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Autophagy and Lc3-associated phagocytosis in host defense against Salmonella

Control of infectious diseases poses continuous challenges for human health.

Masud, S.
12 oktober 2017
Thesis in Leiden Repository

Control of infectious diseases poses continuous challenges for human health. Salmonella bacteria are a major cause of gastrointestinal infections and systemic disease like typhoid fever. We used zebrafish-Salmonella infection models to study host immune responses to Salmonella, particularly focusing on the role of the autophagy machinery. Autophagy and a related process known as Lc3-associated phagocytosis (LAP) trap invading microbes in intracellular vesicles and eventually eliminate them through the lysosomal degradation pathway. We show that macrophages and neutrophils trap Salmonella in Lc3-decorated phagosomes by a process dependent on the host factors Rubicon and NADPH oxidase, which generates anti-bacterial reactive oxygen species. This process could be defined as LAP as it requires some but not all components of the autophagy machinery. Genetic inhibition of LAP and ablation of macrophages resulted in hypersusceptibility to infections with both wild type and attenuated strains, revealing that LAP is an essential line of defense against Salmonella during systemic disease, when macrophages are the main carriers of the infection. Our studies also revealed a novel functional link between the autophagy modulator Dram1 and induction of LAP. This work encourages further studies aimed at the identification of autophagy modulating drugs for host-directed therapy of antibiotic-resistant Salmonella infections.