Lyme disease is a truly intractable puzzle. Scientists used to consider the tick-borne infection easy to conquer: patients, diagnosed by their bull's-eye rash, could be cured with a weeks-long course of antibiotics. But in recent decades the U.S. Centers for Disease Control and Prevention has realized that up to one in five Lyme patients exhibits persistent debilitating symptoms such as fatigue and pain, known as post-treatment Lyme disease syndrome, and no one understands why. The problem is growing. The incidence of Lyme in the U.S. has increased by about 70 percent over the past decade. Today experts estimate that at least 300,000 people in the U.S. are infected every year; in areas in the Northeast, more than half of adult black-legged ticks carry the Lyme bacterial spirochete, Borrelia burgdorferi. Although the issue is far from settled, new research lends support to the controversial notion that the disease lingers because these bacteria evade antibiotics—and that timing drug treatments differently could eliminate some persistent infections.

These ideas stem from the observation of a few rogue bacterial cells. Kim Lewis, director of the antimicrobial discovery center at Northeastern University, and his colleagues grew B. burgdorferi in the laboratory, treated them with various antibiotics and found that whereas most of the bacteria died within the first day, a small percentage—called persister cells—managed to survive the drug onslaught. Scientists first discovered persister cells in 1944 in Staphylococcus aureus, the agent of staph infections, and Lewis and others have observed them in other species of bacteria, too—but the observations that B. burgdorferi also form persisters is new.

“These are some of the most robust persisters we've seen,” says Lewis, whose results were published online in May in Antimicrobial Agents and Chemotherapy. “Over days, in the presence of antibiotic, their numbers don't decline.” Researchers at Johns Hopkins University similarly identified B. burgdorferi persister cells this past spring.

Persisters are not antibiotic-resistant mutants; they are genetically identical to their vulnerable counterparts. Instead they are bacteria that have gone into a dormant state, ceasing the types of cellular activities that antibiotics typically thwart. Previous research has shown that when persisters of other bacterial species are removed from a bath of antibiotics, they begin to grow again. This fact prompted Lewis and his colleagues to try treating B. burgdorferi with antibiotics in pulsed doses—administering the drugs, stopping and then administering them again—to see if they could kill the persisters once they began to regrow. It worked, which suggests that if persisters are responsible for lasting infections in people, treating patients on and off with antibiotics could help. Lewis and his colleagues, as well as the Johns Hopkins scientists, are also exploring other treatment options, such as different drugs and drug combinations.

Not everyone agrees that persister cells play a role in Lyme's lingering symptoms. “There's been no evidence that this persister phenomenon has any relevance for animals or humans,” says Gary Wormser, chief of the division of infectious diseases at New York Medical College. First, he says, lab studies of B. burgdorferi cannot account for the potential effects of the body's immune system, which might be able to eliminate persisters once the brunt of the infection has cleared. Second, labs have yet to grow B. burgdorferi isolated from people treated with antibiotics, and that raises questions about whether the persisters are even viable and capable of making someone sick.

Identifying the causes of and treatments for post-treatment Lyme disease syndrome is “one of the highest priority research needs in the field,” said C. Ben Beard, chief of the bacterial diseases branch at the CDC's Division of Vector-Borne Diseases, at a CDC event in May 2014. So although it is as yet unclear whether B. burgdorferi persister cells drive some of these enduring symptoms, Lewis and his colleagues will take their research to the next level—they will test whether pulse dosing helps to clear B. burgdorferi infections in mice—in an attempt to move one step toward a much needed answer.

Lyme on the Rise

Lyme disease is expanding its geographical reach in almost every direction from its epicenters in the Northeast and upper Midwest, according to a study published in August by CDC scientists. The reasons remain uncertain. Ongoing forest fragmentation could contribute to the problem: as people chop forests into smaller pieces, they unwittingly create landscapes well suited for the deer and small mammals that ticks tend to feed on.

Climate change may also foster new suitable habitats for the arachnids and change the timing of tick feedings in ways that make young ticks—and humans—more vulnerable to infection. Nearly every known tick-borne disease in the U.S. has become more prevalent over the past decade. Scientists have identified four new ones since 2013, bringing the total up to an estimated 16..