Whole-genome sequencing of hundreds of samples of Borrelia burgdorferi, the tick-borne bacterium that causes Lyme disease, has revealed why the severity of the illness varies from place to place and person to person. The findings suggest new strategies for diagnosis, treatment, and prevention of Lyme—the most prevalent vector-borne disease in North America and Europe, and one of the fastest-growing infectious diseases in the United States.
Assistant professor of medicine Jacob Lemieux spearheaded the sequencing effort beginning in 2017. Lemieux had become interested in tick-borne disease several years earlier, when he was a postdoctoral researcher in the lab of professor of immunology and infectious diseases Pardis Sabeti. A colleague had mentioned the genetic similarities between the parasites that cause babesiosis (a disease also spread by ticks) and malaria, which Lemieux had studied previously. Intrigued, he and Sabeti, one of the world’s leading geneticists studying the biology and evolution of human disease, published the whole-genome sequence of the Babesia parasite in 2015.
On the heels of that success, they expected their sequencing of Lyme-causing bacteria to take perhaps six months. “It took more like six years,” says Lemieux. “It turned out that the genetic diversity of Lyme disease is orders of magnitude harder to handle than any other pathogen.” And that complexity is associated with the wide range of Lyme disease symptoms—from severe arthritis in children to fatigue and potentially debilitating joint, neurological, and cardiovascular symptoms in adults—that persist in some patients for months or even years after treatment.
Rather than being concentrated in one place, “The genome of the Borrelia spirochete [it is a spiral-shaped bacterium] is shredded,” he explains. “There is one chromosome,” the double-stranded linear sequence of DNA found in most living cells, “but then there are about 20 plasmids.” Plasmids are small, circular strands of DNA that can replicate independently of the DNA in the main chromosome. And though extremely difficult to sequence, they turned out to be critical to understanding variations in the severity of Lyme disease.
The international Lyme disease experts with whom Lemieux and Sabeti collaborated analyzed 299 samples of Borrelia collected from across North America and Europe between 1992 and 2021, primarily from patients who had developed the bullseye rash characteristic of the infection. Correlating the samples to patient outcomes, they found that the most severe cases were associated with a surface protein coded by patterns of plasmids that occur only in certain strains of Borrelia. Lemieux, whose lab also studies COVID-19, a virus, notes that there is crossover between his lab’s studies of COVID infection and Lyme disease. “If you look at some of these plasmids,” he explains, “they used to be viruses that infected bacteria. In the history of evolution, what we are seeing today is a bacterium that has integrated into itself a range of viruses.” That virus-derived DNA is now linked to both the wide-ranging and lasting nature of symptoms associated with Lyme disease—clinical aspects of infection that are now familiar to the public in the aftermath of the COVID pandemic.
The team, which included professor of medicine Allen Steere (who first identified the disease in children living in and around Lyme, Connecticut) and experts from institutions as distant as the University of Ljubljana in Slovenia, identified distinct strains of Lyme disease that have different observable traits in people. In their report, the group focused on strains that move easily from the initial site of infection into the bloodstream and to the brain, the heart, and the joints. This dissemination, explains Lemieux, is the “key watershed event” that distinguishes a mild infection from a severe one. “We’ve identified different strains that have different rates of dissemination…and different plasmids that are associated with this dissemination, as well as the underlying individual genes that are linked to this behavior,” he says. “Notably, the genes that affect the rate of dissemination reside on the virus-derived plasmid sequences of DNA. Some of the genes encode lipoproteins [composed of fats and proteins] on the bacterial surface, which appear to armor the bacteria against immune assault in the bloodstream.”
Now that the genes associated with the most pathogenic forms of Lyme disease have been described, he continues, it should be possible to develop diagnostic tests that identify patients at risk of severe disease. That, in turn, will enable physician researchers to test whether antibiotic treatments of longer duration are more effective against the most dangerous strains.
An even more compelling question is whether dissemination within the body, causing severe illness, can be blocked. “And I think we could, with specific antibodies that we develop, and potentially with vaccines,” he conjectures. “There has been this realization,” he continues, that everything scientists have done for human genetics for the last 30 years “we can also do for microbial genetics” broadly. His lab, for instance, analyzed the genome of respiratory syncytial virus (RSV) during the autumn 2022 surge. Genetic insights can be used to understand how that and other diseases develop, spread, and evolve—and even their resistance to drugs. “We’re just scratching the surface” of what is possible, he says.
Lemieux suspects, but has yet to prove, that “there is a microbial genetic basis to post-treatment Lyme disease syndrome”—the devastating, persistent symptoms that afflict some patients. “Lyme disease is a really important problem. And by no means is this study the solution to it,” he says, “but it is an incremental step that provides a foundation for further work to address and perhaps solve” the mysteries of this complex disease.
