Projects / Programmes
Microbial and host factors involved in the differences in clinical manifestations, severity and outcome of Lyme borreliosis
| Code |
Science |
Field |
Subfield |
| 3.01.00 |
Medical sciences |
Microbiology and immunology |
|
| Code |
Science |
Field |
| B007 |
Biomedical sciences |
Medicine (human and vertebrates) |
| Code |
Science |
Field |
| 3.01 |
Medical and Health Sciences |
Basic medicine |
Lyme borreliosis, post-Lyme symptoms, post-Lyme syndrome, host-pathogen interactions, genomics, proteomics, GWAS, polymorphisms, immune dysregulation
Researchers (25)
Organisations (2)
Abstract
Background: The greatest remaining clinical problem in Lyme borreliosis (LB) are post-Lyme syndromes such as pain, fatigue, or neurocognitive symptoms after LB, central sensitization, and antibiotic-refractory Lyme arthritis. Although persistent infection is often implied as the cause of these syndromes several clinical trials showed that additional courses of antibiotics are not beneficial. Emerging evidence points to immune system abnormalities as a possible cause for these syndromes. Recently, particularly inflammatory B. burgdorferi strains (RST1) and a host polymorphism (TLR1-1805GG) were identified, the combination of which is associated with excessive immune responses and disadvantageous clinical outcomes, including more symptomatic early infection and antibiotic-refractory Lyme arthritis. Moreover, inappropriate immune responses, including elevated levels of CCL19 and IL-23, may be a factor in post-Lyme symptoms after early LB. These findings establish a link between borrelial and host genetics, inappropriate immune responses, and more severe disease, and present a new “immune” paradigm for the study of such patients. Yet, knowledge of borrelial and host genetic factors in LB pathogenesis remains limited and the mechanisms underlying adverse clinical outcomes are not known.
Hypothesis: Disadvantageous clinical outcomes in LB, including post-Lyme syndromes, may be due at least partly to inappropriate immune responses that involve both host and borrelial genetics.
Objectives: To identify a greater range of borrelial and host genetic factors implicated in adverse clinical outcomes, and to begin to elucidate the underlying immune mechanisms responsible for more severe disease and post-Lyme syndromes.
Specific aims: Aim 1: to identify borrelial proteins and genes associated with greater pathogenicity, by assessing borrelia strains from patients with a range of clinical manifestations using DNA sequencing and mass spectrometry; Aim 2: to characterize a larger range of host genetic factors that may predispose patients to more severe LB and its post-Lyme syndromes, using the GWAS-based Infinium ImmunoArray; and Aim 3: to elucidate the mechanisms by which candidate strains in combination with host polymorphisms lead to dysregulated immune responses and disadvantageous clinical outcomes using Luminex and RNA sequencing.
Study design: This work integrates cutting edge sequencing, genotyping, and proteomics approaches to assess microbial and host genetic factors that are responsible for inappropriate immune responses and adverse clinical outcomes. The study is based on Borrelia isolates and clinical samples from patients with a range of disease manifestations, including patients with post-Lyme syndromes. The findings from discovery-based approaches will be correlated directly with clinical information in patients, including disease severity, treatment outcome, and presence of post-Lyme symptoms/syndromes.
Relevance: We will identify new pathogen and host factors that contribute to more symptomatic infection and the development of post-Lyme complications, and will likely uncover biomarkers for diagnostic tests to identify patients at a greater risk for adverse clinical outcomes. Moreover, better understanding of the underlying mechanism may help lay the groundwork for more rational and effective treatment strategies for patients with these syndromes. Finally, this approach could provide a platform for studying post-treatment complications following other infections.
Innovation: This proposal combines the latest cutting-edge techniques, new concepts in host-pathogen interactions, and translational research in human immunology to unravel the mechanisms for disadvantageous clinical outcomes in LB. The scope of the technological approaches coupled with numerous well-defined clinical samples is unprecedented and will provide completely new information about spirochetal and host genetics in LB pathogenesis.
Significance for science
This proposal is innovative in that it combines the latest cutting-edge techniques, new concepts in host-pathogen interactions, and translational research in human patients to unravel the causes of disadvantageous clinical outcomes in Lyme borreliosis (LB), with the focus on post-Lyme syndromes.
Our recent findings, which implicate both microbial (particularly virulent Bb RST1 strain) and host (TLR1-1805GG polymorphism) genetic factors in disadvantageous immune responses in post-Lyme syndromes, provide a novel paradigm for the study of patients with such syndromes. In the current proposal we are building on these concepts using the latest discovery-based approaches to identifying a greater range of borrelial (proteins and genes) and host (SNPs) factors that may contribute to dysregulated immune responses, more severe infection, and persistent symptoms after erythema migrans, Lyme neuroborreliosis and acrodermatitis chronica atrophicans, and central sensitization syndrome. In collaboration with our partners at MHG/Harvard University, we are using Illumina genome-wide sequencing of B. burgdorferi s.l. isolates from well-characterized human patients with a range of disease severity, duration and outcome. This depth and scope of sequencing coupled with large numbers of well-defined isolates from patients is unprecedented and will provide new information about borrelia genetics. Moreover, the custom GWAS-based genotyping chips to screen ~250,000 disease-relevant SNPs (ImmunoArray) coupled with genome-wide transcriptomics (RNASeq) of well-defined patients with a range of post-Lyme syndromes is also completely new. Using this approach our collaborators have already identified 28 SNPs that can unequivocally distinguish patients who develop antibiotic-refractory Lyme arthritis from those who resolve their arthritis with antibiotics and here we are extending this approach to patients with other post-Lyme phenomena. Thus this work will provide entirely new information regarding host genetic risk-factors and mechanisms underlying adverse clinical outcomes in LB. Finally, the comprehensive assessment of borrelial and host factors in the same set of patients with complete clinical information will allow us to integrate the results from pathogen and the host and help interpret large amounts of information into biologically relevant findings.
In summary, we think that it is this combination of powerful cutting-edge methods coupled with translational human-based research using a unique collection of clinical samples that make this proposal innovative and give it greater ability to dissect complex problems in the pathogenesis of LB and its post-Lyme syndromes. This approach will generate completely new data regarding host and pathogen genetics. Moreover, the approach developed here will provide a platform for studying of other tick-borne diseases and may contribute to novel precision treatment strategies specific to subgroups of patients with post-Lyme syndromes.
Significance for the country
This grant application is focused on the elucidation of borrelial and host factors involved in the course and outcome of Lyme borreliosis. We think the proposed work has significant implications in understanding the pathogenesis of Lyme borreliosis, particularly in elucidating factors and mechanisms involved in the development of post-Lyme complications. Since it is based entirely in a human system, the knowledge gained may influence clinical practice.
First, the findings will inform basic paradigms in infectious diseases, including better understanding of dissemination, genetic predisposition to more severe disease, acute vs chronic infection, and infection-induced autoimmunity.
Second, the systems-wide sequencing and genomic approaches should identify a comprehensive profile of borrelial genes and host polymorphisms (SNPs) that may predispose patients to persistent symptoms after erythema migrans, Lyme neuroborreliosis or acrodermatitis chronica atrophicans, and central sensitization syndrome.
Moreover, we anticipate that the implicated borrelial and host factors could serve as biomarkers for diagnostic assays for early identification of patients at a greater risk for adverse clinical outcomes.
Finally, better understanding of the pathogenesis underlying post-Lyme syndromes may lead to novel treatment strategies for patients with these outcomes (e.g., identification of specific immune pathway such as Th17 could lead to targeted immunotherapies).
Thus, the studies proposed here on the pathogenesis of Lyme borreliosis and its post-Lyme syndromes will lay down the groundwork for development of biomarkers and more effective treatment strategies for patients with more severe disease, including a range of post-Lyme complications.
Most important scientific results
Final report
Most important socioeconomically and culturally relevant results
Final report
