The Science On Chronic Or Persistent Lyme Infection/disease
/disease
two major outer surface proteins of Lyme disease spirochete Science 1985;227:645-5
https://www.ncbi.nlm.nih.gov/pubmed/3969554
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
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:
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…
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
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.
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…
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
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
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.
(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.
borreliosis Rev Infect Dis 1989 Sep-Oct; 11 Suppl 6:
https://www.ncbi.nlm.nih.gov/pubmed/2682965
in as many as 50% of cases of chronic infection..
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.
Sep-Oct; 11, Suppl 6: https://www.ncbi.nlm.nih.gov/pubmed/2682961
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).
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).
https://www.ncbi.nlm.nih.gov/pubmed/2686769
the US can we achieve a true appreciation of the multiplicity of acute and chronic disease
manifestations due to B burgdorferi infection.
chronic phase of infection can develop. Clinical manifestations observed during this chronic
phase include chronic meningitis, meningoradiculitis, encephalitis, peripheral neuropathy,
lymphocytoma, ACA and arthritis
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
with variable degrees of dysfunction. (15, 31-34). Multisystem involvement appears to be random
and unpredictable, with chronic states of persistence in some cases.
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.
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.
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…
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.
are lipoproteins Infect Immun 1990: https://www.ncbi.nlm.nih.gov/pubmed/2318538
disorder characterized by dermatologic, rheumatologic, cardiac, and neurological manifestations.
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.
41-kilodalton antigen (flagellin): Molecular cloning, expression and amplification of the
gene Infect Immun 1990: https://www.ncbi.nlm.nih.gov/pubmed/2341173
including the heart, the liver, the kidneys, the musculoskeletal system, the skin, and the central
and peripheral nervous systems.
Infect Immun 1991: https://www.ncbi.nlm.nih.gov/pubmed/1987083
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.
Rev 1991: https://www.ncbi.nlm.nih.gov/pubmed/2030671
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.
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?
by other bacteria JID 1992: https://www.ncbi.nlm.nih.gov/pubmed/1372635
heart [1]”
of antigens. In the chronic phase of the disease, a much larger repertoire of antigens is recognized (5,6)”
Microbiol 1992: https://www.ncbi.nlm.nih.gov/pubmed/1475522
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…
proteins and non-Borrelia-directed Immunoglobulin M antibodies Infect Immun 1992:
https://www.ncbi.nlm.nih.gov/pubmed/1541558
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)
to B burgdorferi Microbiol Rev 1991
protein of Borrelia burgdorferi An immunodominant protoplasmic cylinder antigen
Infect Immun 1992: https://www.ncbi.nlm.nih.gov/pubmed/1398941
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.
titers (23,35,41,72).
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.
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.
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.
from its prominent pathway of degradation, and that such organisms retain the ability to multiply…
https://www.ncbi.nlm.nih.gov/pubmed/8503006
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).
J Clin Path 1993: https://www.ncbi.nlm.nih.gov/pubmed/8438790
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).
chronic Lyme disease protect mice from Lyme borreliosis JID 1994:
https://www.ncbi.nlm.nih.gov/pubmed/8158028
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,”
and Borrelia burgdorferi Trends Microbiol 1994:
https://www.ncbi.nlm.nih.gov/pubmed/7812663
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.
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.
https://www.ncbi.nlm.nih.gov/pubmed/8146126
of intermittent or chronic arthritis (19), chronic neurologic involvement (48-51), or acrodermatitis
chronica atrophicans (52).
description for “DNA encoding Borrelia burgdorferi OspA and a method for diagnosing
Borrelia burgdorferi infection” 12.10.96 (filed 10.3.94):
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)
from Borrelia burgdorferi, the Lyme disease spirochete Infect Immun 1995:
https://www.ncbi.nlm.nih.gov/pubmed/7768594
aspect of Lyme disease concerns the inability of host immune responses to eradicate persistent
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).
outer surface lipoproteins Proc Natl Acad Sci USA 1996:
https://www.ncbi.nlm.nih.gov/pubmed/8755587
a major revision of current concepts of B burgdorferi ultrastructure and its relationship to immune
evasion during chronic Lyme disease.
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
Treponema pallidum and Borrelia burgdorferi, respectively.
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.
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
inflammation associated with chronic Lyme disease (58).
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
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.
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.
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.
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
and arthritic complications…
subtle antigenic changes which give rise to immunoevasive mutants (13,19,20,33).
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)
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.”
Efficacy in rhesus monkey Vaccine 1997: https://www.ncbi.nlm.nih.gov/pubmed/9413097
may be required if the infection is allowed to become chronic, and in some patients there is no
response to therapy at all.
sequence cassettes Cell 1997: https://www.ncbi.nlm.nih.gov/pubmed/9108482
variation merely permits surface expression of this protein without leading to elimination of the
bacteria by the host’s immune response.
https://www.ncbi.nlm.nih.gov/pubmed/9285701
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.
https://www.ncbi.nlm.nih.gov/pubmed/9403678
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;…”
with chronic Lyme, even those previously extensively treated Infection 1998:
https://www.ncbi.nlm.nih.gov/pubmed/9861561
infection in chronic Lyme disease has been strongly suggested by the persistence of borrelial
antigen, as demonstrated by polymerase chain reaction (3,4)…
treatment well in excess of current recommendations is not necessarily curative.
the variable surface antigen of B burgdorferi J Immunol 1999:
https://www.ncbi.nlm.nih.gov/pubmed/10553085
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.
US from patients with acute or chronic Lyme disease also reacted with the C6 peptide…
anti-C6 Abs in infected monkeys and in patients with chronic Lyme disease (not shown).
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).
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
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.
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].
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
bacteria are able to establish chronic infection even in the face of an intact immune system…
by the immune system, thereby establishing chronic infection.
antibiotic treatment and the effects of corticosteroids: An experimental study J Infect Dis 2000:
https://www.ncbi.nlm.nih.gov/pubmed/10720533
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.
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.
organisms in canine tissues over 500-day postinfection period J Clin Micro 2000:
https://www.ncbi.nlm.nih.gov/pubmed/10834975
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).
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.
Structural analysis, antigenicity and presentation via human dendritic cells Biochem Biophys
Comm 2000: https://www.ncbi.nlm.nih.gov/pubmed/10673388
Lyme disease…
response
https://www.ncbi.nlm.nih.gov/pubmed/11075919
for by the host and would help explain the chronic infection associated with Lyme borreliosis.
infection, immunity and inflammation in the NHP model of Lyme borreliosis Ann Neurol 2001:
https://www.ncbi.nlm.nih.gov/pubmed/11558789
spirochetal presence is a necessary but not sufficient condition for inflammation, and that antibody
measured in serum may not predict the severity of infection.
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.
Infect Dis 2001: https://www.ncbi.nlm.nih.gov/pubmed/11245316
patients with late or chronic illness.
(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:
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).
of B burgdorferi vlsE in response to human endothelial cell membranes Mol Microbiol 2001:
https://www.ncbi.nlm.nih.gov/pubmed/11454215
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.
during infection with Lyme disease spirochetes Infect Immun 2002:
https://www.ncbi.nlm.nih.gov/pubmed/12117928
spirochetes suggest that antigenic variation may play an important role in immune evasion.
in patients with neuroborreliosis — a questionnaire follow-up study Acta Neurol Scand 2002:
https://www.ncbi.nlm.nih.gov/pubmed/12225315
to investigate the existence and kind of persistent symptoms in patients previously treated because
of neurological symptoms as a result of neuroborreliosis.
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.
group showed persistent complaints after their Borrelia infection (P . 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.
neuroborreliosis infection. The pathological mechanisms that lay behind the development of
chronic symptoms, however, are still uncertain.
and transforming growth factor-beta responses are associated with chronic neuroborreliosis
Immunology 2002: https://www.ncbi.nlm.nih.gov/pubmed/12225362
disease. Several reports suggest the occurrence of persistent or reappearing neurological symptoms
in 20-50% of NB patients treated (3-5).
Infection Immunity 2003: https://www.ncbi.nlm.nih.gov/pubmed/12819085
still unknown how this pathogen manages to persist in the host in the presence of competent immune
cells.” [p.3979]
multisystemic disorder which is difficult to cure.” [p.3979]
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]
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]
cytolytic properties of Borrelia-specific interferon-gamma secreting cells in chronic Lyme
neuroborreliosis J Neuroimmunol 2003: https://www.ncbi.nlm.nih.gov/pubmed/14644037
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.
Infect 2006: https://www.ncbi.nlm.nih.gov/pubmed/16842565
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).
and peripheral blood monocytes but differentially regulates HLA-class II expression J Neuropathol
Exp Neurol 2006: https://www.ncbi.nlm.nih.gov/pubmed/16783164
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.
reactivation in relapsing fever borreliosis Microbes Infect 2006:
https://www.ncbi.nlm.nih.gov/pubmed/16782384
are associated with persistent disease and infection of the brain, causing neurological disorders
denoted Lyme neuroborreliosis and neurosyphilis, respectively…
persistent in nature, providing a bacterial reservoir for potential infection of naive vectors…
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.
Microbiol 2007: https://www.ncbi.nlm.nih.gov/pubmed/17600717
will be required before understanding of persistence of Bb in tissues and development of chronic
infections can be achieved
and proteoglycans, and specifically collagen (or its associated molecules), appears to be essential
for persistence and chronic infection.
patients with early disseminated and chronic Lyme borreliosis Adv Med Sci 2007:
https://www.ncbi.nlm.nih.gov/pubmed/18217413
Agents Chemother 2008: https://www.ncbi.nlm.nih.gov/pubmed/18316520
but infectious spirochetes, particularly when antibiotic treatment was commenced during the chronic
stage of infection.
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.
behavior Microbiology 2008: https://www.ncbi.nlm.nih.gov/pubmed/18957595
unregulated, especially during chronic infection of immunocompetent hosts (Liang et al, 2004b).
with the critical role of VlsE in immune evasion during chronic infection of immunocompetent hosts (
Bankhead & Chaconas, 2007; Zhang et al, 1997).
Antimicrob Agents Chemother 2010: https://www.ncbi.nlm.nih.gov/pubmed/19995919
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).
infection, and therefore further work is critically needed.
Narasimhan Phillippi-Falkenstein Purcell Ratterree Philipp Persistence of Borrelia burgdorferi
https://www.ncbi.nlm.nih.gov/pubmed/22253822
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.
aspects Open Neuro 2012: https://www.ncbi.nlm.nih.gov/pubmed/23986790
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]””
and Med Microbiol 2012: https://www.ncbi.nlm.nih.gov/pubmed/22540535
even though a robust humoral and cellular immune response is produced by the infected host.
disease which can result in various disorders of the heart, nervous system, and joints.
Aug 2013:
https://www.frontiersin.org/books/ 13th_International_Conference_on_Lyme_Borreliosis_and_other_tick_Borne_Diseases_/357
genospecies to dog serum complement
infectious disease both in Europe and in the United States.
to B burgdorferi dissemination during infection using massively parallel sequencing
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
dissemination, and evading host immune responses.
Tick-mediated B burgdorferi infection on nonhuman primates for assessment of antibiotic efficacy
neurological dysfunction.
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
clinic were used as sample material.
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.
clinical symptoms – for confirmation of diagnosis and as an activity marker for monitoring patients
with active chronic Lyme borreliosis before and after treatment.
acid-based diagnostic assay for Lyme disease:
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
from whole blood and CSF of patients with acute and chronic Lyme disease (revised)
in Germany from patients with acute and chronic neuroborreliosis.
to the development of novel diagnostic tests for Lyme disease
chronic, and resolved patients.
tertiary care hospitals of Central- southeast Mexico
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.
as disseminated and a chronic stage.
https://www.ncbi.nlm.nih.gov/pubmed/25071771
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
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…
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
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.
persistence of non-cultivable B burgdorferi…
B burgdorferi in tissues of mice at up to 12 months following antibiotic treatment, despite the continued
inability to culture spirochetes fro the tissues…
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…
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
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
organs such as the heart, bladder and joints.
- Sept 2018:
A novel plasmid-encoded factor is essential for efficient colonization of host tissues by the
Lyme disease spirochete:
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.
Source: https://lookingatlyme.blogspot.com/2019/01/the-science-on-chronic-or-persistent.html
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