Role of pro-apoptotic BH3-only proteins in the B cell immune response
Final Report Abstract
The parasite Leishmania major (L. major) has evolved several different strategies to improve intracellular survival, as well as parasite persistence and multiplication. A major obstacle is the host immune system, in particular, the ability of macrophages to undergo apoptosis upon infection. Since these parasites persist in two different developmental stages during their life cycle, little is known how promastigotes and amastigotes interact with host cells to create an environment for better parasite survival. Previous studies have already revealed, that the infection of neutrophils and macrophages with L. major promastigotes resulted in a delay of apoptosis which was associated with a decrease in caspase-3 activity. However, the role of L. major amastigotes in regulating macrophage apoptosis still remained elusive. To elucidate the role of promastigotes and amastigotes in regulating apoptotic processes, we compared uninfected and L. major – infected cells after treatment with different apoptotic stimuli, i.e. staurosporine and camptothecin. We showed that L. major promastigotes inhibit apoptosis in THP-1 (monocytederived macrophages) as we detected a significant decrease of fragmented nuclei accompanied by prevented activation of effector caspase-3, reduced cytochrome C release and significantly lower expression and activation levels of proapoptotic protein Bax. L. major promastigote infection also blocked caspase-3 and Bax activation in human primary macrophages, which further underscores the clinical relevance of these findings. Importantly, we could show that L. major amastigote infection, the developmental stage which propagates disease, lead additionally to the regulation of apoptotic key molecules caspase-3 and Bax in human primary macrophages. Here, we identified that both L. major promastigote and amastigote life stages impair apoptotic host cell processes upstream of the mitochondrial level, thereby providing important insights how these parasites create an environment to ensure their survival and replication.
Publications
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Modulation of host macrophage apoptosis by Leishmania infection. Ergebnisvorstellung bei der Deutschen Gesellschaft für Immunologie, Tagung Arbeitskreis Infektionsimmunologie, Rothenfels 2009
Enzenmüller S, Schropp C, Fulda S, van Zandbergen G, Fischer SF
