"NV19-05-00191" Dotaz Zobrazit nápovědu
Závěrečná zpráva o řešení grantu Agentury pro zdravotnický výzkum MZ ČR
nestr.
Lyme disease is an infection caused by spirochetes of the species complex Borrelia burgdorferi. It is multisystem disease most commmonly manifested as neurological or rheumatic symptoms. In some patients chronic complications persist after treatment. This condition is ussually referred as Post-Lyme disease syndrome and its pathogenesis is unclear. Both the persistence of bacteria and the involvement of autoimmune mechanisms are discussed as a possible cause. A combination of both factors in the form of chronic stimulation of the immune system by persistent inactive forms of Borrelia is also contemplated. The persistence of bacteria in the organism can be facilitated by the non-spiral forms of Borrelia, which has been observed when Borrelia culture is exposed to unfavorable conditions. The project will be focused on the mechanisms of formation of non-spiral forms of Borrelia spirochetes. We will test their infectivity and immunogenicity in vivo and interactions with mammalian cells in vitro. Results obtained during the project has the potential to contribute to a more effective diagnosis and treatment of Lyme borreliosis.
Lymeská borelioza je bakteriální multisystémové onemocnění způsobené spirochetami druhového komplexu Borrelia burgdorferi. Projevuje se nejčastěji kožními, neurologickými nebo kloubními symptomy. Neléčené onemocnění může přecházet do pozdních stádií s chronickým postižením. Přestože u většiny nemocných je efektivní antibiotická léčba, u části pacientů se i přes intenzivní antibakteriální terapii objevují přetrvávající potíže. Tento stav bývá uváděn jako tzv. post-boreliový syndrom. Příčina tohoto stavu dosud není vyjasněna, zvažuje se jak perzistence samotných bakterií, tak zapojení autoimunitních mechanismů. Uvažuje se i o kombinaci obou faktorů ve formě chronické stimulace imunitního systému perzistujícími neaktivními formami Borelií. Na perzistenci bakterií v organismu se mohou podílet nespirální formy Borelií, které byly pozorovány při vystavení Boreliové kultury nepřiznivým podmínkám. V projektu se zaměříme na mechanismy vzniku nespirálních forem Borelií. Budeme testovat jejich infekčnost a imunogenitu in vivo a interakce se savčími buňkami in vitro. Získané poznatky mají potenciál přispěk ke zefektivnění diagnostiky a léčby Lymeské boreliozy.
The initial phase of multiple sclerosis (MS), often known as clinically isolated syndrome (CIS), is a critical period for identifying individuals at high risk of progressing to full-blown MS and initiating timely treatment. In this study, we aimed to evaluate the prognostic value of C-X-C motif chemokine ligand 13 (CXCL13) and interleukin-8 (IL-8) as potential markers for CIS patients' conversion to MS. Our study encompassed patients with CIS, those with relapsing-remitting MS (RRMS), and control subjects, with sample analysis conducted on both cerebrospinal fluid (CSF) and serum. Patients were categorized into four groups: CIS-CIS (no MS development within 2 years), CIS-RRMS (conversion to RRMS within 2 years), RRMS (already diagnosed), and a control group (CG) with noninflammatory central nervous system disorders. Results showed significantly elevated levels of CXCL13 in CSF across all patient groups compared with the CG (p < 0.0001, Kruskal-Wallis test). Although CXCL13 concentrations were slightly higher in the CIS-RRMS group, statistical significance was not reached. Similarly, significantly higher levels of IL-8 were detected in CSF samples from all patient groups compared with the CG (p < 0.0001, Kruskal-Wallis test). Receiver operating characteristic analysis in the CIS-RRMS group identified both CXCL13 (area under receiver operating characteristic curve = .959) and IL-8 (area under receiver operating characteristic curve = .939) in CSF as significant predictors of CIS to RRMS conversion. In conclusion, our study suggests a trend towards elevated CSF IL-8 and CSF CXCL13 levels in CIS patients progressing to RRMS. These findings emphasize the importance of identifying prognostic markers to guide appropriate treatment strategies for individuals in the early stages of MS.
- MeSH
- biologické markery mozkomíšní mok krev MeSH
- chemokin CXCL13 * mozkomíšní mok krev MeSH
- demyelinizační nemoci mozkomíšní mok MeSH
- dospělí MeSH
- interleukin-8 * mozkomíšní mok krev MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- prognóza MeSH
- progrese nemoci * MeSH
- relabující-remitující roztroušená skleróza * mozkomíšní mok krev diagnóza MeSH
- roztroušená skleróza mozkomíšní mok krev diagnóza MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Borrelia burgdorferi sensu lato is a species complex of pleomorphic spirochetes, including species that cause Lyme disease (LD) in humans. In addition to classic spiral forms, these bacteria are capable of creating morphological forms referred to as round bodies and aggregates. The subject of discussion is their possible contribution to the persistence of infection or post-infection symptoms in LD. This study investigates the immunological properties of these forms by monitoring reactivity with early (n = 30) and late stage (n = 30) LD patient sera and evaluating the immune response induced by vaccination of mice. In patient sera, we found a quantitative difference in reactivity with individual morphotypes, when aggregates were recognized most intensively, but the difference was statistically significant in only half of the tested strains. In post-vaccination mouse sera, we observed a statistically significant higher reactivity with antigens p83 and p25 (OspC) in mice vaccinated with aggregates compared to mice vaccinated with spiral forms. The importance of the particulate nature of the antigen for the induction of a Th1-directed response has also been demonstrated. In any of morphological forms, the possibility of inducing antibodies cross-reacting with human nuclear and myositis specific/associated autoantigens was not confirmed by vaccination of mice.
- MeSH
- antigeny bakteriální MeSH
- Borrelia burgdorferi komplex * MeSH
- Borrelia burgdorferi * MeSH
- lidé MeSH
- lymeská nemoc * mikrobiologie MeSH
- myši MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Lyme disease (LD) spirochetes are well known to be able to disseminate into the tissues of infected hosts, including humans. The diverse strategies used by spirochetes to avoid the host immune system and persist in the host include active immune suppression, induction of immune tolerance, phase and antigenic variation, intracellular seclusion, changing of morphological and physiological state in varying environments, formation of biofilms and persistent forms, and, importantly, incursion into immune-privileged sites such as the brain. Invasion of immune-privileged sites allows the spirochetes to not only escape from the host immune system but can also reduce the efficacy of antibiotic therapy. Here we present a case of the detection of spirochetal DNA in multiple loci in a LD patient's post-mortem brain. The presence of co-infection with Borrelia burgdorferi sensu stricto and Borrelia garinii in this LD patient's brain was confirmed by PCR. Even though both spirochete species were simultaneously present in human brain tissue, the brain regions where the two species were detected were different and non-overlapping. The presence of atypical spirochete morphology was noted by immunohistochemistry of the brain samples. Atypical morphology was also found in the tissues of experimentally infected mice, which were used as a control.
- MeSH
- Borrelia burgdorferi komplex * genetika MeSH
- Borrelia burgdorferi * genetika MeSH
- Borrelia * genetika MeSH
- lidé MeSH
- lymeská nemoc * MeSH
- mozek MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
Transmission of the causative agents of numerous infectious diseases might be potentially conducted by various routes if this is supported by the genetics of the pathogen. Various transmission modes occur in related pathogens, reflecting a complex process that is specific for each particular host-pathogen system that relies on and is affected by pathogen and host genetics and ecology, ensuring the epidemiological spread of the pathogen. The recent dramatic rise in diagnosed cases of Lyme borreliosis might be due to several factors: the shifting of the distributional range of tick vectors caused by climate change; dispersal of infected ticks due to host animal migration; recent urbanization; an increasing overlap of humans' habitat with wildlife reservoirs and the environment of tick vectors of Borrelia; improvements in disease diagnosis; or establishment of adequate surveillance. The involvement of other bloodsucking arthropod vectors and/or other routes of transmission (human-to-human) of the causative agent of Lyme borreliosis, the spirochetes from the Borrelia burgdorferi sensu lato complex, has been speculated to be contributing to increased disease burden. It does not matter how controversial the idea of vector-free spirochete transmission might seem in the beginning. As long as evidence of sexual transmission of Borrelia burgdorferi both between vertebrate hosts and between tick vectors exists, this question must be addressed. In order to confirm or refute the existence of this phenomenon, which could have important implications for Lyme borreliosis epidemiology, the need of extensive research is obvious and required.
- Publikační typ
- časopisecké články MeSH
The survival of spirochetes from the Borrelia burgdorferi (sensu lato) complex in a hostile environment is achieved by the regulation of differential gene expression in response to changes in temperature, salts, nutrient content, acidity fluctuation, multiple host or vector dependent factors, and leads to the formation of dormant subpopulations of cells. From the other side, alterations in the level of gene expression in response to antibiotic pressure leads to the establishment of a persisters subpopulation. Both subpopulations represent the cells in different physiological states. "Dormancy" and "persistence" do share some similarities, e.g. both represent cells with low metabolic activity that can exist for extended periods without replication, both constitute populations with different gene expression profiles and both differ significantly from replicating forms of spirochetes. Persisters are elusive, present in low numbers, morphologically heterogeneous, multi-drug-tolerant cells that can change with the environment. The definition of "persisters" substituted the originally-used term "survivors", referring to the small bacterial population of Staphylococcus that survived killing by penicillin. The phenomenon of persisters is present in almost all bacterial species; however, the reasons why Borrelia persisters form are poorly understood. Persisters can adopt varying sizes and shapes, changing from well-known forms to altered morphologies. They are capable of forming round bodies, L-form bacteria, microcolonies or biofilms-like aggregates, which remarkably change the response of Borrelia to hostile environments. Persisters remain viable despite aggressive antibiotic challenge and are able to reversibly convert into motile forms in a favorable growth environment. Persisters are present in significant numbers in biofilms, which has led to the explanation of biofilm tolerance to antibiotics. Considering that biofilms are associated with numerous chronic diseases through their resilient presence in the human body, it is not surprising that interest in persisting cells has consequently accelerated. Certain diseases caused by pathogenic bacteria (e.g. tuberculosis, syphilis or leprosy) are commonly chronic in nature and often recur despite antibiotic treatment. Three decades of basic and clinical research have not yet provided a definite answer to the question: is there a connection between persisting spirochetes and recurrence of Lyme disease in patients?
