New Hope for Treating Chronic Lyme Disease
The Epidemiology of Lyme
Post-Treatment Lyme Disease Syndrome (PTLDS), better known as chronic Lyme disease, is a debilitating medical condition that can cause fatigue, pain and swelling of the knees, shoulders, elbows and other large joints, memory or concentration problems and sleep disturbance. The Centers for Disease Control estimates that one in five Lyme cases will progress to PTLDS. With 300,000 new cases of Lyme disease reported each year, there is an alarming increase in patients suffering from PTLDS. In the Northeastern United States, the bacterium responsible for the disease is found in more than 50% of adult populations of the black-legged tick, Ixodes scapularis (also known as the deer tick). The tick is the only vector (transmitter) of the disease in the Midwest and Eastern United States. On the West Coast the main vector is the western black-legged tick (Ixodes pacificus).
The causative agent in Lyme disease in North America is the bacteria Borrelia burgdorferi, named for the late researcher Wilhelm "Willy" Burgdorfer, who in 1981 identified the spirochete responsible for the disease. The historical medical record of Lyme is extensive, dating back to the eighteenth century and it is described in cases from every continent with the exception of Antarctica. Prior to 1981, it was known by many descriptions including tick-borne meningopolyneuritis, Garin-Bujadoux syndrome, Bannwarth syndrome, Afzelius' disease, Montauk Knee or sheep tick fever. It’s now named for Lyme and Old Lyme, Connecticut, where a cluster of juvenile rheumatoid arthritis cases (eventually dubbed Lyme arthritis) were determined to be a tick-borne disease. The nexus of tick bites and Lyme disease was first made in 1976 by David Snydman and Allen Steere of the CDC’s Epidemic Intelligence Service, and by researchers from Yale University, including Stephen Malawista.
The standard treatment for acute Lyme disease is a two to four week regimen of antibiotics including doxycycline, amoxicillin, and cefuroxime. Under most circumstances, the patient makes a full recovery. However, continued symptoms suggest PTDLS, a chronic condition with a constellation of physical and mental problems that may continue on as life-altering debilitation. According to the CDC, patients with fatigue, pain and cognitive symptoms lasting longer than six months after diagnosis and treatment with antibiotics have Post-Treatment Lyme Disease Syndrome.
The reason why so many Lyme sufferers go on to develop PTLDS remains a mystery to CDC, as it states on its website, “Most medical experts believe that the lingering symptoms are the result of residual damage to tissues and the immune system that occurred during the infection. Similar complications and ‘auto–immune’ responses are known to occur following other infections, including Campylobacter (Guillain-Barre syndrome), Chlamydia (Reiter's syndrome), and Strep throat (rheumatic heart disease).” This view conflicts with that of many researchers who believe PTLDS is the result of continuing infection with B. burgdorferi. And so the debate rages.
Persister Cells and Chronicity
However, recent findings in separate studies by researchers at Northeastern University and Johns Hopkins University suggest that PTLDS is caused by a long-known bacterial manifestation known as persister cells. In 1942, Gladys Hobby, an early researcher in penicillin (that was first used in the treatment of infections that same year) noticed that the antibiotic was fully effective against 99% of cultures of Staphylococcus aureus. In 1944, Joseph Bigger of Trinity College in Dublin referred to the surviving penicillin-resistant population of S. aureus as “persisters.” He described them as cultured bacterial cells that enter dormancy and show no growth in population when antibiotic is added to the media. Due to non-inheritable tolerance to antibiotic, these cells can revive and regrow the population of microbes when the antibiotic is removed. The persister cells remain susceptible to the same antibiotic and continue this cycle of dormancy and renewal each time antibiotic is added to the culture and again removed. For Hobby and Bigger, these findings were limited to penicillin, the first antibiotic to be discovered (1928).
Persister cells are found in other bacteria including Escherichia coli, Pseudomonas aeruginosa, Lactobacillus acidophilus, and Gardnerella vaginalis. They are also found in cultures of the yeast Candida albicans. The Northeastern and Johns Hopkins researchers have recently announced that they have discovered persisters in B. burgdorferi, the spirochete bacterium of Lyme disease. The Northeastern team describes these persisters as some of the most "robust" they have found in all bacteria.
Persisters have the same karyotype (are not genetically different) from the other bacteria in the culture, meaning they haven’t adapted with any mutation that produces resistance to the antibiotic, yet they possess the uncanny ability to become dormant when exposed to the same antibiotic. They then shut down the cellular activities that the antibiotic interrupts when it kills the remainder of the culture. When removed from a bath of antibiotic, the dormant cells renew these cellular activities and begin to grow again. Hence, they are always present to redevelop the symptoms of an infection.
A Possible Breakthrough
This cycle of dormancy followed by resurgence in the presence of repeated antibiotic exposure has led both the Northeastern University and Johns Hopkins University research teams to suggest that “pulsed dosing” with antibiotics may eventually destroy the entire population of bacteria, including the persisters. Pulsed dosing requires antibiotic administration, then stopping the drug and restarting it again when the persisters begin to grow. Effective timing of the pulses may lead to eventual elimination of the bacteria from the patient.
These findings are limited so far to in vitro cultures of Borrelia burgdorferi and in vivo testing in mice will be conducted to determine if the technique may be successful in humans. However, the discovery of persister cells in this microbe and the effectiveness of the pulsed dosing technique are important and promising discoveries on the path to the eventual cure of Post-Treatment Lyme Disease Syndrome.
American Society for Microbiology, Antimicrobial Agents and Chemotherapy. “Borreliaburgdorferi, the causative agent of Lyme disease, forms drug-tolerant persister cells.” Accessed September 18, 2015. http://aac.asm.org/content/early/2015/05/20/AAC.00864-15.
Centers for Disease Control and Prevention. “Post-Treatment Lyme Disease Syndrome.” Accessed September 18, 2015. http://www.cdc.gov/lyme/postlds/.
Healthline. “Chronic (Persistent) Lyme Disease.” Accessed September 19, 2015. http://www.healthline.com/health/lyme-disease-chronic-persistent#Overview1.
National Center for Biotechnology Information. “Bacterial Persister Cell Formation and Dormancy.” Accessed September 18, 2015. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3837759/.
Northeastern University, news@Northeastern. “Researchers’ discovery may explain difficulty in treating Lyme disease.“ Accessed September 18, 2015. http://www.northeastern.edu/news/2015/06/researchers-discovery-may-explain-difficulty-in-treating-lyme-disease/.
Perfendo.org. “Persister Cells and the Paradox of Chronic Infections.” Accessed September 19, 2015. http://www.perfendo.org/docs/Biofilm/persisters%20lewis.pdf.
Scientific American. ”Lyme Disease May Linger for 1 in 5 Because of "Persisters." Accessed September 17, 2015. http://www.scientificamerican.com/article/lyme-disease-may-linger-for-1-in-5-because-of-persisters/.
Wikipedia. “Lyme disease.” Accessed September 19, 2015. https://en.wikipedia.org/wiki/Lyme_disease.
© 2015 M G Del Baglivo