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- Ito, Yuki, et al.
(författare)
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Helicobacter pylori Cholesteryl α-Glucosides Contribute to Its Pathogenicity and Immune Response by Natural Killer T Cells
- 2013
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Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 8:12
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Tidskriftsartikel (refereegranskat)abstract
- Approximately 10-15% of individuals infected with Helicobacter pylori will develop ulcer disease (gastric or duodenal ulcer), while most people infected with H. pylori will be asymptomatic. The majority of infected individuals remain asymptomatic partly due to the inhibition of synthesis of cholesteryl α-glucosides in H. pylori cell wall by α1,4-GlcNAc-capped mucin O-glycans, which are expressed in the deeper portion of gastric mucosa. However, it has not been determined how cholesteryl α-glucosyltransferase (αCgT), which forms cholesteryl α-glucosides, functions in the pathogenesis of H. pylori infection. Here, we show that the activity of αCgT from H. pylori clinical isolates is highly correlated with the degree of gastric atrophy. We investigated the role of cholesteryl α-glucosides in various aspects of the immune response. Phagocytosis and activation of dendritic cells were observed at similar degrees in the presence of wild-type H. pylori or variants harboring mutant forms of αCgT showing a range of enzymatic activity. However, cholesteryl α-glucosides were recognized by invariant natural killer T (iNKT) cells, eliciting an immune response in vitro and in vivo. Following inoculation of H. pylori harboring highly active αCgT into iNKT cell-deficient (Jα18(-/-)) or wild-type mice, bacterial recovery significantly increased in Jα18(-/-) compared to wild-type mice. Moreover, cytokine production characteristic of Th1 and Th2 cells dramatically decreased in Jα18(-/-) compared to wild-type mice. These findings demonstrate that cholesteryl α-glucosides play critical roles in H. pylori-mediated gastric inflammation and precancerous atrophic gastritis.
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- Persson Košenina, Sara, 1993-
(författare)
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Botulinum neurotoxins
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Botulinum neurotoxins (BoNTs) are the most potent toxins known to man, with less than 1 μg of pure toxin being enough to kill an adult man. Despite the high toxicity, BoNTs are widely used in cosmetics and in medicine for the treatment of an increasing number of medical conditions.BoNTs have a conserved structure that consists of three domains (a receptor binding, translocation, and catalytic domain). The receptor binding domain is responsible for binding to neuronal receptors, the translocation domain is a delivery vehicle that transports the catalytic domain into the cytosol, where the latter cleaves its target - proteins of the SNARE family, inhibiting neurotransmitter release and consequently causing muscle paralysis.BoNTs are produced by the bacteria Clostridium botulinum together with several other accessory proteins, which are responsible for shielding BoNTs in the harsh environment of the target gastrointestinal tract and assisting them in crossing the epithelial barrier between the gastrointestinal tract and general circulation.Several BoNT serotypes (A-G) have been identified over the years. Additionally, several BoNT-like toxins have been identified in non-Clostridial types of bacteria. Namely, these proteins are BoNT/Wo, BoNT/En and PMP1.In this thesis, we present six papers, where we studied both the canonical BoNTs and the new BoNT-like toxins as well as their accessory proteins using structural biology techniques, such as X-ray crystallography and cryo-EM. Elucidating the structures of these proteins is crucial for understanding their function and mechanism of action.
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