Projects / Programmes
Host-pathogen interactions in acute and chronic Lyme borreliosis: In depth analysis of pathogen and host contributions in a clinical setting
| Code |
Science |
Field |
Subfield |
| 3.01.00 |
Medical sciences |
Microbiology and immunology |
|
| Code |
Science |
Field |
| B510 |
Biomedical sciences |
Infections |
| Code |
Science |
Field |
| 3.01 |
Medical and Health Sciences |
Basic medicine |
Lyme borreliosis; erythema migrans; acrodermatitis chronica atrophicans; Borrelia afzelii; chronic infection; Borrelia-host interactions
Researchers (21)
Organisations (2)
Abstract
Lyme borreliosis (LB) patients have a range of manifestations which vary in severity and duration, including certain complications that persist after antibiotic therapy. Severe disease, chronic infection, and post-Lyme complications are the greatest clinical challenge in LB, but the underlying causes are not well understood. Inappropriate activation of inflammatory immune responses, which are shaped by both microbial and host genetics, are likely an important factor in these outcomes.
It is not clear why some patients develop acute infection whereas others develop chronic infection which can last for years. Because erythema migrans (EM) and acrodermatitis chronica atrophicans (ACA) represent the prototypic acute versus chronic infection in the skin, which is usually due to a single Borrelia species, B. afzelii, they provide valuable human disease models for studying microbial and host factors involved in chronic infection.
Our hypothesis is that disadvantageous clinical outcomes in LB, including the potential for chronic infection, are due at least in part to inappropriate immune responses which are shaped by both microbial and host genetics. We propose the following specific aims:
Aim 1: To identify spirochetal genes associated with greater inflammation, more severe disease and chronic infection.
a) Characterize B. afzelli strains from patients with mild or severe disease, and from acute or chronic infection, using whole-genome sequencing and correlate the presence of specific genes with immune findings and disease severity in matched patients.
b) Define the functional impact of candidate Borrelia strains by assessing host transcriptional profiles in vivo in EM and ACA skin lesions from patients, and in vitro in cell culture models infected with strains of interest.
Aim 2: To define host genetic risk factors in more severe disease and chronic infection.
a) Determine the frequency of )250,000 SNPs in EM and ACA patients with mild or severe disease using GWAS-based ImmunoArray.
b) Evaluate the functional consequence of candidate SNPs by correlating these SNPs with dysregulated immune responses and disease severity and chronicity in patients, and by mechanistic studies in patient cells and tissue.
Aim 3: To develop new diagnostic approaches by combining several SNPs, B. afzelii antibodies, autoantibodies, and immune mediators into a test to identify patients at greater risk for disadvantageous clinical outcomes and disease chronicity.
The work proposed in this grant, to elucidate mechanisms by which certain Borrelia strains in combination with host genetic factors lead to dysregulated immune responses, and delineation of the pathways involved, could have significant implications in understanding the pathogenesis of chronic LB and also other bacterial infections.
Moving from correlations to causation is typically a great challenge in studies of human disease that requires a collaborative effort between experts in clinical disease and the latest systems-wide biology approaches. In LB, both spirochetal and host heterogeneity contribute to the difficulty. To address this challenge, we are studying patients with well-defined manifestations of early and late disease; we are characterizing spirochetal and host factors in samples from the same patients using both discovery-based and targeted approaches; and we are delineating the functional consequences in vivo in tissue and in vitro in cell culture systems. This knowledge has practical implications for diagnosis and treatment. We envision developing new diagnostic approaches which incorporate a combination of several SNPs, autoantibodies, and inflammatory mediators, into a custom test to identify patients at greater risk for chronic disease. Finally, such a test may help identify patients who may benefit from novel treatment strategies, such as those that combine antibiotics with targeted immunotherapy (e.g. blockers to quiet maladaptive component of the Th1/Th17 immunit
Significance for science
This work has significant implications for pathogenesis of Lyme borreliosis and is likely to influence both the diagnosis and treatment for patients. Previous findings of our collaborators who identified the first interaction between particularly virulent B. burgdorferi RST1 strains and host genetic factors (TLR1-1805GG SNP) created a link between host and microbial genetics, maladaptive immune responses, and more severe disease, and provided a paradigm for the study of untoward clinical outcomes in Lyme borreliosis. We are now in position to expand these studies to identify specific spirochetal genes and a larger range of host genetic factors to gain insight into host pathogen interactions that set the stage for resolution of the infection, or for chronic infection that can last for months to years.
We are working in the best defined human Lyme borreliosis systems: erythema migrans, the most common early manifestation of acute infection, and acrodermatitis chronica atrophicans, the most common late manifestation (chronic infection). Because erythema migrans and acrodermatitis chronica atrophicans represent the prototypic acute versus chronic infection in the skin, which is usually due to a single Borrelia species, B. afzelii, they provide valuable human disease models for studying microbial and host factors involved in chronic infection. Based on these new insights into pathogenesis, we envision developing new diagnostic approaches which combine several SNPs, antibodies, and immune mediators into a test to identify patients at a greater risk for such outcomes.
This work requires a collaborative effort between experts in clinical disease and basic science, and the latest systems-wide biology approaches across several institutions: University Medical Centre Ljubljana (disease pathogenesis, clinical data), Institute for Microbiology and Immunology, Medical Faculty Ljubljana (culturing, sequencing, genetics), Institute for Biostatistics and Medical Informatics, Medical Faculty Ljubljana (bioinformatics), and Massachusetts General Hospital, Harvard Medical School, United States (host-pathogen interactions, disease pathogenesis, translational immunology).
In this grant, we are using the latest discovery-based techniques to delineate specific spirochetal genes and host SNPs that set the stage for immune dysregulation and adverse clinical outcomes including chronic infection, and we are performing functional studies in cells and tissue to elucidate the underlying mechanisms of action. We believe these studies will generate completely new information about microbial and host genetics in the pathogenesis of chronic infection and more severe Lyme borreliosis (and potentially also of other bacterial infections) and have significant implications for both diagnosis and treatment of such patients.
Significance for the country
This work has significant implications for pathogenesis of Lyme borreliosis and is likely to influence both the diagnosis and treatment for patients. Previous findings of our collaborators who identified the first interaction between particularly virulent B. burgdorferi RST1 strains and host genetic factors (TLR1-1805GG SNP) created a link between host and microbial genetics, maladaptive immune responses, and more severe disease, and provided a paradigm for the study of untoward clinical outcomes in Lyme borreliosis. We are now in position to expand these studies to identify specific spirochetal genes and a larger range of host genetic factors to gain insight into host pathogen interactions that set the stage for resolution of the infection, or for chronic infection that can last for months to years.
We are working in the best defined human Lyme borreliosis systems: erythema migrans, the most common early manifestation of acute infection, and acrodermatitis chronica atrophicans, the most common late manifestation (chronic infection). Because erythema migrans and acrodermatitis chronica atrophicans represent the prototypic acute versus chronic infection in the skin, which is usually due to a single Borrelia species, B. afzelii, they provide valuable human disease models for studying microbial and host factors involved in chronic infection. Based on these new insights into pathogenesis, we envision developing new diagnostic approaches which combine several SNPs, antibodies, and immune mediators into a test to identify patients at a greater risk for such outcomes.
This work requires a collaborative effort between experts in clinical disease and basic science, and the latest systems-wide biology approaches across several institutions: University Medical Centre Ljubljana (disease pathogenesis, clinical data), Institute for Microbiology and Immunology, Medical Faculty Ljubljana (culturing, sequencing, genetics), Institute for Biostatistics and Medical Informatics, Medical Faculty Ljubljana (bioinformatics), and Massachusetts General Hospital, Harvard Medical School, United States (host-pathogen interactions, disease pathogenesis, translational immunology).
In this grant, we are using the latest discovery-based techniques to delineate specific spirochetal genes and host SNPs that set the stage for immune dysregulation and adverse clinical outcomes including chronic infection, and we are performing functional studies in cells and tissue to elucidate the underlying mechanisms of action. We believe these studies will generate completely new information about microbial and host genetics in the pathogenesis of chronic infection and more severe Lyme borreliosis (and potentially also of other bacterial infections) and have significant implications for both diagnosis and treatment of such patients.
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