Microbial Determinants of Excessive Inflammation and Severe Lyme Disease

Tufts University Boston, Boston MA

Investigators

Abstract

Project Summary/Abstract Lyme disease has reached epidemic proportions in several regions in United States and Europe and poses a substantial burden on affected communities. The illness encompasses a spectrum of clinical manifestations which vary in severity and duration, including complications that persist after antibiotic-therapy, termed post- Lyme syndromes. However, the reasons for this range in disease severity are not clear and biomarkers to identify patients at greater risk for adverse outcomes are lacking. Our findings suggest that inappropriate immune responses, which are shaped by microbial and host genetics, are an important factor in disease severity. We previously identified a particularly virulent Borrelia burgdorferi (Bb) RST1 strain which leads to excessive inflammation and severe disease, including highly symptomatic early infection and a greater risk for antibiotic-refractory Lyme arthritis, a post-Lyme complication of this disease. These findings provided a new paradigm for studying microbial underpinings of maladaptive immunity and untoward clinical outcomes in Lyme disease. However, Bb components responsible for excessive inflammation and severe disease are not known. Several lines of evidence point to differences in expression or sequence variation in Borrelia lipoproteins as a major determinant of these outcomes. In this proposal, we are leveraging our unique collection of clinical samples from well-defined patients, and functional studies using genetically-engineered isogenic Bb strains to systematically delineate the immunogenic lipoproteins and ascertain their function in dysregulated immune responses and adverse clinical outcomes in Lyme disease. We propose to: Aim 1. Determine the inflammatory capacity of candidate lipoproteins Arp or OspC in vitro by generating strains containing Arp or OspC variants and testing their inflammatory capacity in human PBMC cultures. Aim 2. Delineate the impact of Arp and OspC-A expressing strains on arthritis severity in mice by testing early and late immune responses and arthritis severity in C3H mice infected with isogenic strains expressing Arp or OspC variants, and Ascertain the impact of Arp and OspC on immune response and disease severity in patients by characterizing early and late immune responses in patients with PTLDS, defining the impact of Arp & OspC on these immune responses and, identifying new Bb determinants of immunogenicity and virulence using GWAS with immune and clinical phenotype in patients. These studies will generate new insights into pathogenesis of Lyme disease and may help lay the groundwork for novel diagnostic approaches to identify patients at greater risk for severe disease. The ability to identify such patients could help guide more effective treatment strategies which incorporate immunomodulatory therapies to quiet the immune response; an approach that is already employed for treatment of patients with refractory Lyme arthritis.