Lyme disease: A possible link to Swiss agent?

Greetings

For most of the infections, the culprit is a single pathogen. That is what we are taught and what we believe. The exception are the cases of hospital acquired infection, where of course a lot of them have a polymicrobial cause. There are many different cases of infection, where the treatment response is straightforward and in some cases rather complicated. The argument that it is because of genetics and strain variation doesn't seem to hold true in many case scenarios.

Lyme disease also known as Lyme borreliosis is an infection caused by a bacteria called Borrelia burgdorferi. It is a thin, spiral, motile, extracellular bacterium belonging to the family Spirochaetaceae. The first isolate of this disease-causing spirochete was only obtained in 1981 when Burgdorfer demonstrated a spirochete in Ixodes ticks collected from Shelter Island. B burgdorferi is primarily seen in the United States. The related species Borrelia afzelii and Borrelia garinii are seen in Europe and Asia. All 3 species are collectively referred to as B. burgdorferi sensu lato. Rodents are the primary reservoir of Borrelia species.

Photo 1: Ixodes scapularis.
Source

B burgdorferi infects a wide range of vertebrate animals including small mammals, lizards, and birds. Ixodes species transmit B. burgdorferi between multiple hosts and are the only known natural transmission agents. Humans are actually an accidental host. Analysis of genetic sequence showed that it possess most genes similar to other bacteria but lack any specific identifiable pathogenesis associated genes. This is mostly because B burgdorferi is not designed to infect human and not a classic human pathogen.

Ixodes species  have a three-stage life cycle to be completed in a time period of 2 years- larva, nymph and adult. They need one blood meal per stage. Transovarial transmission does not occur commonly and thus each generation of tick acquires  B burgdorferi through fresh infection.

Photo 2: Erythema migrans caused

by B burgdorferi. Source

B burgdorferi is inoculated into the skin by the bite of an infected Ixodes tick containing tick saliva and bacteria. Tick saliva contains immunosuppressive molecules which help bacteria multiply and migrate radially within the dermis layer. The host inflammatory response to the bacteria in the skin leads to clinical signs of this infection, a distinctive 'bullseye' rash (The classic sign- Erythema chronicum migrans), which occurs at the site of the tick bite three to 32 days after the tick bite. See Photo 2. The bacteria has the capacity for antigenic variation which helps in avoiding immune attack. Laboratory diagnosis of the bacteria is not attempted through culture, but rather by serology and PCR. Culture is difficult due to the requirement of specialised culture techniques and hence done only in specialised laboratories. Serology is not considered as a standard since ELISA's are positive only after the infection has advanced.

The treatment is a short course of antibiotics and most people recover without any sequelae. In a subset of the cases, the patients suffering extends for months or even longer than a year. This is called as Post-treatment Lyme disease syndrome (PTLDS) or chronic Lyme disease. There is no clear understanding of mechanics of this condition and research is focussed on this problem.

Photo 3: After initial tests, Burgdorfer suspected the Swiss Agent caused Lyme. He shared the strong evidence with a close colleague in Switzerland to see whether he could verify the findings in patients there. Source

STAT news has obtained lab notes documents from Burgdorfer’s personal papers found in his garage after his death in 2014. The notes indicate that in late 1970's Burgdorfer had results indicating that he suspected "Swiss agent" or Rickettsia helvetica. But later somehow he was convinced that it is B burgdorferi was the cause which was published in Science in 1982. But the notes indicated that he was still doubtful of the Swiss agent and was constantly communicating with his close colleagues about the possibility.

There are several speculations about this whole story. Certain Lyme experts theorise that Lyme patients who test negative for the infection might be suffering from an illness caused by R helvetica. Another group of experts think that Patients with PTLDS R helvetica occurs as a co-infection. Of course, there is no definitive proof for either. I read somewhere, (unable to recall the source) that following the above CDC has decided to conduct PCR on 30000 samples from patient samples to see of they can find the Swiss agent. Ian Lipkin a virus hunter (If I can call so) has collected 5,000 ticks from New York and Connecticut to look for viruses in them and identified 20 new viruses in these ticks so far. He explains, “Everyone wants to get to the bottom of this. All of this is critical to  finding out why some people respond to antibiotics and some people don’t, and whether or not the antibiotics being used are appropriate, and trying to find ways to link different bacteria and different viruses to different syndromes.

Rickettsia helvetica was first isolated from Ixodes ricinus ticks in Switzerland and is currently in the list of an unconfirmed pathogen. Except for some case reports nothing is clear about the pathogen. In a study by Nilson et al; 2013 20 of 206 patients (0.09%) had seroreactivity to Rickettsia species from patients seeking medical care for erythema migrans or flu-like symptoms after suspected or observed tick bite in the south-east of Sweden. The same also showed that less than 1% of healthy blood donor were also serologically positive. This situation is an example in a case of complexity in identifying if R helvetica is really a pathogen of interest.

That begs the question if similar cases exist anywhere else? As a matter of fact, there does. There is some research suggesting Trichomonas vaginalis a protozoal pathogen involved with Sexually transmitted infections is more aggressive when accompanied with its dsRNA virus (endosymbiotic Trichomonasvirus) mostly through modulating inflammatory cytokines. There is similar evidence in the latest publication by Fasel et al; 2016 suggesting that Leishmania-RNA-viruses has similar role in Leishmaniasis.

It should be noted that in the above cases, these are viruses that modulate the outcome, but R helvetica is no less than intracellular cytoplasmic pathogen in operational terms.

References

Radolf J, Caimano M, Stevenson B, Hu L. Of ticks, mice and men: understanding the dual-host lifestyle of Lyme disease spirochaetes. Nature Reviews Microbiology. 2012; 9;10(2):87-99.

Tilly K, Rosa P, Stewart P. Biology of Infection with Borrelia burgdorferi. Infectious Disease Clinics of North America. 2008;22(2):217-234.

Fichorova R, Lee Y, Yamamoto H, Takagi Y, Hayes G, Goodman R et al. Endobiont Viruses Sensed by the Human Host – Beyond Conventional Antiparasitic Therapy. PLoS ONE. 2012;7(11):e48418.

Hartley M, Bourreau E, Rossi M, Castiglioni P, Eren R, Prevel F et al. Leishmaniavirus-Dependent Metastatic Leishmaniasis Is Prevented by Blocking IL-17A. PLOS Pathogens. 2016;12(9):e1005852.