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Structural characterization of influenza A polymerase PA subunit domains in complex with novel inhibitors
Radilová, Kateřina ; Kožíšek, Milan (advisor) ; Rumlová, Michaela (referee) ; Obšil, Tomáš (referee)
Influenza RNA-dependent RNA polymerase is a heterotrimeric complex and has an essential role in the life cycle of the virus. It is responsible for viral replication and transcription. One of its subunits, the polymerase acidic protein, interacts with the PB1 subunit via a crucial protein- protein interaction at its C-terminal domain. This 310 helix-mediated intersubunit interaction is required for the whole heterotrimer assembly. The N-terminal domain carries the endonuclease active site with two manganese ions. Both domains are considered promising drug targets. Current strategies to fight the influenza virus are limited to seasonal vaccines, and there are only a few anti-influenza drugs targeting mostly other viral proteins. Many used antivirals are susceptible to rapid resistance mutations development or cause severe side effects. This thesis provides structural insights into the two domains of the PA subunit. The first part is devoted to the characterization and optimization of a PB1-derived minimal peptide interacting with the C-terminal domain. Results from this part may be considered as a starting point for the rational design of first-in-class anti-influenza inhibitors of the PA-PB1 protein-protein interaction. In the other half, we have explored the inhibitory potency of flavonoids and...
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The role of innate lymphoid cells in influenza virus infection
Mouyabi, Flaviancia ; Hrdý, Jiří (advisor) ; Kössl, Jan (referee)
Innate lymphoid cells (ILCs) are recently discovered group of innate immune cells. They do not have antigen-specific receptors but they can be activated by cytokines similarly to T lymphocytes. ILCs have a crucial role in the regulation of inflammation, tissue repair, containment of commensals, anti-infection immunity and regulation of tissue homeostasis. The presence of mouse and human ILCs can be detected in the lung during and after influenza virus infection when ILCs contribute to the restoration of damaged lung parenchyma. ILCs directly or indirectly provide protection against viral infections by secretion of various cytokines and co-operation with other cells (e.g. T cells, macrophages). Overall, lung ILCs are important in immune responses and tissue homeostasis, but further studies on this topic are needed to fully understand their role. The aim of this thesis was to specifically characterize these cells, focus on their function in the lung, and describe their role in the course of influenza virus infection.
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DNA/RNA intercalating agents as antivirotics: possible mechanisms of action
Kropáček, Václav ; Španielová, Hana (advisor) ; Šmahelová, Jana (referee)
DNA/RNA intercalating agents are compounds with capability to insert themself between nucleic acids base pairs. This phenomenon is accompanied by structural or functional disruption of said nucleic acid. Some of these compounds are used as therapeutics for cancer, bacterial or parasital infection or are used as antivirotics. This work summarizes different mechanisms which are responsible for antiviral effects of three significant classes of intercalating agents, acridine derivates, quinolines and quinolones. Except for intercalation into nucleic acids, these compounds are also capable of alkalization of cellular organels, inhibition of some viral enzymes (helicase, integrase) and immunomodulation. These abilities enables them to disrupt viral life cycle.
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The role of innate lymphoid cells in influenza virus infection
Mouyabi, Flaviancia ; Hrdý, Jiří (advisor) ; Kössl, Jan (referee)
Innate lymphoid cells (ILCs) are recently discovered group of innate immune cells. They do not have antigen-specific receptors but they can be activated by cytokines similarly to T lymphocytes. ILCs have a crucial role in the regulation of inflammation, tissue repair, containment of commensals, anti-infection immunity and regulation of tissue homeostasis. The presence of mouse and human ILCs can be detected in the lung during and after influenza virus infection when ILCs contribute to the restoration of damaged lung parenchyma. ILCs directly or indirectly provide protection against viral infections by secretion of various cytokines and co-operation with other cells (e.g. T cells, macrophages). Overall, lung ILCs are important in immune responses and tissue homeostasis, but further studies on this topic are needed to fully understand their role. The aim of this thesis was to specifically characterize these cells, focus on their function in the lung, and describe their role in the course of influenza virus infection.
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The role of innate lymphoid cells in influenza virus infection
Mouyabi, Flaviancia ; Hrdý, Jiří (advisor) ; Hájková, Michaela (referee)
Innate lymphoid cells (ILCs) are recently discovered group of innate immune cells. They do not have antigen-specific receptors but they can be activated by cytokines similarly to T lymphocytes. ILCs have a crucial role in the regulation of inflammation, tissue repair, containment of commensals, anti-infection immunity and regulation of tissue homeostasis. The presence of mouse and human ILCs can be detected in the lung during and after influenza virus infection when ILC contribute to the restoration of damaged lung parenchyma. ILCs directly or indirectly provide protection against viral infections by secretion of various cytokines and co-operation with other cells (e.g. T cells, macrophages). Overall, lung ILCs are important in immune responses and tissue homeostasis, but further studies on this topic are needed to fully understand their role. The aim of this thesis was to specifically characterize these cells, focus on their function in the lung, and describe their role in the course of influenza virus infection.
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