Borrelia Ebook

Lyme Strategies

This latest updated text, in digital eBook form and available for immediate download, has been expanded nearly eightfold over the original guide of 2004 in terms of the exact, step-by-step lue-print and essential information designed to maximize this protocol. Just some of the valuable information contained in this 193-page guide includes: How to do the protocol, including the exact, specific method or procedure that is critical to its success. Schedule chart, measurements guide, tips and recommendations. The basic elements of the protocol are actually five, not just salt and vitamin C what these are and why Understanding what a Jarisch-Herxheimer reaction (or Herx) is. Particular djunct items found to be extremely helpful and particular items for special issues. A Technical Section detailing why the protocol works (posited mechanisms), including scientific citations and and studies. The right salt versus wrong salt and why. the low-salt, no-salt myth and scientific truth. the historical, medicinal use of natural salt. Did you know salt was used to treat syphilis, caused by Lyme's bacterial cousin, in the 1800s? Why Vitamin C and what does it do? The protocol and specific body considerations (heart, adrenals, etc.) Key Characteristics of the Lyme bacterium (Borrelia burgdorferi), including nearly 20 extraordinary mechanisms and features it uses to elude the immune and proliferate in the body

Lyme Strategies Summary

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Lyme Disease

though there are currently at least 10 different Borrelia Species within the B. burgdorferi sensu lato complex, only fiorrelia burgdorferi sensu stricto strict sense of B. burgdorferi) as well as B.garinii, B. afzelii, and B. valaisiana are agents of Lyme disease and are transmitted by the bite of Ixodes ticks.17 Lyme disease is the most common Ejector-borne disease in North America and Europe and te an emerging problem in northern Asia.10 Hard ticks, belonging primarily to the genus Ixodes, act as vectors in the United States, including Ixodes pacificus in California 3 d I, scapularis in other areas. The ticks' natural hosts are deer and rodents, although they will attach to pets as w ll as to humans all stages of ticks larva, nymph, and adult can harbor the spirochete and transmit disease, the nymphal form of the tick is most likely to transmit disease because it is active in the spring and summer when people are dressed lightly and in the woods. Because at this stage the tick is...

Spirochetes Borrelia

Visualization in direct preparations is diagnostic for 70 of cases of relapsing fever, a febrile disease caused by Borrelia recurrentis. Organisms may be seen in direct wet preparations of a drop of anticoagulated blood diluted in saline as long, thin, unevenly coiled spirochetes that seem to push the red blood cells around as they move. Thick and thin smears of blood, prepared as for malaria testing and stained with Wright's or Giemsa stain, are also sensitive for the detection of Borrelia. with SPS for 11 days, allowing lor transport of specimens from distant locations. Direct dark-field examination'of peripheral blood is not recommended because many artifacts are present that may resemble spirochetes. If blood must be shipped to a reference laboratory for culture, blood may be collected into heparin, oxalate, or citrate tubes and maintained at ambient temperature.3 (Further information about Borrelia and Leptospira is provided in Chapter 48.)

Chromosome Topology and Number

Bacteria generally have a single, double-stranded circular DNA chromosome. However, a number of bacterial species have a linear chromosome (5,11). The first linear bacterial chromosome identified was that of Borrelia burgdorferi (12). A number of Streptomyces species, including S. lividans 66 (13), S. coelicolor A3 (14), and S. aver-mitilis (15), also have a linear chromosome. It is likely that the Streptomyces linear chromosome evolved from an ancestral circular chromosome (11).

Modern Biology Has Refined Kochs Postulates

We continue to face new types of infection as we modify our environment. Diseases once restricted to tree-tops (monkeypox) have come to ground as we chop down forests, Lyme disease spreads with deer in backyards that were formerly woods, and hantavirus jumps to humans when rodents invade homes. Today we are considering abnormal proteins (prions) as agents of transmissible spongiform encephalitis (mad cow disease).50 Protein-based diseases require new paradigms, because in all other cases the disease-causing agents contain nucleic acids whose replication is easy to understand. Thus, Koch's postulates remain relevant.

Plasmids Structure Size Topology and Evolutionary Role

Plasmids are extrachromosomal genetic elements of diverse sizes ranging from a few kilo basepairs to more than 400 kb. The most common structure of plasmids is a double-stranded circular DNA molecule. However, linear plasmids are found in all species of the Borrelia genus and in many species of Streptomyces (65). Linear plasmids have also been isolated from Rhodococcus fascians (66), Nocardia opaca (67), and Clavibacter michiganensis subsp. Sepedonicus (68).

Chorioallantoic membrane CAM A

Chronic fatigue syndrome (CFS) A severely disabling fatigue with self-reported impairments in concentration and short-term memory, sleep disturbances and musculoskeletal pain. Occurs worldwide. A number of infectious agents have been proposed as etiologic agents of CFS, including Human herpesviruses 4 (EBV), 5 (CMV) and 6 (HHV6) enteroviruses retroviruses and Borrelia burgdorferi. None has proved to be a unique causative agent, but it remains possible that such infections act as a trigger for the syndrome. Synonyms post-viral fatigue syndrome myalgic encephalitis (ME).

The Prospects for Microbial Genomics Providing Novel Exploitable Antibacterial Targets

Currently, the number of microbial genomes that have been sequenced since the initial H. influenzae genome is approximately fifty-nine, with many additional projects in progress. Limiting the examples to pathogens alone, organisms such as Streptococcus pyogenes, several strains of Streptococcus pneumoniae, Chlamydia trachomatis, and Chlamydia pneumoniae, Borrelia burgdorferi, Treponema pallidum, Mycobacterium tuberculosis and an enterohaemorrhagic strain of Escherichia coli (13-21) are among many additional pathogen genome sequences in the public domain. Two important organisms in which the bulk of microbial physiology has been performed, E. coli K-12 and Bacillus subtilis, are also available. These are key, as many of the putative function annotations of pathogen genomes are based on sequence similarities to gene products in these two organisms. With individual microbial genomes running between roughly 400,000 to over 4 million base pairs, the sheer volume of this information has...

Box 79 Antibiotic Resistant Malaria

A variety of serious diseases are spread by ticks, which are arthropods closely related to insects. One of the more troublesome is Lyme disease. This infection is caused by a bacterium (Borrelia) that is currently susceptible to many antibiotics. Although resistance may conceivably emerge in individual patients, the resistant bacteria are not likely to spread to another person because the vector (deer tick) does not commonly travel from one person to another. To generate a resistance problem, we would need to treat deer or mice with antibiotics.

Cutaneous Bcell lymphomas

A small percentage of primary cutaneous B-cell lymphomas was demonstrated to harbour Borrelia burgdorferi DNA sequences within specific skin lesions in studies carried out in different countries, but negative results have also been reported 6-8 . This association may be important for cutaneous immunocytomas. The presence of B. burgdorferi

Direct Detection Methods

B. burgdorferi may be visualized in tissue sections stained with Warthin-Starry silver stain. In general, the number of spirochetes m blood of patients with Lyme borreliosis is below the lower limits of microscopic detection. PCR has become important in diagnosing Lyme disease. PCR has detected B. burgdorferi DNA in clinical specimens from patients with early and late clinical manifestations optimal specimens include urine, synovial tissue, synovial fluid, and skin biopsies from patients with EM.1'15,18 A variety of molecular methods have been used by laboratories to increase sensitivity and specificity and decrease turnaround time for diagnosing Lyme borreliosis. PCR has confirmed EM with an overall sensitivity and specificity of 68 and 100 , respectively. The ability to detect spirochetes in blood or plasma by PCR is dependent on the stage of illness (from 40 of patients with secondary EM to only 9.5 of patients with primary EM) PCR also does relatively well in...

Comparing the Leptospiral Genomes

The genome of L. borgpetersenii serovar Hardjobovis strain L550 comprises two circular chromosomes of 3,614,446 bases and 317,336 bases, with an overall guanine and cytosine (G+C) content of 41.3 . The density of CDS sequences across the genome is 80.3 , with an average gene size of 931 bases. In total 3111 and 292 CDS features were annotated on chromosome 1 and chromosome 2, respectively. The L. borgpetersenii genome is smaller than the L. interrogans genomes (Table 2) and codes for proportionally fewer genes. The G+C content is higher than that found for L. interrogans, consistent with previous estimates of G+C content (3). The relatively lower density of coding regions found in Leptospira compared with Escherichia coli may be related to the fluidity of the arrangement of genes on the genome. Consistent with this viewpoint, the gene layout found in the sequenced Borrelia genomes is conserved and the density of coding regions is around 95 (10). Also likely to contribute to genome...

Regulation of Gene Expression

Leptospira appears to use a number of known strategies to tailor expression patterns to the diverse environments normally encountered by this bacterium. Like the other spirochetes, Leptospira appears to have both Sigma-54 (LA2404, LIC11545, SPN1246) and Sigma-70 (LA2232, LIC11701, and SPN1385) transcription initiation factors. Sigma-70 is essential for the regulation of transcription during exponential growth (15). Specialized sigma factors, such as the extracytoplasmic function (ECF) sigma factors, which respond to specific environmental signals, are not found in the Borrelia genomes, whereas there are one and two examples in the T. pallidum and T. denticola genomes, respectively. By contrast, each of the leptospiral genomes has 11 ECF sigma factors. Notably, these factors are not encoded exclusively on chromosome 1. In other bacteria these factors are normally cotranscribed with an antisigma regulatory factor that is normally located in the inner membrane (16). It is not surprising,...

Large Bcell lymphoma leg type

Large B-cell lymphoma, leg type, can be seen in immuno-compromised patients and has been observed in association with Kaposi sarcoma, but does not seem to be specifically linked to infection by human herpesvirus 8 5-8 . The presence of specific sequences of Borrelia burgdorferi DNA has been demonstrated in rare cases 9,10 .

Protein Secretion Systems

Based on similarity, Leptospira has a Sec translocase that resembles that of E. coli. This complex is responsible for the translocation of both inner membrane and extra-cytoplasmic proteins (19). The processing of the extracytoplasmic proteins occurs via the signal peptidases. Orthologs of Lgt, Lnt, and LspA (signal peptidase II) are present, indicating that Leptospira processes lipoproteins using a mechanism similar to other Gram-negative bacteria, although the specificity of the signal recognition sequence is different (20). In addition, proteins related to LolA, LolC, and LolD are present and are probably involved in the transport and incorporation of lipoproteins into the outer membrane. The signal directing, newly translocated lipoproteins to the outer membrane is encoded by the second amino acid of the mature lipoprotein again, this signal differs from that found for Gram-negative bacteria (20). Two LepB-related proteins are encoded on each of the sequenced genomes indicating a...

Clinical features

Clinically, patients present with localized or generalized erythematous papules, plaques or tumours 1-3 . Peculiar clinical presentations include the so-called 'facies leonina' and the onset of specific skin lesions at sites of previous herpes simplex or herpes zoster eruptions (Figs 14.1 & 14.2) 4 . These latter were often classified in the past as pseudolym-phoma 5,6 , but are in fact specific cutaneous manifestations of the disease 4,7 . It has been recently demonstrated that lesions arising at typical sites of Borrelia burgdorferi infection (nipple, scrotum, earlobe) represent specific manifestations of B-CLL triggered by infection with B. burgdorferi (Fig. 14.3) 8 . Lesions arising on the nipple were well known in the past and were termed 'leukaemia lymphatica mamillae' in old textbooks.

Box 126 Malaria and Short Term Travelers

In the 1950s and 1960s, the United States routinely sprayed residential and urban communities with DDT to suppress mosquito populations. The treatment was highly effective, making mosquito- and tick-borne diseases uncommon. In 1972, DDT was banned due to its profound impact on wildlife. (The American bald eagle almost became extinct see Rachel Carson's classic book Silent Spring.) Vector-borne diseases then rose significantly, and illnesses such as Lyme disease and West Nile Fever spread across the country. Despite environmental reservations, spraying programs have resurfaced, although DDT was replaced by more environmentally friendly pesticides.

Cutaneous inflammatory pseudotumours

Cutaneous inflammatory pseudotumour is a term encompassing at least two main entities plasma cell granuloma and inflammatory myofibroblastic tumour. In particular, plasma cell granuloma can simulate the histopathological picture of cutaneous plasmacytoma or marginal zone lymphoma with prominent plasma cell differentiation 92 . Cutaneous plasma cell granuloma and inflammatory myofibroblastic tumour should probably not be lumped within the same diagnostic group 93,94 . Some cases of plasma cell granuloma may represent postinfective reactions (Epstein-Barr virus, Borrelia, mycobacteria, human herpesvirus-8).

Pseudolymphomas of the

Upper Dermis

With infectious organisms (Borrelia burgdorferi lymphocy-toma) commonly arise in regions with endemic B. burgdor-feri infection. There has also been a rise in the number of cases of Borrelia lymphocytoma in countries where Borrelia species are absent, in patients returning from travels in endemic regions.

The Spirochetes chapter

Brachyspira Aalborgi

Borrelia recurrentis Borrelia burgdorferi sensu stricto Borrelia garinii Borrelia a fzeiii This chapter addresses the bacteria that belong in the order Spirochaetales. Although there are at least eight genera in this family, only the genera Treponema, Borrelia, and Leptospira, which contain organisms pathogenic for humans, are addressed in this chapter. Although there are two other human intestinal spirochetes identified to date, Brachyspira (Serpulina)pilo-sicoli and Brachyspira aalborgi, that have been isolated from biopsy material from patients with intestinal disease, a clear association between their presence and intestinal disease has not been established. A few cases of intestinal spirochetosis with septicemia and dissemination have been reported thereby providing some support as to a pathogenic role for these organisms.8 their morphology (Figure 48-1) Treponema are slender with tight coils Borrelia are somewhat thicker with fewer and looser coils and Leptospira resemble...

Other cutaneous pseudolymphomas

Hemangioma Scalp Infant Histology

Previous paragraphs, the occurrence of other skin conditions simulating clinically and or histopathologically cutaneous lymphomas has been reported sporadically. Cases of inflammatory lesions of vitiligo and of eruption of lymphocyte recovery with histopathological features mimicking those of mycosis fungoides have been observed 99,100 . A condition termed 'annular lichenoid dermatitis of youth' has been reported recently as a simulator of mycosis fungoides, but it may in truth represent a variant of this disease in children 101 . Besides the entities listed in the paragraph on CD30+ cutaneous pseudolymphomas (see p. 163), we have rarely observed the presence of dense lymphoid infiltrates with scattered CD30+ cells in skin lesions of mycotic infections. True B-cell pseudolymphomas have been observed at the site of previous herpes zoster eruptions 102 . However, it must be stressed that only a few cases of clear-cut pseudolymphoma have been documented in association with herpes zoster...

Real Time PCR in Infectious Disease Diagnosis

The application of real-time PCR in infectious diseases enables the diagnosis of microbial pathogens both with accuracy and expediency. The clinical significance of using molecular diagnosis of infectious agents can be characterized by the following aspects. (1) Pathogens that show fastidious slow growth or inability to grow in vitro Mycobacterium, Legionella, Bartonella, Leptospira, Borrelia, Bordetella, Mycoplasma, and Tropheryma whippelii may require days or weeks of incubation under specific conditions (2) obligatory intracellular organisms (Chlamydia, Rickettsia, Coxiella, Ehrlichia, DNA and RNA viruses) (3) prior antibiotic use (4) biochemically inert for phenotypic characterization (5) additional waiting time for drug-resistance determination, (6) diagnostic speed from bench to bedside. Qualitative real-time amplification has outpaced conventional culture methods in detection of a long list of specific pathogens that are difficult to cultivate Bartonella henselae, Bordetella...

Symptoms And Signs

The postencephalitic syndrome refers to the development, following acute TBE, of chronic symptoms and signs. This may occur in a significant proportion of cases. A Swedish study cited 36 of patients during a median of 47 months of follow-up. A range of non-specific symptoms including headache, reduced stress tolerance, impaired memory, balance and coordination disturbance, hearing loss, tremor and chronic fatigue have been described. Differential diagnosis. Clues are given by the biphasic course, perhaps combined with pareses and polymorphonuclear leukocytosis. It should be noted that Lyme disease, caused by Borrelia burgdorferii, may be transmitted by the same vectors as TBE. The same is the case for Ehrlichia species. Both may cause disease that is similar to TBE, and co-infections between TBE and the other two agents have been described. As Lyme disease may be cured by antibiotic therapy, care must be taken to differentiate, and also to consider co-infections.

Application

Positive fourfold rise or fall in titer between acute and convalescent sera tested at the same time in the same test system Negative no current Infection or past infection, or patiBnt is immunocompromised and cannot mount a humoral antibody response, or convalescent specimen collected before increase In IgG (Lyme disease, Legionella

TLR2 TLR6 and TLR1

TLR2 recognizes compounds from many microorganisms, including peptidoglycan (PGN) and lipoteichoic acid from Gram-positive bacteria (e.g., Staphylococcus aureus or Bacillus subtilis), and lipoproteins from Gram-negative bacteria (e.g., Borrelia burgdorferi, Treponema pallidum, and Mycoplasma fermentans) (29-34). These ligands for TLR2 were confirmed by several studies. Lipoproteins or PGN were found to induce NF-kB activation in human embryonic kidney 293 cells or Chinese hamster macrophages transfected with TLR2. Furthermore, only anti-TLR2 antibody or a mutant TLR2 (TLR2-P681H, with inhibitory activity) were found to block TNF-a production induced by lipoprotein or whole Mycobacterium tuberculosis in human peripheral blood mononuclear cells or RAW264.7 macrophages. Akira's group also confirmed that macrophages form TLR2 knockout mice are hyposensitive to PGN derived from S. aureus (30,35). Other possible ligands of TLR2 are lipoarabinomannan from Mycobacteria (e.g., M. tuberculosis)...

Diagnosis

Drugs needlessly and risk suffering an ADE. A study of the diagnosis of Lyme disease in children revealed a correct diagnosis in only 51 of 146 patients. Thirty-eight percent were overdiagnosed, whereas a smaller percentage was underdiagnosed for Lyme disease (7). In the southwestern United States, many patients receive antibacterial drugs for treatment of pulmonary coccidioidomycosis. If the correct diagnosis were made, antibacterial therapy could be avoided, and only patients with complications of the primary pulmonary infection would require antifungal treatment (8). Appropriate therapy requires a thorough evaluation of the disease process and knowledge of the clinical entity.

FfiSjffi1

A43-year-old woman was referred to the Infectious Disease Clinic for recurrent symptoms beginning about 4 months after noticing a painful, swollen spot on her leg after removal of a tick. She had been treated with doxycycline for 14 days for presumed Lyme disease, documented by a positive IFA titer and presentation with migratory arthralgias, which were worse in the small joints of the hands. She also complained of fatigue, poor mentation, and occasional headaches. Because her1 symptoms recurred 2 months after treatment, she was unable to continue employment. Six months after afl course of amoxicillin and later two courses of ceftrias xone, she again became symptomatic. A Western blot and PCR of her serum were ordered. The Western blot result was equivocal but the PCR was positive for the agent of Lyme disease.

Concluding Remarks

The remarkable feature of the relationship between Leptospira and the other spirochetes is the near absence of a relationship. Although there are fundamental features that have been conserved among the sequenced spirochetes, such as the endoflagella and the systems for protein translocation, the systems used for nutrient acquisition and metabolism have virtually no similarities. However, these differences are probably related to the apparent extensive genome reduction that T. pallidum and Borrelia have undergone. 8. Fraser, C. M., Casjens, S., Huang, W. M., et al. (1997) Genomic sequence of a Lyme disease spirochaete, Borrelia burgdorferi. Nature 390, 580-586. 10. Glockner, G., Lehmann, R., Romualdi, A., et al. (2004) Comparative analysis of the Borrelia garinii genome. Nucleic Acids Res. 32, 6038-6046.

Bacterial

Staphylococcus aureus Beta-hetnolytjc streptococci Streptococci (other) Haemophilus influenzae Haemophilus spp. (other) Bacteroides spp. Fusobacterium spp. Neisseria gonorrhoeae Pseudomonas spp. Salmonella spp. Pasteurella multoclda Moraxella osloensis Kingelia kingae Moraxella catarrhalis Capnocytophaga spp. Corynebacterium spp. Clostridium spp. Peptostreptococcus spp. Eikenella corrodens Actinomyces spp. Mycobacterium spp. Mycoplasma spp. Ureaplasma urealyticum Borrelia burgdorferi FUNGAL

Relapsing Fever

Human relapsing fever is caused by more than 15 spe* cies of Borrelia and is transmitted to humans by the b *.r of a louse or tick. B. recurrentis is responsible for loused bome or epidemic relapsing fever. This spirochete & transmitted by the louse Pediculus humanus sub5pj humanus and disease is found worldwide humans arr the only reservoir for B. recurrentis. All other borreliaf that cause disease in the United States are transmitted via tick bites and are named after the species of tic' j usually of the genus Ornithodoros (soft tick), from whii they are recovered. Common species in the Uni' States include B. hermsii, B. turicatae, B. parkeri, and, ' mazzottii. Depending on the organisms and the disease their reservoir is either humans or rodents in most case J Although their pathogenic mechanisms are undedjf these spirochetes exhibit antigenic variability that i account for the cyclic fever patterns assodated with lift disease.

Viruses

When an etiologic agent cannot be isolated from an inflamed joint fluid specimen, either the absence of viable agents or inadequate transport or culturing procedures can be blamed. For example, even under the best circumstances, BorreJia burgdorferi is isolated from the joints of fewer than 20 of patients with Lyme disease. Nonspecific test results, such as increased white blood cell count, decreased glucose, or elevated protein, may seem to implicate an infectious agent but are not conclusive. A role has been postulated for the persistence of bacterial L-forms (cell-wall-deficient forms) in joint fluid after systemic infection, but such theories have not been proved. Overall Staphylococcus aureus is the most common etiologic agent of septic arthritis, accounting for approximately 70 of all such infections. In adults younger than 30 years of age, however, Neisseria gonorrhoeae is isolated most frequentiy. Haemophilus influenzae has been the most common agent of bacteremia...

The Spirochetes

She acquired the disease most likely from the bite of the nymphal form of the Ixodes tick infected with Borrelia burgdorferi. Even though symptoms were not manifest for a few weeks, her description of the initial lesion is consistent with erythema migrans (see Figure 48-3). 3. There are many reasons why patients do not respond to therapy. First, the patient could have another disease that is similar in symptoms but does not respond to the therapy for Borrelia. Second, the