B burgdorferi life cycle in both ticks and reservoir hosts, and likely pertains to
incidental hosts, such as humans. Persistent biology may pose a challenge in antibiotic therapy, though antibiotics ameliorate the majority of host persisting bacteria, by virtue of their immune-evasion biology, may survive in hosts that are unable to clear infection.
Discussion This study validates a mouse model that can be used for investigation of post-antibiotic persistence of non-cultivable B burgdorferi...
Results of this study demonstrated not only persistence, but also resurgence of non-cultivable B burgdorferi in tissues of mice at up to 12 months following antibiotic treatment, despite the continued inability to culture spirochetes fro the tissues...
Although various animal studies may each have their flaws (as do human clinical studies), the comparative evidence in dogs, mice, non-human primates, and perhaps humans, is compelling, and suggests that something unique is happening with B burgdorferi following antibiotic treatment...
Rogovskyy (College Vet Med,Texas A&M) Zelikovsky (Dept Computer Sci, Georgia State Univ) Antibody response to Lyme disease spirochetes in context of VlsE- mediated immune evasion Infect Immun 2016:https://www.ncbi.nlm.nih.gov/pubmed/27799330
When missed and therefore left untreated, LD becomes chronic, presenting itself as skin lesions, arthritis, and carditis and occasionally with subsequent nervous system involvement. Grillon Westermann Cantero Jaulhac Voordouw Kapps Collin Barthel Ehret- Sabatier Boulanger identification of Borrelia protein candidates in mouse skin for potential diagnosis of disseminated Lyme borreliosis Nature Sci Rep 2017: https://www.ncbi.nlm.nih.gov/pubmed/29196626
In competent reservoir hosts, Borrelia pathogens establish a chronic infection in the skin and other organs such as the heart, bladder and joints.
15th International Conference on Lyme borreliosis and other tick borne diseases - Atlanta - Sept 2018:
Poster P51 Crowley Casselli (Univ ND) Highland (USDA) Tourand Bankhead (Wash State Univ) A novel plasmid-encoded factor is essential for efficient colonization of host tissues by the Lyme disease spirochete:
With over 300,000 cases per year, Lyme disease is the most common tick-borne disease in North America. While antibiotic therapies exist, they are only effective when administered soon after exposure, which is challenging given the difficulty of diagnosis and detection of the etiological agent, B burgdorferi, in infected patients. The most dangerous aspect of infection with B burgdorferi is the pathogen’s ability to disseminate from the blood stream and colonize distal tissues, leading to chronic and potentially severe disease manifestations.