Ying Zhang and Valeria Culotta

Two Takes on Lyme

By David Glenn • Photo by Chris Hartlove

Almost 40 years after Lyme disease emerged, scientists are still unraveling the mysteries of Borrelia burgdorferi, the tick-borne bacterium that causes the illness. The pathogen, which is tricky to cultivate in laboratory settings, uses a huge array of defenses to protect itself against the human immune system.

A fuller blueprint of B. burgdorferi might bring some relief to the roughly 25,000 Americans who are diagnosed with Lyme disease each year. (The disease is also a global problem, with a particularly high incidence in Eastern Europe.) When left unchecked, the infection can cause joint inflammation, cardiomyopathy and facial paralysis. Now two Bloomberg School scientists believe they have found important new avenues for understanding the disease, and in May they each received grants from the Lyme Research Alliance to support their work.

Ying Zhang, MD, PhD, a professor of Molecular Microbiology and Immunology, has a hunch that pyrazinamide—a drug that has been used for more than 60 years to treat tuberculosis—might have some effect against Lyme disease. “It’s a very curious drug, but an amazing drug,” Zhang says. “Most antibiotics work only against bacteria that are growing, but pyrazinamide works against ‘persister’ tuberculosis bacteria that are in a dormant, non-growing state.”

That’s an uncontroversial statement when applied to tuberculosis—but Lyme disease is a different story. The very idea that B. burgdorferi might have a “persister” form is hotly debated. Many scholars and practitioners insist that Lyme can always be treated with a relatively short course of antibiotics. The practice guidelines of the Infectious Diseases Society of America, for example, declare that there is no evidence that anyone has suffered significant chronic B. burgdorferi infection after the standard treatment. But some scholars and patient advocacy groups disagree, asserting that even after standard antibiotic treatment, B. burgdorferi can persist in a difficult-to-detect form, causing chronic neurological problems.

Zhang is in the latter camp. He suspects that under certain conditions, B. burgdorferi might change to an unusual form known as L-forms, one type of heterogeneous persisters. In the L-form state, bacteria lack cell walls—a major target of most commonly used antibiotics. Pyrazinamide, however, targets different sites (energy production and protein degradation) in the cell, and Zhang’s lab has demonstrated that the drug is uniquely effective against tuberculosis bacteria that have transitioned into a dormant “persister” state and are tolerant to most antibiotics.

Might pyrazinamide (or a similar compound) have the same kind of power against Lyme disease? That is what Zhang hopes to learn in the next several years. His lab’s early studies have been promising. He and his colleagues have already found that the active form of pyrazinamide—pyrazinoic acid—has some effect against B. burgdorferi in vitro. Now they are preparing to test the drug’s power against B. burgdorferi in mice.

Zhang and his team also will test hundreds of different medicinal compounds to see if they have any in vitro effectiveness against the dormant form of the bacterium.

Valeria Culotta, PhD, a professor of Biochemistry and Molecular Biology, is following a different strategy. Her lab has been using biochemical and spectroscopic methods to study the unusual ways in which B. burgdorferi metabolizes metals.

Most microorganisms need to acquire iron for survival, but scientists discovered several years ago that B. burgdorferi is almost uniquely indifferent to iron levels. (That property leaves it invulnerable to one of the body’s basic immune responses, which involves starving pathogens of iron.) Culotta and her colleagues recently discovered a possible explanation for how B. burgdorferi functions with such indifference to iron: It has an extremely strong capacity to take up manganese, an element that, like iron, can be used to power bacterial enzymes.

Culotta hopes that this insight might someday lead to new molecular targets for anti-Lyme medications. In the meantime, however, Culotta cautions that Lyme patients should not try to starve themselves of manganese. “This organism has such a high capacity for taking up manganese that even if you removed it from your diet, it would still find an adequate amount,” she says.

The drug therapies that might emerge would target the unique metallo-enzymes that bind with manganese, Culotta says. “We still have a great deal to learn about this organism,” she says. “I’m hopeful about new therapies, but they would come way down the line.”