Since the 90’s, there has been a continuous debate between the persistence and non-persistence of Lyme Disease. On each side of the battle, there seems to be a lot of half-truths.
On one hand, the Centers for Disease Control and Prevention (CDC) believe that 30 days of antibiotics are enough to kill the bacteria and continuously assert that the persistence of spirochetes is not the reason Lyme Disease sufferers remain ill after treatment.
On the other hand, the International Lyme and Associated Diseases Society (ILADS) challenges this notion and has provided an abundance of literature on the persistence of spirochetes as the driver of disease and that long-term antibiotics are essential to treat people from Lyme Disease. However, this is cyclical and both sides ignore the main driver of disease: immunosuppression.
Even though there is plenty of science that demonstrates what Lyme Disease and its Outer Surface Proteins (Osps) do inside the human host, both sides of the Lyme debate seem to ignore this fact.
There are two reasons we need to expose the truth about why Lyme Disease is such a “controversy”.
- There is an abundance of stakeholders who either profit and/or at least benefit from the false persistence vs non-persistence dichotomy. So, by exposing the truth about the immunosuppressive effects of Lyme Disease, billions of dollars could potentially be lost.
- Agencies like the CDC/IDSA/ALDF in the US and AAMI in Canada continue to assert that any evidence-based activists that challenge their fraudulent guidelines are merely pseudoscientists. In brief, “pseudoscience consists of statements, beliefs, or practices that are claimed to be both scientific and factual, but are incompatible with the scientific method” (Pseudoscience, 2018). When it comes to the Lyme debate, any information that challenges either side of the debate get brushed off as pseudoscience.
The purpose of this blog is to examine facts and literature from scientists who are considered “credible” in the medical world. This includes: systematic observation, measurement, experiment, formulation, testing, and modification of hypotheses.
Another thing to keep in mind is the disease mechanisms provided in this blog are also shared by other abused groups such as Fibromyalgia (FM), Myalgic Encephalomyelitis (ME), Chronic Fatigue Syndrome (CFS), Gulf War Illness (GWI) etc. (That will be explained in another blog).
All that said, the key purpose of this blog is to help show Lyme activists that OspA, Pam3cys, and immunosuppression are key factors that both sides of the Lyme debate seem to ignore.
In order to properly understand what Lyme Disease does to the body, it is essential for Lyme activists to begin speaking about the Osps that Spirochetes shed in order to evade the immune system.
Borrelia species undergo constant antigenic variation, whereby they shed Osps (i.e OspA) as a means of evading the immune system. Osps like OspA are a key mechanism when it comes to understanding why Lyme Disease persists after treatment. In addition, OspA is also a key factor in why most Lyme Disease sufferers are infected with the same reactivated viruses and opportunistic infections.
Spirochetes are a relapsing fever organism. They are constantly pinching off their Osps to evade the immune response through a mechanism that Alan Barbour calls ‘blebbing’ (Barbour, Todd & Stoenner, 1982). These shed blebs consist of lipoproteins known as variable major proteins (Vmps).
(Barbour, Todd & Stoenner, 1982).
Since the definition of Lyme Disease was fraudulently changed in 1994, most of the current Lyme literature published from CDC/IDSA/NIH is based off of pseudoscience/research fraud. Thus, in order to properly understand the immunosuppressive effects of Lyme Disease, any research used to expose the truth has be based off studies that show its true disease mechanisms in parallel with similar types of organisms (Toll-like receptor agonists).
Toll Like Receptors (TLR):
Toll-like receptors “are a class of proteins that play a key role in the innate immune system” (Toll-like Receptor, 2019, p. 1). TLR “are single, membrane-spanning, non-catalytic receptors usually expressed on sentinel cells such as macrophages and dendritic cells, that recognize structurally conserved molecules derived from microbes” (Toll-like Receptor, 2019, p. 1).
Simply put, are immune receptors that participate in the first line of defense against invading pathogens. They play a critical role in the innate immune response by recognizing the distinct molecular structure of invading pathogens.
TLR 2’s mechanisms: TLR2 manages mycobacteria or fungal endotoxins
“The innate immune system utilizes multiple receptors to recognize fungal pathogens, and the net inflammatory response is controlled by interactions between these receptors. Many fungi are recognized, at least in part, by Toll-like receptor 2 (TLR2).”(Goodridge & Underhill, 2008).
“The agonists include bacterial lipoproteins, Gram-positive bacterial lipoteichoic acids, mycobacterial lipomannans and lipoarabinomannans, pneumococcal peptidoglycans, and Treponema-derived glycolipids. Thus, LBP and CD14 may function to disaggregate and deliver a variety of acylated microbial agonists to the TLR2 system.” (Goodridge & Underhill, 2008).
Although this may be difficult to understand, understanding this information is imperative when it comes to understanding how OspA operates in the human body. Here are some of the organisms that bear TLR2 agonists.
Pam3cys is a “TLR1/TLR2 agonist” (Pam3Cys, 2018). More specifically, it is a synthetic analog of the triacylated N-terminal part of bacterial lipoproteins” (Pam3Cys, 2018). Simply put, Pam3cys is a molecule that stops the immunity chain reaction in the immune systems Toll Like Receptors.
In this paragraph, we will explore the structural similarities between Pam3cys and OspA. Scientists from the Immunobiology Research Institute published a study that found “OspA is a 30-kDa membrane-associated lipoprotein with a typical tripalmitoyl-S-glycerylcysteine (Pam3Cys) moiety covalently attached to the N terminus of the protein.” (Goodridge & Underhill, 2008). Another study done by Heilbrun et al (2003) from the Department of Pathology, University of Utah, in Salt Lake City found that “OspA is one of the tripalmitoyl-S-glyceryl-cysteine (Pam3Cys)-modified lipoproteins abundantly expressed on the surface of B. burgdorferi in the gut of the unfed tick.” (Heilbrun et al, 2003). Finally, in one of their many patents, Dattwyler, Gomes-Solecki & Seegers (2009) found that:
The primary translation product of the full-length B. burgdorferi OspA gene contains a hydrophobic N-terminal sequence, of 16 amino acids, which is a substrate for the attachment of a diacyl glyceryl to the sulflhydryl side chain of the adjacent cysteine (Cys) residue (at position 17). Following this attachment, cleavage by signal peptidase II and the attachment of a third fatty acid to the N-terminus occurs. The completed lipid moiety, a tripalmitoyl-S-glycerylcysteine modification, is termed Pam3Cys (or is sometimes referred to herein as Pam(3)Cys or Pam3Cys)” (p.1).
In summary, “Pam3Cys modification of bacterial lipoprotein has adjuvant properties independent of TLR2 signaling” (Heilbrun et al, 2003). When you understand that Pam3Cys and OspA are lipoproteins (can cause immunosuppression), it is clear to see that more research needs to be done by agencies like ILADS if they want to figure out why Spirochetes persist in up to 50% of people after long term antibiotic treatment.
The spirochetal lipoproteins are TLR 2/1 agonists (agonists are a substance that initiates a physiological response when combined with a receptor). TLR 2 agonists are fungal-like because they cause permanent immune suppression in the Toll Like Receptors that handle fungal antigens.
OspA/Pam3cys is managed by TLR2
As previously mentioned, OspA and Pam3cys are TLR 2/1 agonists. Heilbrun et al (2003) found that “Toll-like receptor 2 (TLR2) is a transmembrane signal transducer for tripalmitoyl-S-glyceryl-cysteine (Pam3Cys)-modified lipoproteins, including OspA from the Lyme disease spirochete Borrelia burgdorferi.” (p.2).
Furthermore, Pam3Cys-modified proteins, such as OspA, have been reported to act as potent inflammatory stimulants though the toll-like 2 receptor mechanism (TLR2)” (Dattwyler, Gomes-Solecki & Seegers 2009).
As confusing as this may sound to people who have no science backgrounds, what this means is that there is plenty of literature that proves that OspA/Pam3cys are TLR 2 agonists that cause a cytokine storm that can lead to a form of sepsis induced immunosuppression (see other blogs).
OspA/TLR2 agonists are much more toxic and stealth than typical bacteria
One thing that is important for activists to understand is that unlike sepsis caused by regular bacteria (managed by TLR 4 and is generally reversible), sepsis caused by TLR 2 agonists can cause permanent and irreversible damage.
More specifically,”TLR2 mediates inflammatory responses to a wide variety of lipidated microbial components, including bacterial lipoproteins, atypical lipopolysaccharides, and lipomannans” (Kelley, Ranoa & Tapping, 2013). Among these microbial agonists, bacterial lipoproteins are by far the most potent (Kelley, Ranoa & Tapping, 2013).
Moreover, “it became apparent that specific TLRs such as TLR2 and TLR4 play differential roles in the activation of the various arms of the innate immune response” (Kullberg, Meer & Netea, 2007). In the Journal of Immunology, Akira, Hayashi, & Nobrega (2005) published a study whereby “experiments with TLR2-knockout mice confirmed that the inhibitory effects of Pam3Cys depend on the expression of TLR2” (p.6640).
Furthermore, their study concluded that “Pam3Cys keeps the precursors on a more immature stage” (Akira, Hayashi, & Nobrega, 2005). Taken together, the study done by Akira, Hayashi, & Nobrega (2005) “suggest that TLR4 signaling favors B lymphocyte maturation, whereas TLR2 arrests/retards that process, ascribing new roles for TLRs in B cell physiology.” (p. 6645). In sum, there is plenty of research that shows that OspA/Pam3cys are TLR 2 agonists (fungal like) that can cause immature B-cells. An antibody deficient form of immunosuppression.
OspA is the main driver in the persistence of spirochetes
Now that we understand how OspA affects the host, the next part of this blog will use published evidence-based literature that proves that OspA is the main driver of disease in Lyme patients.
In one study, researchers found that vaccinating with OspA caused the same neuro-immune outcomes as tick-borne Lyme Disease.
Alaedini et al (2003) reported that six patients “developed neuropathy or cognitive impairment, within several days to 2 months, following vaccination with the OspA antigen of Borrelia burgdorferi (p. 165). Furthermore, two of the patients developed cognitive impairment, one chronic inflammatory demyelinating polyneuropathy (CIDP), one multifocal motor neuropathy, one both cognitive impairment and CIDP, and one cognitive impairment and sensory axonal neuropathy” (Alaedini et al. 2003, p. 165). In the end, the study concluded that the “similarity between the neurological sequelae observed in the OspA-vaccinated patients and those with chronic Lyme disease suggests a possible role for immune mechanisms in some of the manifestations that are resistant to antibiotic treatment.” (Alaedini et al. 2003, p. 165). As you can see, OspA was the main driver of disease in this study.
In another study (with Gary Wormser) done on dogs, Chiao, Schwartz, Villalon, & Wormser (2000) found that “after exposure to either the unaltered vaccine preparation or OspA prepared in saline, normal lymphocyte responses to the mitogens concanavalin A, phytohemagglutinin-M or pokeweed mitogen, or the antigen BCG were consistently reduced” (p. 193). They found that “the magnitude of modulation was directly dependent on the quantity of OspA” (Chiao, Schwartz, Villalon, & Wormser, 2000, p. 196). Namely because they found that, “OspA interferes with the response of lymphocytes to proliferative stimuli including a blocking of cell cycle phase progression” (Chiao, Schwartz, Villalon, & Wormser, 2000, p. 196).They concluded that “future studies designed to delete the particular region or component of the OspA molecule responsible for this effect may lead to improved vaccine preparations (Chiao, Schwartz, Villalon, & Wormser, 2000, p. 196). So, my question is, where are these studies?
In this study, one of the OspA vaccine trial administrators of the LYMErix vaccine raised caution neurological effects of OspA. Marks (2011) found that a “wide range of neurological complications have been reported via the medical literature and the VAERS system after vaccination with recombinant outer surface protein A (OspA) of Borrelia” (p.89). After looking at the Vaccine Adverse Event Reporting System (VAERS) about the LYMErix vaccine, he examined causation in 24 patients reporting neurological adverse events (AE) after vaccination with LYMErix, out of a group of 94 patients reporting adverse events after LYMErix vaccination (Marks, 2011, p. 89). Marks (2011) evaluated “five reports of cerebral ischemia, two transient Ischemic attacks, five demyelinating events, two optic neuritis, two reports of transverse myelitis, and one non-specific demyelinating condition” (p. 89). In the end, Marks concluded that caution should be raised “on not actively looking for neurologic AE, and for not considering causation when the incidence rate is too low to raise a calculable difference to natural occurrence.” (Marks, 2011, p. 89). With studies like this available on public record, why are organizations like ILADS not looking closer at the effects of OspA?
At the 1998 FDA Vaccine Meeting on LYMErix, Benjamin Luft discussed how you can’t tell the difference between chronic neurological Lyme Disease and people who were injured from the LYMErix vaccine. Luft stated “the point that I wanted to make in regard to the study is that there is very heavy dependence on serologic confirmation. And when we start thinking about the adverse events” (Lyme, n.d). In addition, “it was stated originally when we got an overview of the disease that the disease is really quite protean. And actually, the adverse events are very similar to what the disease manifestations are” (Lyme, n.d). Finally, Luft claimed that “if you start to kind of say well how often do you actually become seropositive, you can start to have a different take on when someone has an adverse event or whether it is disease specific or infection specific versus vaccine specific” (Lyme, n.d). So, if you can’t tell the difference between infection and LYMErix damage, does that mean OspA is the main driver of disease? Why are both the CDC and ILADS refusing to answer these questions?
Even when you look at Dave Persing’s patent on OspA, it clearly mentions that OspA can cause disease indistinguishable from Lyme acquired from a tick bite. It states, “Additional uncertainty may arise if the vaccines are not completely protective; vaccinated patients with multisystem complaints characteristic of later presentations of Lyme disease may be difficult to distinguish from patients with vaccine failure” (Persing, n.d.).
Because of the Bayh-Dole Act of 1980, the CDC was able to patent the main driver of disease in Lyme Disease patients.
According to the science presented, it’s clear OspA affects the immune system. OspA, like other lipoproteins can cause serious damage to the brain. In their study, Kim & Palmore (2017) found that “OspA from B. burgdorferi is able to cross the BBB by binding to CD40 of brain-microvascular endothelial cells” (p.3). Like all the other studies, they also found that “OspA in the brain activates TLR2 on microglia and astrocytes, which initiates immune activity and causes damage to brain tissue” (Kim & Palmore, 2017, p. 3). In the end, the study showed that OspA significantly decreased the number of presynaptic sites, whereas it did not affect the number of postsynaptic sites” (Kim & Palmore, 2017, p. 3). In sum, the results of this study “suggests “that ospA directly disrupts neuronal function by damaging pre synapses exclusively” (Kim & Palmore, 2017, p. 3). Thus, not only does OspA affect the immune system, it also can cause damage to the brain.
Based on a meta-analysis of the available data (and the date on other TLR 2 agonists/lipoproteins, it appears that OspA has the ability to cause immunosuppression and brain damage. OspA, like other TLR 2 agonists, can lead to immature B-cells which consequently impairs the immune system from responding to antigens that are managed by TLR 2.
In addition, OspA can cause cross-tolerance (see other blogs) whereby the immune system is no longer able to recognize and fight off other viral, parasitic, and bacterial pathogens.
Other Toll Like Receptors affected by Lyme Disease (OspA)
TLR4 (lipopolysaccharides, known as the more typical bacteria)
One study showed that “the role of IRAK4 kinase activity in TLR2 and TLR4 homotolerance and TLR2-mediated heterotolerance of TLR” (Medvedev, Pennini, Vogel & Xiong, 2013, p. 299). Furthermore, “IRAK4 kinase activity is dispensable for endotoxin tolerance, as evidenced by suppressed p-ERK, p-JNK, and p-p38, IκB-α degradation, induction of proinflammatory cytokines, and up-regulation of negative regulators IRAK-M and A20” (Medvedev, Pennini, Vogel & Xiong, 2013, p. 299). In contrast, IRAK4 kinase activity is critical for TLR2-elicited inhibition of Pam3Cys- and LPS-inducible p-JNK and p-p38 MAPKs. Studies are in progress to discern the molecular mechanisms by which IRAK4 kinase activity regulates TLR signaling, tolerance, and sensitivity to microbial infections, septic shock, and autoimmunity” (Medvedev, Pennini, Vogel & Xiong, 2013, p. 299). That being said, this data suggests that tolerance caused by TLR 2 agonists can also lead to cross tolerance to pathogens managed by TLR 4.
In this study, researchers found that “Lipoproteins from Borrelia burgdorferi, the agent of Lyme disease, activate inflammatory cells through TLR2 and TLR1 (Cabral et al, 2006, p. 849). Cabral et al (2006) showed that “stimulation of human monocytes with B. burgdorferi lysate, lipidated outer surface protein A, and triacylated lipopeptide Pam3CysSerLys4 results in the up-regulation of both TLR2 and TLR1 but the down-regulation of TLR5, the receptor for bacterial flagellin, and that this effect is mediated via TLR2” (p. 849). In the end, the results of this study indicate that diverse stimuli can cause differential TLR expression, and we hypothesize that these changes may be useful for either the pathogen and/or the host” (Cabral et al, 2006, p. 849). Therefore, TLR 5 are also affected by OspA’s immune altering properties.
TLR7/9 (Herpesviruses, Epstein-Barr and all other viral infections)
It was difficult to find any articles on OspA and TLR 7/9 cross-tolerance. However, other TLR agonist mycobacterium show date parallel to OspA. In one study, researchers found that “TLR2 signaling by Mycobacterium tuberculosis or other TLR2 agonists inhibited TLR9 induction of IFN-I and IFN-I-dependent MHC-I Ag cross processing” (Abbott, 2012, 1019). In addition, “TLR2 also inhibited induction of IFN-I by TLR7, another MyD88-dependent IFN-I-inducing receptor, but did not inhibit IFN-I induction by TLR3 or TLR4 (both Toll/IL-1R domain-containing adapter-inducing IFN-β dependent, MyD88 independent)” (Abbott, 2012, 1019). Finally, because IRAK1 is required for TLR7/9-induced IFN-I production, we propose that TLR2 signaling induces rapid depletion of IRAK1, which impairs IFN-I induction by TLR7/9” (Abbott, 2012, 1019). In sum, this study found that “TLR2 inhibits IFN-I induction by TLR7/9, may shape immune responses to microbes that express ligands for both TLR2 and TLR7/TLR9, or responses to bacteria/virus coinfection” (Abbott, 2012, 1019). Therefore, like m. Tuberculosis, OspA is a powerful TLR 2 agonist that has a direct affect on inducing TLR 7/9 ability to clear out viruses. More research needs to be done. It is not a coincidence that Lyme Sufferers all suffer from infections like EBV and CMV.
If ILADS truly cares about the welfare of Lyme patients, they must properly study the neuro-immune effects that OspA has on the human host. From the literature available, it appears OspA or TLR2/1 agonists are toxic, and that the body shuts down the immune system to avoid a septic cytokine storm. Xiong et al (2015) from the Department of Microbiology and Immunology at the University of Maryland School of Medicine found that “Endotoxin tolerance protects the host by limiting excessive ‘cytokine storm’ during sepsis, but compromises the ability to counteract infections in septic shock survivors” (p. 172). Furthermore, “it reprograms Toll-like receptor (TLR) 4 responses by attenuating the expression of proinflammatory cytokines without suppressing anti-inflammatory and antimicrobial mediators, but the mechanisms of reprogramming remains unclear” (Xiong et al, 2015).
In another study, researchers found that the “development of endotoxin tolerance following the initial cytokine storm phase of sepsis is thought to protect the host from an over exuberant immune response and tissue damage but at the same time, may render the host immunocompromised and more susceptible to secondary infection” (Medvedev, Pennini, Vogel, & Xiong, 2013). As you can see, the complexities of Lyme Disease go far beyond what both ILADS and CDC lead us to believe.
Based on the research studies provided in this blog, we know that spirochetes are constantly undergoing antigenic variation by shedding their outer surface to avoid immune detection.
In addition, we learned that these shed blebs are covered in fungal-like Osps that have the ability to cause sepsis-induced immunosuppression in its victims.
Spirochetes shed these OspA “blebs” that get eaten up by immune cells.
As a result, B-cell germinal centers often collapse which can prevent B-cells from properly maturing (Leading to a reduction in detectable antibodies/false negative ELISA tests).
This type of immunosuppression can lead to an immune system that becomes tolerant to opportunistic infections and reactivated viruses (Epstein-barr, HHV-6, cytomegalovirus, coxsackie, zoster, candida, mycoplasma, streptococcus, etc.).
In at least half the cases, Lyme Disease can cause serious B-cell immune disorders (immature B-cells, not a lack thereof). Think of OspA as the detonator of this neuro-immune nightmare.
Therefore, despite what ILADS claims, the persistence of spirochetes is not the main driver of disease in Lyme patients; it’s the exposure to fungal-like antigens (Osps/Pam3cys) that creates an environment where reactivated viruses and opportunistic infections can thrive due to tolerance and cross-tolerance in the immune system.
Being that OspA is the driving force behind Lyme Disease, how convenient is it that the CDC removed OspA from the “case definition” at the same time the vaccine was on trial?
From the multitude of evidence-based studies used to source this blog, it is clear that you cannot inject people with TLR 2/1 agonists because they cause immunosuppression (B-cell immune disorders).
All fungal bearing vaccine attempts managed by TLR2/1 were epic failures causing the same outcome in which they “intended” to prevent (Tuberculosis, Brucella, HIV, Borrelia are parallel models in fungal-like vaccines).
If OspA alone causes the same multi-system disease, when are ILADS going to help fight to include this for a case definition that encompasses all cases of Lyme Disease?
It’s important to note that these disease mechanisms are shared by many other abused groups (FM, ME, CFS, GWI, etc.), and not all are caused by Lyme Disease. This is one of the key reasons why these are the most common misdiagnosis (for autoimmune outcome information, see other blogs).
These diseases are caused by TLR 2/1 agonists that cause a fungal-like sepsis which can lead to permanent immunosuppression. In the end, we all need ILADS to acknowledge and conduct research on the neuro immune- effects of OspA. Something needs to change, or else sepsis-induced (antibody deficient) immunosuppression will become (if it already isn’t) the largest genocide in recorded history.
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