A novel therapeutic for Lyme arthritis based on a secretory leukocyte protease inhibitor

PROJECT SUMMARY/ABSTRACT Lyme disease (LD), the most common tick-borne disease in the United States, is caused by a spirochete, Borrelia burgdorferi. An estimated 500,000 people are diagnosed and treated each year. Antibiotic therapy is mostly successful in cases diagnosed in the early stage of the infection. However, in some patients, early B. burgdorferi infection is asymptomatic and Lyme arthritis (LA) is the primary manifestation of long-term LD, which usually occurs months after the tick bite. LA is the leading cause of Lyme disease-associated morbidity, affecting around one third of B. burgdorferi-infected individuals. Symptoms of LA include intermittent or persistent attacks of joint swelling and pain that can lead to permanent joint dysfunction and debilitation. Most patient respond to a 30-day course of oral or IV antibiotic therapy. However, in a small percentage of LA patients, arthritis persists after antibiotic therapy and can last for months or several years. Distinct from LA, research has shown that up to 34% of Lyme patients have Post Treatment Lyme Disease Syndrome (PTLDS). Symptoms include fatigue, pain, joint and muscle aches, and cognitive decline, with an onset ranging from months to years. Long-term antibiotic therapy has not been proven to be beneficial for PTLDS. Therefore, better therapeutic agents are urgently needed to resolve both LA and PTLDS. A human secretory leukocyte protease inhibitor (SLPI) was identified as binding to B. burgdorferi from the BASEHIT yeast display library of 3,336 human exoproteins. SLPI is an evolutionarily conserved, multi-functional protein. SLPI expression inhibits neutrophil activity and the NF-κB pathway in macrophages, leading to an overall anti-inflammatory effect. A high percentage of neutrophils and macrophages have been observed in the synovial fluid of LA patients during active LA and post-treatment LA respectively. SLPI also has broad-spectrum antibacterial, antifungal, and antiviral activities. Using a SLPI knockout mice, our preliminary data showed a significantly higher B. burgdorferi infection load and severe swelling and synovitis in the tibiotarsal joints of SLPI knockout mice in comparison to the WT mice. The data indicate that SLPI expression suppresses the B. burgdorferi infection load and inhibits the development of murine Lyme arthritis. The prior knowledge of SLPI and our preliminary data form the foundation of our hypothesis that therapeutic dosing of SLPI will significantly mitigate human LA. This proposal aims to show the feasibility of that in the murine LA model. Our long-term product goal is a novel secretory leukocyte protease inhibitor (SLPI) based therapeutic indicated for advanced Lyme disease, including both LA and PTLS.