Microbial genetic variation in the pathogenesis of Lyme Disease - Project Summary/Abstract
Lyme disease has reached epidemic proportions in the northeastern United States and poses a substantial
burden on affected communities. The illness can present with a spectrum of clinical manifestations which vary
in severity and duration, including certain 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 clinical outcomes are lacking. This presents a challenge for both physicians
and patients whose symptoms do not resolve with standard antibiotic therapy. Our recent findings suggest that
inappropriate immune responses, which are shaped at least in part by microbial genetics, are an important
factor in these outcomes. We previously identified a particularly virulent Borrelia burgdorferi RST1 OspC type A
strain which leads to excessive inflammation and more severe disease, including more 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 inappropriate immune responses and untoward clinical
outcomes in Lyme disease. However, specific spirochetal genes associated with RST1 OspC type A strains
are not yet know, and knowledge of microbial genetic determinants of immunogenicity and virulence are
limited. In this proposal, we are applying our multi-prong approach using cutting-edge methodologies, clinical
samples from well-defined patients, and functional studies in cells and tissue to delineate spirochetal genes
and variants associated with dysregulated immune responses and adverse clinical outcomes in Lyme disease.
We propose 2 specific aims: Aim 1: To identify microbial genes implicated in greater virulence a) by
characterizing Bb isolates from patients with mild or severe disease using whole genome sequencing, b) by
delineating genes associated with RST1 strains using GWAS, and c) by correlating candidate genes with
immune and clinical phenotype in patients. Aim 2: To test the functional impact of Bb RST1 strains on
host immune responses a) by assessing transcriptome profiles in skin lesions and synovial tissue from
patients infected with an RST1 strain and b) by delineating Bb-sensing pathways that mediate excessive
inflammation to RST1 in macrophage, fibroblast, and PBMC. The work proposed here will provide new insights
into pathogenesis and is likely to lay the groundwork for novel diagnostic approaches to identify patients at
greater risk for severe disease, including post-Lyme syndromes. The ability to identify such patients could help
guide more effective treatment strategies such as combination of antibiotics and immunotherapy.
