Host Mentor: Dr. Irv Weissman
Stanford University Institute for Stem Cell Biology and Regenerative Medicine
Developing a treatment for Lyme Disease
Lyme Disease (LD) is the most common vector-borne illness in America with ~300,000 new cases each year. Classic symptoms include widespread joint pain/swelling, debilitating fatigue, and neurocognitive dysfunction. LD is caused by an infection with Borrelia burgdorferi after transmission from an infected tick. Antibiotic treatment during early stages of disease has a 90% success rate; however, not all LD patients receive adequate treatment during the early stages of disease. It is reported that around 10% of LD patients (~30,000 people in America per year) continue to have persistent symptoms for longer than 6 months after treatment. Additional treatment options and investigation into the pathogenesis of Post-Treatment Lyme Disease Syndrome (PTLDS) is needed to address this public health issue. CD47 is a surface protein that provides an anti-phagocytic “don’t eat me” signal to prevent clearance of healthy cells. We have shown that this is exploited by cancer cells and infected cells to evade immune clearance. Phagocytes (such as macrophages, neutrophils, and dendritic cells) express the inhibitory receptor SIRP which prevents the cytoskeletal reorganization required for phagocytosis upon binding to CD47. Past Weissman Lab members Weiskopf and Ring led a team to develop CV1-G4, an engineered SIRP variant fused to an IgG4 Fc domain that binds human CD47 with a 50,000 fold higher affinity than wild-type SIRP. Using CV1-G4 as a high affinity probe for CD47, we confirmed B. burgdorferi expresses a CD47 mimic protein. In vitro, we demonstrated that CV1-G4 binding inhibits the CD47 - SIRP interaction leading to increased phagocytosis of B. burgdorferi by primary human macrophages. Through mass spectrometry and immunoprecipitation, we identified the CD47 mimic to be the B. burgdorferi p66 protein, a relevant diagnostic protein and one that is essential for B. burgdorferi to establish infection. Using knockout B. burgdorferi strains, we show that phagocytosis of B. burgdorferi by primary human macrophages is significantly increased when B. burgdorferi lacks p66. We find that p66 is a bacterial “don’t eat me” signal with immunomodulatory therapeutic potential to target this protein and enable clearance by phagocytes. Developing a treatment for Lyme Disease by targeting an innate immune checkpoint rather than only targeting the bacteria itself may complement antibiotics in a more efficacious strategy for those who are at risk of developing PTLDS or currently live with chronic Lyme disease.