Research Op-Ed and Commentaries

In this section, key articles are summarized and commentary is provided.  This section also serves as an opportunity for specific topics to be reviewed in detail. Contributions to this section by scientists, researchers, and/or physicians are welcome and will be reviewed for inclusion by members of our Center Research Staff and by members of the Center’s Scientific Advisory Board with expertise specific to the commentary or review. 

Persistence of Borrelia burgdorferi in mice after antibiotic therapy. 

Two studies have recently been published which reveal that Bb may persist in the mouse despite antibiotic therapy.   These studies support much earlier work by Straubinger et al in the dog model (1997) and Bockenstedt et al (2002) in the mouse model.  Bockenstedt et al (2002) showed that Bb persistence can occur after antibiotic treatment and that these spirochetes could be acquired by ticks (xenodiagnosis) but that the infected ticks could not transmit infection to naïve hosts – suggesting that the spirochetes were attenuated in that they had become non-infectious. Straubinger et al (1997) had shown that even after 30 days of antibiotic treatment, Bb spirochetes could be demonstrated in 3/12 dogs by culture, and DNA could be demonstrated by PCR in 9/12 dogs long after treatment. 

More recently, Hodzic et al from UC Davis in California reported in Antimicrob Agents Chemother. (2008;52(5):1728-36) a study which examined the effectiveness of antibiotic treatment using ceftriaxone or saline for 1 month.  Mice were treated either early in the infection (3 weeks) or later (4 months).  Tissues were tested by immunohistochemistry, PCR, culture, transplantation of allografts, and xenodiagnosis at 1 and 3 months after treatment.  Tissues from the mice treated with antibiotics were culture negative, but tissues from some of the mice remained PCR positive and intact antigen-positive organisms with spirochetal morphology were visualized in collagen-rich tissues.  Xenodiagnosis demonstrated that uninfected larval ticks after feeding on the antibiotic-treated mice were able to acquire spirochetes (confirmed by PCR) and then transmit these spirochetes to naïve SCID mice which became PCR positive but culture negative.  This study therefore demonstrated that antibiotic treatment in the mouse model does not result in eradication of the Bb spirochetes and that some of these spirochetes were infectious, although attenuated in activity.

Yrjanainen et al from Univ of Turku in Finland reported in J Infectious Disease (2007; 195(10):1489-96) a study which examined whether anti-tumor necrosis factor-alpha would have a beneficial effect on Bb-infected mice.  C3H/He mice were infected with B. garinii A218 or B. burgdorferi sensu stricto N40. In study 1 (with B. garinii) and in study 2 (with Bb SSN40), 2 weeks after infection, 10 mice were treated with ceftriaxone only for 5 days and 10 mice were treated with anti-TNF-alpha only. In another group of 10 mice, anti-TNF was added simultaneous to the ceftriaxone at 2 weeks after infection while in another group of 10 mice anti-TNF was added at 6 weeks after infection (ie, 4 weeks after ceftriaxone). Finally, a fifth group of mice was treated with saline as a sham treatment. For the group that received ceftriaxone only, no samples were positive by culture or by PCR at 2 weeks after infection.  However, among those mice treated with anti-TNF-alpha either at 2 weeks or 6 weeks after infection, spirochetes grew from one-third of the mice.  Contrary to earlier findings by Bockenstedt et al (2002) in which the spirochetes detected after antibiotic treatment were attenuated in activity, the recovered spirochetes in this study did not appear to be attenuated, as ceftriaxone sensitivity rates, plasmid profiles, and virulence rates were similar to those of bacteria used to infect the mice. This study demonstrated that a portion of B. burgdorferi-infected mice still have live spirochetes in their body, which are activated by anti-TNF-alpha treatment.

Commentary.  These two studies demonstrate that Bb spirochetes can persist in the mouse after ceftriaxone therapy.  The Finish study was remarkable in that culture and PCR were negative after ceftriaxone but, after additional treatment with anti-TNF-alpha, viable spirochetes were recovered.  TNF is a pro-inflammatory cytokine which, when blocked, typically results in a reduction in clinical inflammation; for this reason, such treatment is used for patients with rheumatoid arthritis.   To the surprise of the authors, viable spirochetes were recovered in these PCR- and culture-negative mice after TNF blocking treatment was given. Also interesting is that anti-TNF treatment did not result in the expected finding of a reduction of joint swelling.

The Finnish study was the first study to demonstrate that immunomodulatory treatment of animals infected with Bb could convert them from culture negative to culture positive.  The California study was remarkable in that only tick-feeding was capable of extracting infectious but non-replicating attenuated spirochetes; without having done that step of xenodiagnosis and then transferring the tick to feed on naïve SCID mice, the authors’ conclusion would have been that infectious spirochetes do not persist in the mouse model as culture was negative.   The authors further concluded that negative culture and PCR can not be relied upon as markers of treatment success.

We do not know the extent to which these findings can be translated to the human situation.  Nevertheless, the activation of infectious spirochetes after anti-TNF therapy in mice should alert clinicians to the possibility that anti-cytokine therapy may result in a similarly increased risk of activating latent infection among patients with a history of treated Lyme disease.  At this point, we do not know whether attenuated spirochetes are capable of inducing illness-symptoms in mice or humans; while it is possible that spirochetal mRNA may be producing surface lipoproteins that stimulate systemic symptoms, this hypothesis needs to be tested in the next phase of this important research. 

BAFallon, MD

 

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