Unraveling Lyme Disease Though Innovative Approaches to Bacterial Infection and Immune Evasion

By Mase Peterson

John Leong is the Edith Rieva and Hyman S. Trilling Professor and chair of the Department of Molecular Biology and Microbiology at Tufts University School of Medicine (TUSM). His research explores how bacterial pathogens—such as Escherichia coli that cause diarrhea, Streptococcus pneumoniae, and Borrelia burgdorferi, the Lyme disease spirochete—interact with host cells. By uncovering the mechanisms behind infection and disease progression, his work aims to inform the development of innovative therapies for prevention and treatment.

The Tufts Lyme Disease Initiative represents one of the world’s most comprehensive groups of tick-borne disease researchers. Led by Co-Directors Linden Hu, Paul and Elaine Chervinsky Professor of Immunology, and Robert P. Smith, a physician at Maine Medical Center and professor of medicine at TUSM, the team recently secured a $20.7 million federal grant. This achievement further solidifies Tufts’ position as a global leader in Lyme disease research.

In this Q&A, part of a feature series spotlighting members of the Tufts Lyme Disease Initiative, Professor Leong shares insights into his background, his current research, and the unique perspectives he brings to the field.

How do you feel your work at TUSM has contributed to a deeper understanding of Lyme disease persistence and immune invasion?

"I started my work on Lyme disease in 1989 when Allen Steere, who was instrumental in identifying and defining Lyme disease, moved to Tufts Medical Center (then New England Medical Center) to head the Division of Rheumatology and Immunology. I started collaborating with him while I was still a postdoctoral fellow at TUSM in the Department of Molecular Biology and Microbiology under Ralph Isberg.

At the time, I had no training in the Lyme spirochete, or in any spirochete. I was working on a bacterium that was very easily manipulated in the lab. So, it was a big jump for me to move into Lyme disease research. However, Allen and his lab provided me with the means to learn practical aspects of handling the bacterium in the lab.

My work in the Isberg Lab focused on interactions of the bacterium with host cells so that was the area I started working on in Lyme disease, with the notion that these interactions promote persistence and spread within the host and survival in the host. Our first goal was to identify proteins on the bacterial surface or on the host cell that promote bacterium-host cell interaction. One approach my laboratory took early on was to artificially produce bacterial surface proteins in a “disabled” bacterial strain, one that had been grown for years in the laboratory and had lost most pathogenic properties, including the ability to attach to host cells or escape killing mechanisms. We then characterized any newly acquired binding or immune evasion properties. This “gain-of-function” approach is now fairly commonplace and has contributed to what we understand about how the spirochete infects the host."

You completed all your degrees at Brown University before joining Tufts. What brought you to TUSM, and how has the school influenced your work?

"I was at Brown for 12 years to earn a BS, PhD, and MD. I came to Tufts because my future wife was in medical school at TUSM. After investigating various labs in Boston for a postdoctoral fellowship, I learned that Ralph Isberg, who finishing his own postdoctoral fellowship at Stanford, was moving to Tufts. I reached out to him because I had known of his terrific PhD work when I was a graduate student, and because of his (then) recent paper on bacterial entry into host cells, which is now considered a classic paper. It is very unusual for a postdoctoral candidate to consider joining the lab of a new assistant professor, but I really enjoyed meeting with him so, in 1987, I joined the Tufts Department of Molecular Biology and Microbiology as a postdoctoral fellow and had a fantastic time working with Ralph.

In addition to loving the Isberg Lab, the wider department was a rich environment in which to learn about microbial pathogenesis. The culture of the department, which I think had been set years and years before, was really one of a shared community. The faculty welcomed all newcomers. In particular, I joined regular lab meetings of the Andrew Wright Lab, located next to Ralph’s lab, and generally felt at home there, borrowing equipment and getting advice.

After I finished my fellowship, I spent five years in Allen Steere’s division at Tufts Medical Center (TMC), then moved to UMass Medical School in Worcester. I enjoyed my time there and made great friends and colleagues. However, in 2011, when the opportunity arose to chair Tufts Department of Molecular Biology and Microbiology, I remembered the sense of community and the quality of science and was drawn back."

How do you think TUSM’s research community shapes public health responses and clinical approaches to diagnosis and treatment?

"Linden Hu, who is also a professor of molecular biology and microbiology, has devised a multipronged approach to investigate Lyme disease, which is such a complex entity. I first met him when I was an infectious disease fellow at TMC. Although he was working on Lyme disease in the lab of a senior investigator, it was clear that he was driving groundbreaking research.

In the last few years, he has built the Tufts Lyme Disease Initiative, which takes advantage of the strengths of TUSM in Lyme disease. There is great history here: not only was Allen Steere here, but David Snydman, who also contributed to the discovery of Lyme disease, is a professor of medicine at TUSM and former chief of the Division of Geographic Medicine and Infectious Diseases at TMC. Importantly, Tufts is home to the Cummings School of Veterinary Medicine, where Sam Telford, a gifted entomologist, has been studying tick-borne diseases, including Lyme disease. (I met Sam when I was first starting out as an assistant professor). The Cummings School recently recruited Yi-Pin Lin, a former postdoctoral fellow in my laboratory, as an associate professor, and he has been investigating the tick-animal cycle that is essential to maintenance of the Lyme disease spirochete in nature.

The integration of clinical expertise, basic research, and veterinary science at Tufts makes it uniquely positioned to address Lyme disease holistically, from understanding its enzootic cycle to improving diagnostics and patient care."

You study multiple bacterial pathogens, but Lyme disease presents unique challenges in terms of detection and long-term effects. What role do you see TUSM playing in advancing Lyme diagnostics and treatment strategies?

“It's true, Lyme has unique challenges. It is difficult to culture and many of the long-term effects occur in mysterious ways. By the time patients suffer these long-term effects, viable organisms are likely no longer present, so these manifestations are likely triggered by infection, but how we don’t know. Because Tufts now has strengths in so many areas of Lyme disease, it will have a major role in advancing the understanding of their development. We hope this will lead to new diagnostics and treatments for Lyme disease.”

If you could rally the TUSM community around one key takeaway from your Lyme disease research, what would it be?

“I think the TUSM community could welcome investigators with new and diverse expertise into our network. These investigators might be newly recruited to TUSM, Cummings, Arts & Sciences, Engineering, Fletcher, or TMC. Lyme disease is such a complicated disease, we need multiple avenues of investigation in order to be able to get a fuller understanding. The support for building the Lyme Disease Initiative at Tufts, which embraces this approach, has been great.”

Outside of the lab, what’s something you enjoy doing that helps you step away from research and recharge?

“Outside of the lab, I step away from research and recharge through physical activity. I used to take spin classes at a club and developed a group of 10 to 15 friends there. When the pandemic started, we migrated to twice a week on-line spin classes—my wife and I are lucky enough to have a basement that we could converted into a gym, including spin bikes. And so, for the last five years, we do online spinning, led by a wonderful friend of ours, and never looked back.”