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Signalization of adenylate cyclase toxin of Bordetella pertussis in macrophages.
Černý, Ondřej ; Kamanová, Jana (advisor) ; Kuthan, Martin (referee)
Adenylate cyclase toxin (CyaA) is a key virulence factor of Bordetella pertussis, the causative agent of whooping cough. The toxin targets primarily myeloid phagocytes expressing CD11b/CD18 (αMβ2, CR3, Mac-1) and by elevation of cytosolic cAMP levels it paralyses their macropinocytic and opsono-phagocytic functions. Here, we dissected the cAMP-regulated pathway responsible for the block of macrophage macropinocytosis and characterized the capacity of CyaA-treated macrophages to shut- down Akt (protein kinase B, PKB) signaling; that controls nitric oxide (NO) production by macrophages. By using specific activators of protein kinase A (PKA) and for the exchange protein activated by cAMP (Epac), we show that activation of the cAMP effector Epac inhibits macropinocytosis in macrophages. Moreover, upon transfection of macrophages by the constitutively active and dominant negative variants of a downstream effector of Epac, the small GTPase Rap1, inhibition or upregulation of macrophage macropinocytosis was observed, respectively. It was reported previously that the Epac/Rap1 pathway regulates activity of tyrosin phosphatase SHP-1 as well as of protein phosphatase 2 A (PP2A). We show that inhibition of both tyrosin phosphatases and PP2A interferes with CyaA-mediated block of macropinocytosis. These...
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Fish Herpesviruses
Čečetka, Petr ; Forstová, Jitka (advisor) ; Kuthan, Martin (referee)
Herpetic viruses that attack fish are ones of the most widespread virus pathogens, threatening modern day fish population not only in the wild but also those that are farmed. There are many types of the pathogen, from the ones those do not cause severe diseases to those that are extremly dangerous, spread without any control and caused vast losses in commercial farming and in wild populations. Most of the viruses exhibit increased sensitivity on heat and stress factors, which are the most common reasons of the repeating outbreak of disease. To the best described fis herpesvirus viruses attacking fresh water fishes belong. Nowadays more and more herpetic viruses which attack mainly salt water fis are beeing discovered. Powered by TCPDF (www.tcpdf.org)
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Seroprevalence of polyomaviruses in human
Blagoevová, Kateřina ; Drda Morávková, Alena (advisor) ; Kuthan, Martin (referee)
Human BK polyomavirus, also known as Polyomavirus hominis type 1, is a small animal tumorigenic virus. It penetrates into the host cell by caveolin-mediated endocytosis and then through the ER pathway to get into the nucleus where the virus replicates and expresses viral proteins. BKV primary infection typically occurs during childhood and id mostly asymptomatic, it is only occasionally accompanied by mild respiratory or urinary tract illnesses associated with viruria. After primary infection the virus occurs mainly in the kidney and urinary tract and in immunocompetent individuals remains in nonreplicative state. Healthy individuals have no health problems and it persists as a lifelong infection. In immunosuppressed individuals, particularly renal and bone marrow transplant patients, causing virurie, viremia, ureteral stenosis and serious nephropathy, this can lead to graft failure. The prevalence of this virus in the world is significant, scientific publications indicate that up to 80% of the human population has specific antibodies. Any small amounts of the virus prevalence reported in some publications are probably caused by using various sensitive detection methods and different types of samples.
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Antiparasitic and antimycotic effect of different iron chelators
Šipková, Anna ; Šuťák, Róbert (advisor) ; Kuthan, Martin (referee)
Iron plays a key role in many metabolic pathways in the cell, but it may become toxic at higher concentrations. Therefore, the maintenance of iron homeostasis is crucial for cell viability and is strictly regulated. This element has also an important role in the host-parasite interaction. Parasites are fully dependent on iron uptake from the host environment. Iron uptake is a very difficult process thanks to effective sequestration of the host's iron supplies, which makes iron almost inaccessible to parasites. Imported iron is mostly transported to the mitochondria where it is necessary for its proper function. This work is focused on the effect of modified chelators on pathogenic fungi and the chosen kinetoplastid parasites, which cause serious human diseases. These diseases are becoming a great threat due to emerging drug resistances. Modified chelators are able to target mitochondrial functions and affect iron homeostasis, which can lead to a promising antiparasitic and antimycotic effect. Modified chelators in tested organisms can inhibit their gorwth even in nM concetrations, affect mitochondrial respiration, membrane potential and membrane permeability. Thanks to mitochondrial targeting the potency was much higher compared to the unmodified compounds. This work contains also research of new...
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Nuclear lamina, its function in the cell and its role in interaction with non-enveloped DNA viruses
Pápež, Samuel ; Bruštíková, Kateřina (advisor) ; Kuthan, Martin (referee)
The nuclear lamina is a protein network found in all metazoa. It is composed of intermediate filaments V, namely type A and type B lamins. It is a multifunctional cellular structure adjacent to the inner nuclear membrane, giving the nucleus its shape, ensuring its mechanical stability and participating in the regulation of many nuclear processes. The nuclear lamina also has a protective function manifested in the infection of cells with DNA viruses, whose life cycle takes place in the nucleoplasm. These include small non-enveloped DNA viruses. The nuclear lamina is an obstacle that viruses have had to learn to overcome in order to multiply. To do this, they use their own, but also cellular mechanisms, which disrupt the nuclear membrane together with the nuclear lamina and thus allow the virus nuclear entry and exit. This work summarizes the knowledge about changes in the nuclear lamina induced by viruses of the families Polyomaviridae, Parvoviridae and Circoviridae, on the way through the nuclear envelope. Keywords: Nuclear lamina, disassembly of nuclear lamina, DNA viruses, Polyomaviruses, Parvoviruses, Circoviruses
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Cryptococcus neoformans virulence factors
Bauer, Martin ; Kuthan, Martin (advisor) ; Abrhámová, Kateřina (referee)
Cryptococcus neoformans is an opportunistic pathogenic yeast causing around 600 000 deaths annually. Its ability to cause a chronic infection is given by multiple virulence factors, which include the ability to grow in high temperature, polysaccharide capsule, oxidative stress tolerance and the expression of surface proteins. Unusual and resistant titan cells, which develop through the process of titanization, and the process of phenotypic switching can also be included. Despite intensive research, these virulence factors are yet to be fully described. Inducing factors of titan cells and participating signalling pathways are known. However, a complete model of titanization does not yet exist. So far, the mechanism of phenotypic switching is also unknown. In this work the current knowledge of virulence factors of C. neoformans is presented and summarised.
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Phenotypic switching and cell differentiation in yeast Cryptococcus neoformans
Bauer, Martin ; Kuthan, Martin (advisor) ; Abrhámová, Kateřina (referee)
Cryptococcus neoformans is an opportunistic pathogenic yeast causing around 600 000 deaths annually. Its ability to cause a chronic infection is given by the emergence of different morfotypes. These morphotypes differ in cell structures and mechanisms (virulence factors) which have an influence on the resistance to stress factors encountered in the host. This work first describes molecular mechanisms of formation of these virulence factors. Next, it presents morphotypes occurring during infection and the hypovirulent pseudohyphal morphotype. However, this morphotype is interesting because of a modification in the signalisation leading to its manifestation. Finally, described signalling pathways present possible ways of regulating the virulence factors, and so the manifestation of different morphotypes. Understanding these signalling pathways could ultimately lead to improving the development of new drugs, given that Cryptococcus neoformans is highly resistant to the existing ones. Keywords: Cryptococcus neoformans, phenotypic switching, titan cells, cell differentiation, virulence, Vad1, Rim101, Usv101, RAM
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Role of autophagy in yeast cell adaptation
Brádlerová, Michaela ; Kuthan, Martin (advisor) ; Zikánová, Blanka (referee)
Autophagy is an evolutionarily conserved degradative pathway. Autophagy occurs constitutively at a basal level and it is involved in the recycling and turnover of damaged or superfluous organelles and proteins. It has a critical role in cellular homeostasis. Autophagy can be induced in response to starvation or other types of stress. Induction of autophagy during these conditions has a major role in protection and adaptation of the cell. Autophagy needs to be properly regulated. A wide range of diseases is associated with dysregulation of autophagy. Better understanding of autophagy mechanisms can help to develop strategies designed to modulate autophagic responses occuring in a number of diseases. This work is focused on current knowledge of main types of autophagy and how autophagy helps yeast cells to adapt. Key words: autophagy, yeast, degradative pathway, adaptation, TORC1
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