Time to stop voicing opinions and look at the science available on LYME DISEASE.
Lets start 2019 voicing science thank you
Basic science (mostly) Lyme/Borrelia references referring to chronic or persistent infection
/disease
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 [1]”
“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)
24 = Steere Lyme disease NEJM 1989 25 = Szczepanski Benach Lyme borreliosis Host responses
to B burgdorferi Microbiol Rev 1991
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.
Discussion
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 [27], 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
Identification of such variable determinants may shed light on additional escape variants selected
for by the host and would help explain the chronic infection associated with Lyme borreliosis.
Pachner Cadavid Shu Dail Pachner Hodzic Barthold Central and peripheral nervous system
infection, immunity and inflammation in the NHP model of Lyme borreliosis Ann Neurol 2001:
https://www.ncbi.nlm.nih.gov/pubmed/11558789
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.
RESULTS:
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]
Ekerfelt Jarefors Tynngard Hedlund Sander Bergstrom Forsberg Ernerudh Phenotypes indicating
cytolytic properties of Borrelia-specific interferon-gamma secreting cells in chronic Lyme
neuroborreliosis J Neuroimmunol 2003: https://www.ncbi.nlm.nih.gov/pubmed/14644037
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 [2]}
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 [11]””
These spirochetes are unique in that they can cause chronic infection and persist in the infected human,
even though a robust humoral and cellular immune response is produced by the infected host.
Infected individuals that do not receive antibiotic therapy are at risk for developing chronic forms of the
disease which can result in various disorders of the heart, nervous system, and joints.
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.
