Lyme & Tick Borne Disease Science

Alpha-gal syndrome is a food allergy to red meat and other products made from mammals. It's caused by a sugar molecule called alpha-gal, which is found in the tissues of all mammals except humans and other primates. In the US, AGS is usually triggered by the bite of a lone star tick, which transfers alpha-gal into the bloodstream. In some people, this causes mild to severe allergic reactions to red meat, such as beef, pork, or lamb. It also can cause reactions to other foods that come from mammals, such as dairy products or gelatins, magnesium stearate and other additives. When people who are allergic to alpha-gal eat beef, pork, lamb, or meat from other mammals, they have an allergic reaction that causes a range of symptoms, including a rash, nausea, vomiting, and diarrhea. Symptoms usually occur three to six hours after eating. In some cases, people may have an immediate life-threatening anaphylactic reaction that requires medical attention. There's currently no treatment other than avoiding red meat and other products made from mammals.

Visit Alpha Gal Foundation for more information.

There are a number of Survival strategies of Borrelia burgdorferi, the etiologic agent of Lyme disease. Borrelia releases antigens to neutralize antibodies which prevents bacteria from being tagged for destruction and induces immune cells to release anti-inflammatory cytokines which down regulates the immune response. 

Borrelia bacteria utilize a plethora of immune evasion strategies which involves capturing of host-derived complement regulators, terminating complement activation as well as shedding of cell-destroying complement complexes to manipulate and to expeditiously inhibit human complement. It inhibits the complement system by decreasing its ability to create pores into the bacteria for lysis Hide and Seek: How Lyme Disease Spirochetes Overcome Complement Attack

Borrelia bacteria disable the complement system through the regulation of outer surface proteins, the binding of complement regulators, and the use of tick salivary proteins. Resistance to antimicrobial proteins and ROS-mediated killing, as well as the disabling of macrophages, prevents the removal of B. burgdorferi spirochetes from the host. B. burgdorferi also evades detection through the antigenic variation of its outer surface protein VlsE. The Brilliance of Borrelia: Mechanisms of Host Immune Evasion by Lyme Disease-Causing Spirochetes

Borrelia can also suppress humoral immunity. Infection with B. burgdorferi results in strong antibody response induction, which can be used clinically as a diagnostic measure of exposure. However, clinical studies have shown a sometimes-precipitous decline of such antibodies shortly following antibiotic treatment, revealing a potential deficit in the host’s ability to induce and/or maintain long-term protective antibodies. B. burgdorferi infected mice show a similar rapid disappearance of Borrelia-specific antibodies after infection and subsequent antibiotic treatment. This failure was associated with the development of only short-lived germinal centers (locations from which long-lived immunity originates). The germinal centers showed structural abnormalities and failed to induce memory B cells and long-lived plasma cells for months after the infection, rendering the mice susceptible to reinfection with the same strain of B. burgdorferi. The inability to induce long-lived immune responses was not due to the particular nature of the immunogenic antigens of B. burgdorferi, as antibodies to both T-dependent and T-independent Borrelia antigens lacked longevity and B cell memory induction. Furthermore, influenza immunization administered at the time of Borrelia infection also failed to induce robust antibody responses, Suppression of Long-Lived Humoral Immunity Following Borrelia burgdorferi Infection

Persistence of spirochetes within macrophages provides a possible pathogenetic mechanism for chronic or recurrent Lyme disease in man. Moreover, we can reculture spirochetes from macrophages after infection. The fate of Borrelia burgdorferi, the agent for Lyme disease, in mouse macrophages. Destruction, survival, recovery. 

There is much controversy about whether Borrelia can survive after antibiotic therapy. Borrelia has some unusual survival tactics that make it understandable why there is so much controversy. In addition to immune evasion and suppression, there are also numerous studies that show persistence of Borrelia after antibiotic therapy.

Persisters are dormant variants of regular cells that form in microbial populations and are highly tolerant to antibiotics. Persister Cells Persister cells arise due to a state of dormancy, in which cells are metabolically inactive. They comprise a subpopulation of bacteria that become highly tolerant to antibiotics and reach this state without undergoing genetic change. Persister cells in biofilms appear to be responsible for the recalcitrance of chronic infections.  Antibiotics kill most cells; however persisters remain viable and repopulate biofilms when the level of antibiotics drops. Based on decades-old research, persisters are thought to be less sensitive to antibiotics because the cells are not undergoing cellular activities that antibiotics can corrupt, which results in tolerance (i.e., no growth and slow death) Bacterial Persister Cell Formation and Dormancy

Studies have been done in test tubes, mice, dogs, monkeys, ponies, and humans and there are now over 700 studies that show Borrelia can develop persister cells.     

One study showed that a small group of surviving cells formed a new subpopulation of antibiotic-tolerant cells, indicating that these are persisters. Borrelia burgdorferi, the causative agent of Lyme disease, forms drug-tolerant persister cells.   

Another study showed a persistent biofilm-like microcolony (MC) which could not be eradicated by doxycycline (Doxy), ceftriaxone (CefT), or vancomycin (Van), or Doxy+CefT or Van+CefT, but could only be eradicated by the persister drug combination daptomycin+doxycycline+ceftriaxone. Stationary phase persister/biofilm microcolony of Borrelia burgdorferi causes more severe disease in a mouse model of Lyme arthritis: implications for understanding persistence, Post-treatment Lyme Disease Syndrome (PTLDS), and treatment failure.

Some studies show that Borrelia bacteria that do survive are non-cultivatable. Generality of Post-Antimicrobial Treatment Persistence of Borrelia burgdorferi Strains N40 and B31 in Genetically Susceptible and Resistant Mouse Strains. Other studies show the Borrelia bacteria are not dividing, but still infectious - Persistence of Borrelia burgdorferi following antibiotic treatment in mice.  In one study, mice treated with antibiotics were consistently culture negative, but tissues from some of the mice remained PCR positive, and spirochetes could be visualized in collagen-rich tissues. Furthermore, when some of the antibiotic-treated mice were fed on by Ixodes scapularis ticks (xenodiagnosis), spirochetes were acquired by the ticks, as determined based upon PCR results, and ticks from those cohorts transmitted spirochetes to naïve SCID mice, which became PCR positive but culture negative. Results indicated that following antibiotic treatment, mice remained infected with nondividing but infectious spirochetes

One interesting study utilized a ceftriaxone treatment regimen in the mouse model that resulted in persistence of non-cultivable B. burgdorferi. Results confirmed previous studies, in which B. burgdorferi could not be cultured from tissues, but low copy numbers of B. burgdorferi flaB DNA were detectable in tissues at 2, 4 and 8 months after completion of treatment, and the rate of PCR-positive tissues appeared to progressively decline over time. However, there was resurgence of spirochete flaB DNA in multiple tissues at 12 months, with flaB DNA copy levels nearly equivalent to those found in saline-treated mice. Despite the continued non-cultivable state, RNA transcription of multiple B. burgdorferi genes was detected in host tissues, flaB DNA was acquired by xenodiagnostic ticks, and spirochetal forms could be visualized within ticks and mouse tissues by immunofluorescence and immunohistochemistry, respectively. Resurgence of persisting non-cultivable Borrelia burgdorferi following antibiotic treatment in mice.

Additional studies seem to confirm that antibiotic treatment is unable to clear persisting spirochetes, which remain viable and infectious, but are nondividing or slowly dividing. Ineffectiveness of tigecycline against persistent Borrelia burgdorferi, Variable manifestations, diverse seroreactivity and post-treatment persistence in non-human primates exposed to Borrelia burgdorferi by tick feeding.

Recognizing persister cells exist with Borrelia infections explains many of the controversial results in Lyme research.

There are numerous studies that show antibody levels can rise months after antibiotic treatment even without re-infection. This makes sense if persister cells become active once the environment is more favorable for growth.  

Studies in dogs showed that serum antibody levels to B. burgdorferi in all treated dogs declined after antibiotic treatment. However, in dogs that were kept in isolation for 6 months after antibiotic treatment was discontinued, antibody levels began to rise again, presumably in response to proliferation of the surviving pool of spirochetes. Persistence of Borrelia burgdorferi in experimentally infected dogs after antibiotic treatment

Another study describes the persistence of Borrelia burgdorferi in six patients. Borrelia burgdorferi was cultivated from iris biopsy, skin biopsy, and cerebrospinal fluid after antibiotic therapy for Lyme borreliosis. In two patients both IgM and IgG were negative. Patients may have subclinical or clinical disease without diagnostic antibody titers. Persistence of B. burgdorferi cannot be excluded when the serum is negative for antibodies against it. First Isolation of Borrelia burgdorferi from an Iris Biopsy (1993)  

Culture of body fluids and tissues was performed in a randomly selected group of 12 patients with persistent Lyme disease symptoms who had been treated or who were being treated with antibiotics. Cultures were also performed on a group of ten control subjects without Lyme disease. The cultures were subjected to corroborative microscopic, histopathological and molecular testing for Borrelia organisms in four independent laboratories in a blinded manner. Results: Motile spirochetes identified histopathologically as Borrelia were detected in culture specimens, and these spirochetes were genetically identified as Borrelia burgdorferi by three distinct polymerase chain reaction (PCR)-based approaches. Spirochetes identified as Borrelia burgdorferi were cultured from the blood of seven subjects, from the genital secretions of ten subjects, and from a skin lesion of one subject. Cultures from control subjects without Lyme disease were negative for Borrelia using these methods. Conclusions: Using multiple corroborative detection methods, we showed that patients with persistent Lyme disease symptoms may have ongoing spirochetal infection despite antibiotic treatment. Persistent Borrelia Infection in Patients with Ongoing Symptoms of Lyme Disease

In a review of 50 studies, 18 were included where the tests were commercially available, and samples were proven to be positive using serology testing, evidence of an erythema migrans rash, and/or culture. Additional requirements were a test specificity of ≥85% and publication in the last 20 years. The weighted mean sensitivity for all tests and for all samples was 59.5%. Individual study means varied from 30.6% to 86.2%. Sensitivity for each test technology varied from 62.4% for Western blot kits, and 62.3% for enzyme-linked immunosorbent assay tests, to 53.9% for synthetic C6 peptide ELISA tests and 53.7% when the two-tier methodology was used. Commercial test kits for detection of Lyme borreliosis: a meta-analysis of test accuracy

Standard Lyme testing is based on an intact antibody response. The studies above show that Lyme can neutralize antibodies and that patients can be seronegative and still have infectious disease. This decreases the effectiveness of antibody testing. Standard testing is also only based on a single strain of Borrelia. There are several strains that can infect humans. The AcuDart Lyme Disease Screening Test identifies antibodies to the following nine Borrelia species: B. burgdorferi B31, B. burgdorferi 297, B. californiensis, B. mayonii, B. afzelii, B. garinii, B. spielmanii, B. bissettii and B. valaisianaa. Most Lyme disease tests look for only one species, B. burgdorferi B31, and therefore miss many positive cases. 

Traditional Lyme testing has also removed 2 antibodies that are very Lyme specific. Tests that include these extra antibodies and more species of Borrelia can be more accurate as long as physicians are aware the Lyme vaccine can trigger these extra 2 bands.   

Patient surveys show that 84% of patients improve with longer treatments for Lyme symptoms.  The studies that concluded longer courses of antibiotics do not improve patient symptoms have a poor study design for a bacteria that is persistent. The 2 studies that conclude that long term antibiotics are not effective did not assess patients symptoms until 6 months after the antibiotic treatment was discontinued. If Lyme bacteria persist, as indicated by research, waiting to assess the effectiveness of the antibiotics allows the bacteria to reemerge and symptoms to return.    

In a study using a treatment designed to address biofilm and persistence, the 8 major symptoms in PTLDS all improved. Treatment with dapsone combined with other antibiotics and agents that disrupt biofilms decreased the severity of eight major Lyme symptoms and improved treatment outcomes among patients with chronic Lyme disease/PTLDS and associated coinfections.     

Finally, patient outcomes were evaluated from a cohort of 210 Canadian Lyme disease patients seeking treatment at one US Lyme disease clinic following a treatment regimen conforming to the ILADS treatment guidelines. It was found that the majority of Lyme disease patients at the clinic responded positively to treatment and a significant (p < 0.05) decrease in symptoms was observed over time. Lyme Disease Patient Outcomes and Experiences; A Retrospective Cohort Study