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Metabolic setup of Drosophila macrophages during the immune response
KREJČOVÁ, Gabriela
Adjustment of cellular metabolism is a key function that allows macrophages to fulfill their roles in the body. While the pro-inflammatory polarization of macrophages has been extensively studied in mammalian models, it has not yet been satisfactorily investigated in insects. The study presented in this thesis therefore attempts to elucidate the metabolic setup of macrophages during the immune response in Drosophila melanogaster.
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The role of macrophages in the regulation of systemic metabolism in Drosophila
KREJČOVÁ, Gabriela
Macrophages are immensely versatile cells in the mammalian body, fulfilling roles ranging from protection against pathogenic intruders and engulfing apoptotic cells to morphogenesis and maintenance of tissue homeostasis. This impressive functional versatility may be achieved due to plasticity of macrophage cellular metabolism called metabolic polarization. The adoption of different polarization phenotypes by macrophages determines their function and is essential for the health of the organism. Nonetheless, if the cells lose their metabolic plasticity or polarize inadequately to a particular situation, it can lead to the development of chronic pathological states such as metabolic syndrome. Metabolic polarization of immune cells is thus a key factor in determining whether macrophage function within the organism will be adaptive or pathological. Despite Drosophila melanogaster represents a major model organism for immunological studies, the metabolic setup of activated immune cells has not been addressed up to now. The results of this thesis document that Drosophila immune cells undergo metabolic polarization toward aerobic glycolysis when challenged by extracellular bacteria. Mammals alike, this cellular metabolic switch is regulated by the transcription factor HIF1, thus documenting the conservation of this process between insects and vertebrates. Furthermore, we show that the adoption of aerobic glycolysis is directly linked to the production of the signaling factor IMPL2, which induces the mobilization of lipid stores from the fat body via the silencing of insulin signaling. By this mechanism, immune cells secure sufficient nutrients for successful elimination of the pathogen. Moreover, the mammalian ImpL2 homolog IGFBP7 appears to act analogously in the mammalian liver not only during severe infectious states but also in the liver of obese individuals. While such macrophage activity in regulating systemic metabolism is beneficial to the host during bacterial infection, it becomes maladaptive when chronically activated. Further evidence for a metabolism-regulatory role of immune cells has been found during insect metamorphosis and early post-metamorphic development. This thesis documents that during this period, macrophages infiltrate and engulf the histolyzing larval fat body and convert nutrients into storage peptides and lipoproteins. Subsequently, these nutrients are exploited by the maturing adult structures.
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Mebrane adaptor proteins in hematopoiesis and immune response
Pavliuchenko, Nataliia ; Brdička, Tomáš (advisor) ; Brábek, Jan (referee) ; Smrž, Daniel (referee)
Membrane adaptor proteins are proteins associated with cellular membranes that do not themselves serve as receptors. Instead, they propagate or modify the signals of these receptors by recruiting other signaling and regulatory proteins and arranging them into supramolecular complexes. In this thesis, I sought to describe selected membrane adaptor proteins and their roles in inflammation and regulation of hematopoiesis in mouse models using a reverse genetics approach. The main part of the work focused on the role of the membrane adaptor protein PSTPIP2 in suppressing inflammation. In mice, missense mutations in the Pstpip2 gene causing loss of PSTPIP2 protein lead to the development of autoinflammatory disease chronic multifocal osteomyelitis (CMO) characterized by sterile inflammatory lesions in the bones and adjacent soft tissue. These mice represent a model of the human autoinflammatory disease, chronic recurrent multifocal osteomyelitis. At the molecular level, neutrophils in the absence of PSTPIP2 exhibit pathological hyperactivity of pathways regulating IL-1β and reactive oxygen species (ROS) production, which are both implicated in the etiology of the disease. PSTPIP2 interacts with several signaling regulators, including PEST family protein tyrosine phosphatases (PEST-PTPs) and inositol...
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Host immune response in cutaneous versus visceral form of leishmaniasis
Matějková, Barbora ; Leštinová, Tereza (advisor) ; Jelínková, Kristýna (referee)
Parasitic protozoans of the genus Leishmania circulate between vectors and hosts during their life cycle, in which they come into contact with the immune system. In the host body, infection can lead to the development of a disease called leishmaniasis. This can manifest itself in a number of ways, with the best known forms being referred to as visceral, mucocutaneous and cutaneous leishmaniasis. This thesis focuses on the host immune response during the cutaneous and visceral forms of leishmaniasis. In addition, attention has been given to host, vector and parasite factors that differ between cutaneous and visceral leishmaniasis forms and that may influence the different clinical manifestations. Attention is paid not only to factors related to immunity, but also to factors such as parasite inoculum dose sizes, temperature differences between skin and internal organs, parasite genetics, and others. Keywords - Leishmania, visceral leishmaniasis, cutaneous leishmaniasis, immune response, parasite, immunity
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The Role of TRPV1 in Macrophage Activation and Polarisation
Fikarová, Natálie ; Krulová, Magdaléna (advisor) ; Frič, Jan (referee)
The ability to sense painful stimuli is essential to protect the body. Up to date, the underlying molecular mechanisms are still not completely understood; therefore, the treatment of chronic inflammatory pain remains challenging. The TRPV1 channel is one of the known nociceptors mediating the sensation of burning stimuli. Its agonist is capsaicin, the pungent compound of chilli peppers. This channel has been extensively studied in neurones; however, its function in immune cells is not well understood. Especially in macrophages, data regarding the role of TRPV1 in macrophage polarisation are often contradictory. Thus, further research in this area is desired to clarify the function of TRPV1 in immune cells. This diploma thesis aims to investigate the role of TRPV1 in macrophage polarisation during the inflammatory response. In this work, macrophages were stimulated with capsaicin prior to, after or concurrently with the application of LPS to determine the effect of TRPV1 activation on the inflammatory response. The involvement of MAP kinases in signalling after TRPV1 activation by capsaicin was addressed confirming that ERK 1/2 is part of the signalling cascade. Furthermore, this work proposes that activation of TRPV1 in the context of the LPS-induced inflammatory response could lead to the switch...
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Translation potential of current preclinical techniques for gene therapy of neurological diseases in clinic. A critical review.
Žideková, Paulína ; Novák, Ondřej (advisor) ; Jendelová, Pavla (referee)
Research in the field of gene therapy has potential to become a revolutionary way to the existing treatment for a wide spectrum of neurological diseases. To treat these disorders causally, by specific substituting, deleting, silencing or editing faulty genes could be a privilege of gene therapy. The concept of translational medicine is to facilitate the transfer of working principles in preclinical research into treatment in humans. Its key issue is to overcome limitations associated with the gap between the tremendous variety molecular biology tools of preclinical research and the lack of simple corresponding options in humans. Clinical implementation of most of the preclinical approaches is still considered to be limited. The main focus of this thesis is to summarize latest advancements of molecular and genetic engineering tools that themselves or in combination have the potential to promote most preclinical gene therapy of neurological diseases to clinical use. Based on that, this study aims to suggest perspective methods of treatment for selected neurological diseases.
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Úloha Adenylát kinázy 1 v aktivaci a metabolismu imunitních buněk larev \kur{Drosophila melanogaster}
KAISLEROVÁ, Nikola
The aim of this thesis was to study the role of Adenylate kinase 1 (Ak1) in the immune system of Drosophila melanogaster larvae upon the infection by parasitoid wasp Leptopilina boulardi. Using the immune specific Ak1 RNA interference, it was analyzed the effect of Ak1 reduction on the immune response and viability of Drosophila. The importance of Ak1 was also evaluated within the metabolism of immune cells. It has been shown that Ak1 is crucial in energy metabolism of immune cells and important for the proper functioning of immune system.
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Role makrofágy produkovaného cytokinu IMPL2 v regulaci systemického metabolismu během bakteriální infekce u \kur{Drosophila melanogaster}
VARGOVÁ, Hana
The main goal of this bachelor thesis is to verify whether ImpL2, produced by activated immune cells, is responsible for changes in systemic metabolism during the immune response during the acute phase of bacterial infection in Drosophila melanogaster. The theoretical part includes previously known information about the immune system of mammals and D. melanogaster, especially about polarization and cellular metabolism of macrophages, as well as knowledge about the roles of the ImpL2 gene and its mammalian homologue Igfbp7. The practical part of the bachelor thesis deals with the role of the ImpL2 gene in the induction of changes in systemic metabolism during the immune response. The effect of the cytokine IMPL2 on selected metabolic genes in adipose tissue after Streptococcus pneumoniae infection was tested by means of macrophage-specific RNA interference. The work also clarifies whether this signaling factor has an effect on the concentration of selected metabolites in circulation and in macrophages during the acute phase of bacterial infection.
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The role of humoral factors in the snail immune response against schistosomes
Košťáková, Monika ; Horák, Petr (advisor) ; Dvořák, Jiří (referee)
Digenetic trematodes such as Schistosoma mansoni use molluscs, mainly Gastropoda in their life cycle, as their intermediary hosts. e internal defense system (IDS) of snails is composed of immune cells called hemocytes, which are the main effectors and act jointly with soluble components. Humoral factors could in uence directly the parasite's larval stage, the activity of hemocytes and also may serve in recognition of the parasite. Lectins are considered to be the main component of humoral immunity. ey have a primary role in non-self recognition. Other protein group with lectin-like activity called FRePs was found in Biomphalaria glabrata. eir unique structure contains a brinogen and an immunoglobulin-like domain. Cytokine-like molecules may play very important role in defense as well. Many molecules are present in hemolymph and their levels change during infection. e response to parasitosis is therefore very complex and still awaits further clari cation.
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Cytokines and chemokines, their role in the infections with helminths.
Majer, Martin ; Panská, Lucie (advisor) ; Leštinová, Tereza (referee)
Parasitic helminths belong to extracellular pathogens of mammals, including human. Immunologic response depends on their migration and site of dwelling within host body. The response is among other affected by cytokines and chemokines. These small proteins are responsible for appropriate proliferation and migration of other components of immune system. These bachelor thesis summarizes current knowledge about their role during helminth infection in mammals.
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