Projects / Programmes
Tick-transmitted illnesses and their causative agents in Slovenia
January 1, 2015
- December 31, 2021
| 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; tick-borne encephalitis; erythema migrans; Borrelia afzelii; Borrelia garinii; Borrelia burgdorferi; outcome; post Lyme symptoms; tick-borne encephalitis virus; postencephalic syndrome; pathogenesis; clinical characterisics; immune response; cytokines; chemokines
Researchers (47)
Organisations (2)
Abstract
Background. Lyme borreliosis (LB), tick-borne encephalitis (TBE), and human granulocytic anaplasmosis (HGA), are endemic in Slovenia.
Main research topics
Are arthropode-borne illnesses other than LB, TBE and HGA present in Slovenia? We will use novel microbiological and molecular-genetic approaches for detection of known and potential etiological agents.
Completion of deficient data on LB and TBE including efficacy of diagnostic and treatment approaches, frequency of reinfections, and clinical course and outcome based on age, sex, and immune status.
Concomittant infecions. We plan to determine the frequency, clinical characteristics and outcome of illness in patients coinfected with Lyme borreliae, TBE virus and/or Anaplasma phagocytophylum.
Elucidation of LB and TBE pathogenesis and post-treatment symptoms. We hypothesize that differences in the clinical course of LB and TBE result from altered immune responses driven by host and microbial factors. We will assess these factors using cutting edge microbiological, immunological and genetic approaches.
Aims
1) To demonstrate that other arthropod-borne diseases, in addition to LB, TBE and HGA, are present in Slovenia.
2) To complete deficient information in LB and TBE.
3) To ascertain coinfections with LB, TBE and/or HGA agents and to determine disease course in coinfected patients.
4) To identify the genotypes within the European B. burgdorferi s.l. species that vary in virulence, by optimizing a genotyping system and correlating individual subtypes with clinical findings in the same patients. Borrelia genotypes will be determined by RFLP and MLST. Persistence will be assessed by tissue culture, PCR and serology before and after treatment.
5) To identify genetic variants within the European TBE virus and characterize differences in virulence by correlating variants with clinical findings in the same patient. Genetic material will be obtained from blood acquired during the initial phase of TBE; TBE virus genetic variants will be determined by sequencing TBE virus E and NS5 protein genes.
6) To determine the underlying pathogenic mechanisms in LB and TBE by characterizing patients' transcriptome, immune protein profiles, and genetic variants and correlating these results with clinical findings in the same patients. Cytokines and chemokines will be assessed by Luminex in sera of patients with LB and TBE and in skin samples of patients with erythema migrans and acrodermatitis chronica atrophicans obtained during active infection and thereafter. Disease-relevant polymorphisms will be assessed by ImmunoChip. Transcriptome profiling of patients’ immune cell subtypes will be conducted by RNA sequencing.
7) To develop clinically-relevant predictive models using mathematical modeling and biostatistics to correlate strain differences and immune profiles with clinical parameters, including: in LB - frequency of dissemination, disease severity, and post-Lyme symptoms; in TBE - severity of acute illness and the presence of postencephalitic syndrome.
Significance for science
Importance for the development of science is depicted by four research topics.
The aims in this programme are set to fill the void in knowledge on the etiology, diseases course, pathogenic mechanisms, and treatment efficacy for the known arthropod-borne illnesses in Slovenia (LB, TBE, and HGA), asses and characterize other arthropod-borne diseases, and identify new diseases. Since this programme 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 to potentially include studies of new viral and spirochetal genotypes, etiology of new diseases, factors in acute versus chronic infection, and immune mechanisms of post-treatment symptoms.
The studies in topic 1 and topic 3 will provide new insight in arthropod-transmitted diseases including clinical course and treatment. In addition to providing new knowledge on LB, TBE, and HGA, which exist in Slovenia, we expect to uncover other arthropod-borne illnesses, such as West Nile fever, which has been reported in neighboring countries. Furthermore, we may identify a new illness, similar to the first European case of HGA, which we discovered 17 years ago in a prospective study on the etiology of febrile illnesses after tick bite. We will also determine the frequency, clinical characteristics, and disease outcome in patients coinfected with Lyme borreliae, TBE virus, or A. phagocytophilum. This information is currently very limited.
In topic 2 we aim to substantially expand on and elucidate the pathogenesis of LB, the most common arthropod-borne illness in Northern hemisphere. We will obtain new information on the laboratory findings and immune mechanisms in LB patients, the course and outcome of LB according to age, pregnancy and severe immunodeficiency, and infection with different Borrelia species, and the efficacy of various treatment and diagnostic approaches. We will also gain insight into immune and genetic traits in LB patients with acute skin manifestation (solitary EM) or with chronic skin involvement (ACA) to ascertain factors associated with chronic illness. Finally, based on already acquired data on )11.000 EM patients, we will determine the frequency and type of reinfections with B. burgdorferi s.l., the circumstances in which the reinfections occur, and the clinical, etiological, and immunological distinctions in patients with primary and repeat infections.
In patients with febrile illness after tick bite, we anticipate to obtain new information on the frequency and on clinical and laboratory characteristics of the isolated initial phase of TBE. Currently, these data are very limited and contradictory. Acquisition of the TBE virus genetic material from blood in the initial phase of illness will allow us to correlate variants of TBE virus causing the illness with clinical data in the same patient. This approach has not yet been tested/reported. In addition, we will assess the inflammatory mediators at the time of acute TBE and after treatment, and correlate these findings with disease severity and outcome. Since cytokines and chemokines serve as markers and mediators of the immune response, this information will provide insight into pathogenic mechanisms and may identify a biomarker of disease activity. Moreover, the findings may help elucidate the mechanisms in the development of TBE in individuals vaccinated against TBE.
The studies in Topic 4 will provide important new insight into the mechanisms of post-treatment symptoms after LB or TBE. Patients will be assessed and their samples collected before treatment, and during follow up, within months after treatment. This approach has several advantages. First, the studies are based in a human system using samples and clinical information from the same well-defined patients, rather than cell culture and animal models which may not be applicable to humans. Second, patients will be followed from active i
Significance for the country
Direct impact of the programme on the economy and society
Topic 1: Are arthropode-borne illnesses other than LB, TBE and HGA present in Slovenia? Discovery of an arthropod-borne illness other than LB, TBE and HGA in Slovenia, such as West Nile fever, will enable introduction of rational public health measures and may have enormous impact on public health not only in Slovenia but also elsewhere. Establishment of a new (bacterial disease) would most probably enable an effective etiological treatment.
Topic 2: Lyme borreliosis and tick-borne encephalitis
- Comparison of the efficacy, side effects and cost of therapy with different antibiotics may enable optimization of treatment strategies. For example if treatment with less costly antibiotic or for shorter duration is as effective as more expensive or longer therapy, this will have a direct positive economic impact.
- Understanding the course and outcome of early LB in severely immunocompromised patients, and in pregnant women will enable rational management of these groups of patients, while the assessment of the value of different laboratory approaches for the diagnosis of Lyme neuroborreliosis may lead to optimization of diagnostic approaches.
- Data on clinically manifested reinfections with B. burgdorferi sensu lato will make possible a valuable source of information for LB vaccine preparation.
Topic 3: Concomittant infecions. Identification of coinfections with Lyme borreliae, TBE virus, and/or A. phagocytophilum would enable the implementation of a rational approach for diagnostic testing and treatment of coinfected patients.
Topic 4: Elucidation of LB and TBE pathogenesis and post-Lyme and post-TBE symptoms will impact the management of patients, particularly those with post-treatment symptoms after LB. This group of patients represents a substantial scientific, medical and practical challenge that has been further augmented by numerous individuals and groups using unscientific and potentially detrimental treatment approaches.
Indirect impact of the programme on the society
In addition to the direct impact, a successful implementation of the programme will also have substantial indirect influence in several key areas. We envision these areas to include development/enhancement of professional expertise and promotion of profesional excelency; improvement, augmentation, and intensification of clinical research; stimulation and facilitation of interdisciplinary international collaboration; and effective promotion of the country through publication of the findings in high ranked journals and by presentation of the findings at international meetings (congresses).
Most important scientific results
Annual report
2015,
interim report
Most important socioeconomically and culturally relevant results
Annual report
2015,
interim report
