Lyme disease: Chronic Lyme (part 7)

It is not clear why some Lyme patients are asymptomatic while others have debilitating symptoms, and why some develop EM and others don’t. Research foci on this topic include efficiency of host immune response; what amount of Borrelia introduced by a bite is always enough to provoke seroconversion compared to the amount necessary to provoke symptoms; host genetic factors; and combinations of these.

Borrelia is noteworthy for its numerous mechanisms for host immune evasion. It is able to change the proteins on its surface. An example of this is change from an OspA protein dominant surface to an OspC dominant one when blood swallowed by the tick reaches the midgut, where Borrelia lives prior to infecting humans. OspA promotes adhesion to the midgut. OspC allows Borrelia to establish infection in the new host. In the host, the surface protein OspC is downregulated while upregulating VlsE. This genes associated with VlsE undergo a complicated process called recombinational switching that means the sequence of this protein is highly variable.

Borrelia is also able to bind and deactivate complement proteins. It can also bind extracellular matrix proteins and use matrix metalloproteinases to enhance their ability to enter tissues. The body demonstrates a variety of immune mechanisms to response to Borrelia. IL-4, IL-10, IL-12p70, IFN-g and TNF-a are secreted by dendritic cells. IL-1b, IL-6, IL-8, IL-10, IL-12p70, TNF-a, RANTES, MCP-1, MIP-1a, MIP-1b and eotaxin are also elevated in whole blood during infection. Increased TNF-a secreting dendritic cells and T helper type 1 inflammatory responses may be associated with effective mitigation of Lyme disease. Borrelia has been shown to induce TNF-a secretion and degranulation in mast cells, but only low level degranulation and only at extremely high spirochete to mast cell ratio, such as would likely be impossible inside the body. (Talkington 1999) The immune response to Lyme disease has been thoroughly studied by many groups around the world and is well described for most stages of disease.

This characterized immune response has caused some to hypothesize that Lyme disease induces an autoimmune activity that continues after infection. Patients with antibiotic refractory Lyme arthritis, but not those who respond to antibiotics, more often carry the HLA type DRB1*0401. This is also associated with a more severe presentation of rheumatoid arthritis. It is thought that this activity perhaps persists after resolution of infection.

What is interesting about this is that eventually all cases of Lyme arthritis resolve, so does that mean that the autoimmune activity goes away? However, Behcet’s syndrome is known to spontaneously resolve over time, and rheumatic heart disease following Streptococcus infection also eventually wanes. Both of these fit the classic definitions of autoimmune disease.

Plasma cells from joint tissue of patients with antibiotic refractory Lyme arthritis show that antibiotics to Borrelia become continually robust, despite PCR negative results for Borrelia. (Ghosh 2005) Mouse studies have demonstrated that antigenic material can persist in joints after Lyme infection, despite repeated failure to culture and PCR negativity. (Bockenstedt 2012)

The fact that a number of patients go on to suffer post-Lyme disease treatment syndrome, as well as relapsing-remitting Lyme arthritis, has caused people to wonder whether or not Borrelia persists inside the body and causes a persistent infection. One important finding is that spirochetes have been isolated from ACA lesions more than ten years after infection (ACA is a skin manifestation of European Lyme disease, much like EM in the US.) Borrelia may also be able to hide inside host cells. In vitro, Borrelia has been able to remain viable in various types of cells for several weeks.

Imaging with electron microscopes has found that structures resembling spirochetes persist in synovium and ligaments.   Antibiotic refractory Lyme arthritis patients test positive for Borrelia DNA in their synovial fluid or tissue, sometimes for up to nine months after treatment (Lipowsky 2003). Such positivity is not associated with poor outcome, recurrence or longer duration of arthritis. Additionally, PCR is not able to distinguish between living and dead organisms. One study tried to identify mRNA transcripts in such PCR+ samples, which would indicate that these organisms were making proteins and viable. They were unable to detect mRNA transcripts. (mRNA is difficult to isolate as it is easily and quickly degraded, so I don’t assume that a researcher failing to isolate mRNA means the cell is not viable.) Wormser also published a paper regarding the presence of a few spirochetes in culture of synovial fluid from an untreated patient (Wormser 2012). These organisms could not be subcultured, which means they were not able to make new cells. They also could not move and seemed to be trapped in some sort of protein complex. Such findings have spurred forward the idea that the immune response to Lyme disease in some way attenuates the organisms and prevents them from being infectious, but leaves them structurally intact. There is precedent for this elsewhere in infectious disease (attenuated spores). Organisms incapable of producing new cells can still incite a host responsible, albeit in a much more limited fashion.

By contrast, three papers have reported that Borrelia has been grown in culture from synovium or tendon up to ten months after antibiotic treatment. (Frey 1998) I find this noteworthy as Borrelia is quite difficult to grow in culture and thus these successes indicate a vigorous and viable organismal state. Borrelia is known to exhibit multiple morphological states: spirochete, spheroplast and cystic/ roundbody forms. Round body forms are more common during lag phase growth, when the cells are maintaining and not increasing count. Round bodies (Brorson 2009) are formed during times of selective pressure (such as application of antibiotics), but can reversibly reform spirochetes. Each form has variable antibiotic susceptibility, and common first line Lyme treatments are not efficacious against roundbodies. However, there is not proof that roundbodies persist in humans during disease, especially as successful cultivation has involved spirochetes, and spirochete-like structures have been seen using imaging techniques, rather than roundbodies. More research is needed into this area. In my opinion, I think there is a chance that roundbody forms persist and become integrated into tissue. I am not convinced they later become spirochetes, but I don’t see why it’s not possible.

Patients with chronic Lyme sometimes tell me that their symptoms cycle as a result of Herxheimer reactions. I looked it up because I had only ever heard of Herxheimer reactions due to syphilis, but it is in fact seen in other infections. Herxheimer reactions are caused by the release of endotoxins from dying organisms when treating with antibiotics.

I want to summarize a few points here, mostly based on what I found on Lyme websites. Doctors who treat serology negative, chronic Lyme posit the following:

  • Borrelia persist in the body to cause long term symptoms.
  • When Lyme disease is treated with first line antibiotics, the Borrelia are driven to form round bodies, which are resistant to antibiotics.

However, many also posit:

  • Patients are persistently seronegative because of immune evasion by forming these roundbodies.
  • Patients cycle with flaring symptoms every four weeks because these round bodies make new viable cells every four weeks. This concept is based upon remarks of Dr. Burrascano:

“It has been observed that symptoms will flare in cycles every four weeks. It is thought that this reflects the organism’s cell cycle, with the growth phase occurring once per month (intermittent growth is common in Borrelia species). As antibiotics will only kill bacteria during their growth phase, therapy is designed to bracket at least one whole generation cycle. This is why the minimum treatment duration should be at least four weeks. If the antibiotics are working, over time these flares will lessen in severity and duration. The very occurrence of ongoing monthly cycles indicates that living organisms are still present and that antibiotics should be continued. With treatment, these monthly symptom flares are exaggerated and presumably represent recurrent Herxheimer-like reactions as Bb enters its vulnerable growth phase then are lysed.”

  • So following this logic, the Borrelia stay dormant for four weeks, then quickly change morphology and generate new cells. During this time, they are susceptible to antibiotics that target cell wall division, and are killed. Many Lyme patients are told this is the reason for their monthly flare and that they are experiencing Herxheimer reactions.

Okay, I have some things to say about this. The first is that I can’t find any evidence for this four week growth cycle. Borrelia is slow growing, but not that slow.

Second, Herxheimer reactions are associated with the release of toxins from the interior of the cell when it is lysed. I hear a lot about Lyme toxins and that you need to detox them out. Borrelia does not make any known toxins. None.

Third, I have heard that these roundbodies contain lots of “babies” and release them during these four week cycles and that is what causes the Herx type reaction rather than toxins. I agree roundbodies are real. But they represent one cell. Electron microscopy has shown a flagellum inside the cell, so I think this might read as confusing. One spirochete turns into one roundbody, which can turn back into one spirochete. It is not a reproductive reservoir that then releases lots of spirochetes at once. In theory, a large reintroduction of spirochetes could happen when all the roundbodies turn back into spirochetes, but that’s not the same thing. And regardless, we are likely talking about a small number of organisms, here. Because if there were so many of them, they would be detected readily on biopsy.

Up next: Co-infections.

 

References:

Wormser GP, Nadelman RB, Schwartz I. The amber theory of Lyme arthritis: initial description and clinical implications. Clin Rheumatol 2012;31:989-94.

Lipowsky C, Altwegg M, Michel BA, Bruhlmann P. Detection of Borrelia burgdorferi by species-specific and broad-range PCR of synovial fluid and synovial tissue of Lyme arthritis patients before and after antibiotic treatment. Clin Exp Rheumatol 2003; 21:271.

Andrea T. Borchers, Carl L. Keen, Arthur C. Huntley, M. Eric Gershwin. Lyme disease: A rigorous review of diagnostic criteria and treatment. Journal of Autoimmunity 57 (2015) 82-115.

Ghosh S, Steere AC, Stollar BD, Huber BT. In situ diversification of the antibody repertoire in chronic Lyme arthritis synovium. J Immunol 2005;174:2860-9.

Bockenstedt LK, Gonzalez DG, Haberman AM, Belperron AA. Spirochete antigens persist near cartilage after murine Lyme borreliosis therapy. J Clin Invest 2012;122:2652e60.

Frey M, Jaulhac B, Piemont Y, Marcellin L, Boohs PM, Vautravers P, et al. Detection of Borrelia burgdorferi DNA in muscle of patients with chronic myalgia related to Lyme disease. Am J Med 1998;104:591-4.

Talkington, Jeffrey, Nickell, Steven P. Borrelia burgdorferi Spirochetes Induce Mast Cell Activation and Cytokine Release. Infect Immun. 1999 Mar; 67(3): 1107–1115.

Stricker RB, et al. Counterpoint: long-term antibiotic therapy improves persistent symptoms associated with Lyme disease. Clin Infect Dis. 2007; Jul 15; 45(2):149-57.

Emir Hodzic, Sunlian Feng, Kevin Holden, Kimberly J. Freet, and Stephen W. Barthold. Persistence of Borrelia burgdorferi following Antibiotic Treatment in Mice. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, May 2008, p. 1728–1736.

Lynn Margulis, Andrew Maniotis, James MacAllister. Spirochete round bodies Syphilis, Lyme disease & AIDS: Resurgence of “the great imitator”? SYMBIOSIS(2009) 47, 51–58

Brorson O, Brorson SH. An in vitro study of the susceptibility of mobile and cystic forms of Borrelia burgdorferi to hydroxychloroquine. Int Microbiol. 2002 Mar; 5(1): 25-31.

Brorson O, Margulis L, et al. Destruction of spirochete Borrelia burgdorferi round-body propagules (RBs) by the antibiotic Tigecycline. Proc Natl Acad Sci U S A. 2009 Nov 3; 106(44): 18656–18661.

Feng, Jie, et al. Identification of novel activity against Borrelia burgdorferi persisters using an FDA approved drug library. Emerging Microbes & Infections (2014) 3.

Barthold, Stephen W., et al. Ineffectiveness of Tigecycline against Persistent Borrelia burgdorferi. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Feb. 2010, p. 643–651.

 

2 Responses

  1. Shelley July 19, 2015 / 5:23 pm

    Researching histamine intolerance and mast cell disease, it cycles in women with their monthly cycle, worse, I believe, when ovulating. Could it be that mast cells are more involved with Lyme disease, and the cycle of symptom increase is due to this, rather than the life cycle of the Lyme bacteria?

    • Lisa Klimas July 20, 2015 / 1:05 am

      I am a microbiologist by training, specifically an infectious diseases microbiologist. I have done a lot of research on Lyme this last year, including contacting some researchers. I am very familiar with bacterial infections. I have never seen anything that leads me to believe that there is a 28 day life cycle for Borrelia (or any coinfecting organisms). I believe you can have severe symptoms as a result of Lyme, but it has always made much more sense to me that the symptom increase is due to hormone changes associated with the menstrual cycle. This symptom increase is mirrored in the mast cell population. In fact, many women report significant improvement following hysterectomy.

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