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Genes participating in response to Leishmania major revealed by targeted mutation.
Ezrová, Zuzana ; Lipoldová, Marie (advisor) ; Krulová, Magdaléna (referee)
Leishmania major is an intracellular parasite which often successfully multiplies and disseminates in a body of the host thanks to strategies that help it to escape the components of immune system of the host organism. Thus, the parasites evoke an impairment of regulatory pathways that in physiological conditions lead to an expression of genes involved in a response to L. major and its efficient elimination. Gene targeted deletion, also called gene knock-out, can result in phenotypic alteration and associated enhanced susceptibility or resistance of the host. Although such detected genes do not have to signify their variability in population and hence they may not be responsible for the worsened outcome of leishmaniasis of some people necessarily, studies in which they are analysed and general knowledge being also a subject of this thesis help us together with techniques of forward genetics to reveal the biochemical pathways during the infection and their elements that influence the outcome of the disease and might be useful for researches of new medicine drugs or gene therapy.
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Leishmania tropica: immunopathology and genetic control
Sohrabi, Yahya ; Lipoldová, Marie (advisor) ; Pravenec, Michal (referee) ; Sádlová, Jovana (referee)
Leishmaniasis is a neglected tropical disease caused by protozoan parasites of the genus Leishmania and transmitted by female sand flies. The outcome of Leishmania infection depends both on host and pathogen factors. Similarly as L. major, L. tropica very often causes cutaneous leishmaniasis in humans, but in rare occasions can also visceralize and cause systemic disease. Leishmaniasis cause by L. tropica has become a major public health problem in different endemic foci due to recent outbreaks in several urban areas and spread to new regions. The complications of the disease and lack of safe and effective drug and vaccine against the L. tropica infection require considerable attention to studies of the host-L. tropica interaction. Until recently, the research of leishmaniasis caused by L. tropica was limited due to lack of suitable inbred model and difficulties in inducing infection in animals. The aims of the present project were development of a suitable mouse model of the infection caused by L. tropica, and the study of mechanisms of the disease, and also mapping controlling genes/loci. We analysed susceptibility to L. tropica infection using recombinant congenic (RC) CcS/Dem mouse strains. These strains differ greatly in susceptibility to L. major due to random distribution of 12.5% of STS...
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Immunotherapy of HPV16 - associated cancers and regulation of antitumour immune response
Štěpánek, Ivan ; Reiniš, Milan (advisor) ; Lipoldová, Marie (referee) ; Němečková, Šárka (referee)
The MHC class I status of tumour cells during immunotherapy is often underestimated. It represents one of important tumour escape mechanisms and thus can contribute to the failure of most of the cancer clinical trials that are usually based on the induction of cytotoxic T cell responses. Epigenetic changes in the promoters of genes involved in the MHC class I Ag presentation can result in decreased expression of the cell surface MHC molecules on tumour cells. Thus, epigenetic modifiers can restore an expression of the MHC class I molecules and make tumours visible to the CD8+ effector cells. Besides the epigenetic changes on the tumour cells, epigenetic modulators affect cells of the immune system such as dendritic cells (DC). Tumour cells can escape from the immune response not only by changes in the cancer cells, but also by influencing, expanding and/or activating immunoregulatory cell populations, such as regulatory T cells (Treg). This thesis focuses on the potential of the DC-based vaccines against HPV-16-associated tumours with a different MHC class I expression, on the combination of cancer immunotherapy with the treatment using epigenetic modifiers, with special attention paid to their effects on DC, and, finally, on the impacts of the anti-CD25 antibody (used for Treg elimination) on Treg and NKT...
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Experimental murine leishmaniasis and its application for drug discovery and study of host-pathogen interactions
Grekov, Igor ; Lipoldová, Marie (advisor) ; Krulová, Magdaléna (referee) ; Šírová, Milada (referee)
Leishmania spp. have a great clinical significance, being a causative agent of leishmaniasis. Leishmania is transmitted to its vertebrate hosts by phlebotomine sand flies. In vertebrates, the parasites infect professional phagocytes (neutrophils, monocytes and macrophages) and a variety of other cells. Clinical symptoms of leishmaniasis range from lesions, local or disseminated, to mucosal and visceral pathology. Twelve million people are infected with Leishmania and 350 million people are under risk of infection in 88 countries. Yet, no vaccine has been developed and the treatment needs significant improvement. In this regard, animal models of leishmaniasis play a key role in understanding the mechanisms of the disease and in finding ways to treat and prevent it. This thesis summarizes the results of my Ph.D. project devoted to refinement of procedures relevant to Leishmania studies and to the use of the optimized protocols for gene mapping and search for antileishmanial drugs. Large-scale cultivation of infective Leishmania parasites is important in a wide range of experimental setups. We adapted a biphasic SNB-9 medium for the large-scale cultivation of Leishmania and compared it with a common liquid medium. We also modified and optimised detection and quantification of Leishmania with PCR-ELISA by using...
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Methods for Leishmania parasite detection and quantificatio as a tool for study of the pathogen-vector-host interactions
Kobets, Tetyana ; Lipoldová, Marie (advisor) ; Kodym, Petr (referee) ; Kopecký, Jan (referee)
Methods for Leishmania parasite detection and quantification as a tool for study of the pathogen-vector-host interactions Leishmaniasis in human is caused by total 21 species of the intracellular protozoan parasite Leishmania, which are transmitted by about 30 species of phlebotomine sand flies. Besides human, Leishmania can infect a number of vertebrate hosts. The major host cell is the macrophage, in which parasites multiply, eventually rupturing the cell and spreading to uninfected cells. Infected monocytes and macrophages circulating in the peripheral blood are thought to be carriers of the parasite to distal sites. Depending on the infected sites of the body, there are three forms of leishmaniasis: cutaneous, mucocutaneous and visceral. Leishmaniasis is a disease for which we still lack effective, affordable and easy to use drugs. In addition, surveillance and control are also neglected. This thesis summarizes the results of several projects using different approaches for parasite load measurement in the mouse model of leishmaniasis, including two methods that were developed and optimized in our laboratory. Detection and quantification of pathogens belongs to the major topics of the research of various infectious diseases. This parameter is necessary for confirmation of the diagnosis, characterization...
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Genetic influenceof Trypanosoma brucei brucei infection in mice
Šíma, Matyáš ; Lipoldová, Marie (advisor) ; Krulová, Magdaléna (referee)
Genetic influence of Trypanosoma brucei brucei infection in mice The African trypanosomes are zoonotic parasites transmitted by Tse-Tse flies. Two of the three subspecies, Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense, cause sleeping sickness in humans whereas the third subspecies, Trypanosoma brucei brucei is not infective to humans. These parasites are members of Kinetoplastida. Trypanosomes are extracellular parasite witch have complex life cycles involving both insect and mammalian hosts. African trypanosomes after infection penetrate mainly vascularized organs and get into brain where cause serious pathology. Parasite can manipulate with immune system of mammal host in wide spectrum of interactions witch are not clearly understood so far. Discovering of a new immune mechanisms, whitch participite in reaction on african trypanosomes, can reveal some general characteristics of immune system. The results of these studies can help to prepare effective drugs and vaccines against this disease. The best way to observe pathological manifestation and genetical analysis is study on animal models . Study on suitable animal model to find genes which are responsible for control of immune response to T. brucei can help us to find homologous genes in humans. It was found that immune responces to...
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