Projects / Programmes
Comprehensive clinical, microbiologic and immunologic characterization of reinfections with Borrelia burgdorferi sensu lato
| 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; Borrelia afzelii; Borrelia garinii; Borrelia burgdorferi; reinfections; clinical characteristics; erythema migrans; immune response
Researchers (27)
Organisations (2)
Abstract
Lyme borreliosis is the most common tick-borne disease in the Northern Hemisphere. It is epidemic in many areas in Europe, Asia and North America. In Slovenia, over 6000 new cases ()300 cases/100.000 inhabitants) are reported annually, and the incidence is on the rise at a rate of aproximately 20% each year. It is estimated that in the next two decades, aproximately 1% of the population of Slovenia may be affected by disease each year.
The disease is caused by several species of the Borrelia burgdorferi sensu lato complex. Borrelia burgdorferi sensu stricto (B. burgdorferi) is the only causative agent in North America, whereas in Europe Lyme borreliosis is caused predominantly by Borrelia afzelii and Borrelia garinii, rarely by B. burgdorferi, and only exceptionally by other Borrelia species. The most common manifestation of the disease is a solitary skin lesion called erythema migrans. If left untreated, the infection can disseminate to other skin sites and other organ systems, including the nervous system, joints, and hearth.
Prevention strategies to limit exposure to tick bite and infection have had limited effect and Lyme borreliosis has become a substantial and growing burden on affected communities. There is an increasing need for a safe and effective vaccine in humans. The vaccine requires the mounting of a broad and sustained immunological response to convey long-term protection from infection with various Borrelia species. Unfortunately the information on protective immunity and pathogenesis of reinfections in Lyme borreliosis that would guide the development of such vaccines is lacking. In fact, data on reinfection with Lyme borreliae and resulting clinical manifestation are limited to a few small case series and individual case reports conducted primarily in the United States. Although published reports demonstrate that reinfection occurs, the underlying pathogenesis remains poorly understood.
We hypothesize that the development of a protective immune response to Lyme borreliae is shaped by both microbial and host factors, and that deficiencies or variations in these factors also shape the events allowing for reinfection to occur.
Herein we propose a novel, cutting edge microbiological and immunological approaches to assess the frequency, genotype of the infecting strains, and immunological and serological responses in reinfections in a large cohort of patients to delineate the causative microbial agents and host immune responses in the pathogenesis of clinically manifested reinfections.
Our specific objectives are:
1) To determine the frequency of reinfections and the type of clinical manifestations
in ~12000 European patients with erythema migrans and ~1000 patients with early
extracutaneous or late Lyme borreliosis.
2) To determine differences in clinical presentation, outcome, and antibody response
in patients with erythema migrans for the first time and as a result of reinfection.
3) To assess the microbial etiology of reinfections by characterizing paired
Borrelia isolates from initial erythema migrans and from erythema migrans at
reinfection in the same patients.
4) To characterize the inflammatory and cellular immune responses in patients with
initial infection and reinfection by assessing:
a) cytokine and chemokine profiles in serum,
b) frequency, phenotype, and function of specific immune cells, and
c) genome-wide transcriptome profiles in patients’ cells using NexGen RNASeq.
Lyme borreliosis is a substantial and growing burden on affected communities. The work proposed here has significant implication in better understanding of the mechanisms underlying protective immunity and reinfection and these findings could help guide preparation of an effective vaccine.
Significance for science
The aims in this project set to fill the void in knowledge on the etiology, disease course and pathogenic mechanisms of reinfections with B. burgdorferi sensu lato. Since the project is based entirely in a human system, the knowledge gained may influence clinical practice. Moreover, we anticipate that the generated data will foster new areas of investigation.
The work proposed here has significant implication in better understanding the pathogenesis of reinfection. Since information on clinically manifested reinfections with Lyme borreliae is limited we expect that the study will provide several novel clinical findings. Based on already acquired data on )12000 erythema migrans patients, we will determine the frequency and type of reinfections with B. burgdorferi sensu lato, the circumstances in which the reinfections occur, and the clinical, etiological, and immunological distinctions in patients with primary and repeat infections.
In addition, with our genotyping methods we hope to identify the borrelial genotypes that are associated with reinfection. We also anticipate that the comprehensive RNASeq and multiplex protein analyses of patients' serum and cell samples will identify host inflammatory factors that are associated with reinfection or protection from reinfections. Finally, we expect that our study will provide new knowledge about the etiology and immunological mechanisms of reinfection which could be useful in vaccine development.
The study will foster international collaboration and enable close interactions between physicians and basic scientists.
Significance for the country
Our study will provide new knowledge about the etiology and immunological mechanisms of reinfection which could be very useful in vaccine development. A safe and effective Lyme borreliosis vaccine will most probably have a substantial direct influence on the economy and a huge beneficial medical and social impact for populations living in Lyme borreliosis endemic regions.
Most important scientific results
Final report
Most important socioeconomically and culturally relevant results
Final report
