Comparative analysis of inflammation induced by aspergillus.fumigatus and chlamydia.trachomatis
- Author(s): Said, Najwane
- Advisor(s): Ojcius, David M.
- et al.
The elaboration of an effective immune response is a key factor in fighting against invading pathogenic microbes and eliminating them. Upon microbial sensing, the innate immune system initiate the inflammatory response by secreting cytokines and chemokines responsible for recruiting immune cells to the site of infection and inducing the establishment of adaptive immunity. During my thesis, I focused my studies on a cytoplamic protein complex called “inflammasome” which had been found to regulate the inflammation process by activating the cystein protease, caspase-1 which has as a substrate the potent pro-inflammatory cytokine IL-1β. During infection, monocytes and macrophages challenged with different microbial molecules get activated and induce the expression and the synthesis of pro- IL-1β waiting for a second signal called Danger signal essential for pro-IL-1β cleavage by caspase-1 and its secretion. Growing number of studies reveal the importance of inflammasomes assembly during several bacterial, viruses and fungal infections as they sense different signals characteristic of a pathogenic infection. The activation of an inflammasome during the fungus Aspergillus.fumigatus and the bacteria Chlamydia.trachomatis infection have never been investigated so far. Therefore I investigated whether these two pathogens are able to induce inflammasome assembly in a human monocyte cell line and identified the molecules and the signals triggering this activation. The results demonstrated that both Aspergillus.fumigatus and Chlamydia.trachomatis induce the activation of an inflammasome in which the Nod Like Receptor 3 (NALP3) is involved requiring the presence of the adaptor ASC that bridges NALP3 to caspase-1. Additionally, I proved using Knocked down cells and different inhibitors that Reactive oxygen species, potassium efflux as well as the activation of the spleen tyrosine kinase (Syk) are required for this activation. As a conclusion, we showed for the first time the activation of NALP3 inflammasome during infection with both pathogens, highlighted how different microbes presenting distinct antigenic molecules, exhibiting different infectious strategies are capable of inducing common intracellular modifications that converge to the activation of the same inflammasome.