Lyme disease, caused by a number of closely related members of the Borrelia burgdorferi sensu lato family (B. burgdorferi sensu stricto in the United States) that are transmitted by closely related members of the Ixodes persulcatus family (I. scapularis and I. pacificus in the United States) is endemic in many parts of the world, with particularly high prevalence in the United States and Europe. Prevalence of human disease continues to rise, as does the geographic distribution of endemic areas. These events are enhanced by perturbation of the environment by humans, as well as global climate change, which favor habitation of the environment by Ixodes spp. vector ticks and suitable reservoir hosts. Interest in Lyme disease is rising globally, as Lyme disease is increasing in southern Canada, where infected ticks and reservoir hosts are extending their range from the United States, as well as an increase in prevalence throughout Europe and Asia.
I have been engaged in Lyme disease research since its initial discovery in coastal Connecticut in the late 1970’s/early 1980’s. At that time, I was on the faculty of the Yale School of Medicine, and collaborated with Dr. Steere and others to develop an animal model for studying mechanisms of disease and vaccine development. I have continued Lyme disease research upon joining the faculty at the University of California at Davis in 1997. I have been actively funded by NIH in Lyme disease research for over 25 years.
During the course of my Lyme disease research career, I have become saddened by the negative discourse and division that exists among various factions of the Lyme disease community, including the lay community, the medical community, and the scientific community (the so-called “Lyme Wars”). In particular, debate has intensified regarding efficacy and appropriate regimens for antibiotic treatment. Central to this debate is the Infectious Disease Society of America (IDSA) position that this is a simple bacterial infection that is amenable to simple antibiotic treatment, while also recognizing that something is happening in patients after treatment, known as Post Lyme Disease Syndrome (PLDS).
Lyme disease is exceedingly complex in humans, and this poses major challenges to accurate diagnosis and measuring outcome of treatment. It has been known for years that the acute signs of Lyme disease (erythema migrans, cardiac conduction abnormalities, arthritis, etc.) spontaneously regress without benefit of antibiotics, but their resolution is accelerated by treatment. There is overwhelming evidence in a variety of animal species as well as humans that B. burgdorferi persists without treatment, but the crucial question is does it survive following treatment, and if so, do surviving spirochetes cause “chronic” Lyme Disease or PLDS? These questions cannot be answered by speculative and expensive human clinical trials motivated by firmly held dogmatism.
Something strange is happening with Lyme disease. Borrelia burgdorferi persistently infects a myriad of fully immunocompetent hosts as the rule, not the norm of its basic biology. When such a situation occurs, antibiotics may fail, since it is generally accepted that antibiotics eliminate the majority of bacteria, and rely upon the host to “mop up” the rest. If the bacteria are able to evade host “mopping”, then the logic of the scenario falters. It is not surprising, therefore, that experimental studies, using a broad spectrum of animal species (mice, dogs, monkeys) and a variety of antibiotics (doxycycline, amoxicillin, ceftriaxone, tigecycline) have all shown a failure to completely cure the animals of B. burgdorferi infection. What is surprising is that the surviving spirochetes can no longer be cultivated from tissues (culture is considered by some to be the gold standard for detecting viable B. burgdorferi), but their presence can be readily detected with a number of methods, including B. burgdorferi-specific DNA amplification (PCR), xenodiagnosis (feeding ticks upon the host and testing the ticks by PCR), detection of B. burgdorferi-specific RNA (indicating live spirochetes), and demonstration of intact spirochetes in tissues and xenodiagnostic ticks by labeling them with antibody against B. burgdoreri-specific targets. These surviving spirochetes are not simply “DNA debris” as some contend, but are rather persisting, but non-cultivable spirochetes. It remains to be determined if their persistence following treatment is medically significant. For example, humans are known to be persistently infected with a number of opportunistic pathogens, including viruses, bacteria, and fungi, which are held in abeyance by the immune response, without clinical symptoms. Their significance varies with individual human patients and their ability to keep them in check. Lyme disease is likely to be similar.
The following report is a bit technical, but provides a summary of documented evidence of published and yet to be published experimental studies that provide compelling evidence for B. burgdorferi persistence following antibiotic treatment in animal model systems. It remains to be determined if humans are different, but the wide range of animal species studied (including non- human primates) predicts commonality from which extrapolation to humans is logical. Because of firmly entrenched opinion within the medical scientific community, evidence of persisting viable but non-cultivable spirochetes is slow to be accepted, and research proposals submitted to NIH that feature persistence following treatment are likely to receive prejudicial peer review in the contentious environment of Lyme disease*. Negative comments by peer reviewers of grant applications in the current financially austere NIH climate result in unfundable scores, if they are scored at all (triaged). I have no personal stake in this issue any more, as I am retiring within a year.
In my opinion, for such important and controversial studies to go forward, NIH will need to publish a specific call for applications, known as a “Request for Applications” (RFA), that requests research on the biological significance of persisting spirochetes following antibiotic treatment.