By: Raquel Garcia Lobato Tavares
Date: 14 December 2017, 10.00 AM - 13.00 AM
Venue: Vivi Täckholmsalen (Q-salen), NPQ-huset, Svante Arrhenius väg 20 

Examination board
Åsa Sjöling, Dept. of Microbiology, Tumor and Cell Biology, Karolinska Institute (opponent)
Anna Norrby-Teglund, Dept. of Medicine, Karolinska Institute
Bertrand Joseph,  Institute of Environmental Medicine, Karolinska Institute
Linus Sandegren, Dept. of Medical Biochemistry and Microbiology, Uppsala University
Ulrich Theopold, Dept. of Molecular Biosciences, Wenner-Gren institute, Stockholm University
Eva Sverremark-Ekström, Dept. of Molecular Biosciences, Wenner-Gren institute, Stockholm University (chairman)


Host cell responses to Helicobacter pylori secreted factors

Abstract
The infection of the human gastric mucosa by the bacterium Helicobacter pylori can lead to the development of gastritis, gastroduodenal ulcers, and cancer. The factors that determine disease development in a small percentage of infected individuals are still not fully understood.
In this thesis, we aimed to identify and functionally characterize novel virulence factors of H. pylori and to understand their effect on host cell responses.
In Paper I, we found that JHP0290, an uncharacterized secreted protein of H. pylori, induced macrophage apoptosis concomitant to the release of pro-inflammatory cytokine TNF via the regulation of the Src family of kinases and ERK MAPK pathways. In paper II, we demonstrated that JHP0290 exhibits both proliferative and anti-apoptotic activity, together with a faster progression of the cell cycle in gastric epithelial cells. During these responses, ERK MAPK and NF-κB pathways were activated. Paper III revealed a pro-apoptotic effect of another H. pylori-secreted protein HP1286 in macrophages via the TNF-independent and ERK-dependent pathways. No apoptosis was observed in HP1286-treated T cells or HL60 neutrophil-like cells, suggesting cell-type specific effect of HP1286. In Paper IV, we observed the proinflammatory activity of H. pylori secreted protein HP1173 in macrophages. The protein was found to induce TNF, IL-1β, and IL-8 in macrophages through MAPKs, NF-κB, and AP-1 signaling pathways. Furthermore, differential expression and release of JHP0290, HP1286, and HP1173 homologues was observed among H. pylori strains (papers II, III, IV).
Due to their ability to regulate multiple host cell responses, proteins JHP0290, HP1286, and HP1173 could play an important role in bacterial pathogenesis.

Keywords: Helicobacter pylori, Secreted proteins, Host cell responses, Macrophages, Apoptosis, Pro-inflammatory cytokines, MAPKs.