Abstract
SummaryPathogenic bacteria secrete virulence factors that interact with the human host to establish infections. The human immune system evolved multiple mechanisms to fight bacterial invaders, including immune proteases that were demonstrated to contribute crucially to antibacterial defense. Here we show that granzyme B degrades multiple secreted virulence mediators from Listeria monocytogenes, Salmonella typhimurium, and Mycobacteria tuberculosis. Pathogenic bacteria, when infected in the presence of granzyme B or granzyme-secreting killer cells, fail to grow in human macrophages and epithelial cells owing to their crippled virulence. A granzyme B-uncleavable mutant form of the major Listeria virulence factor, listeriolysin O, rescued the virulence defect in response to granzyme treatment. Hence, we link the degradation of a single factor with the observed decrease in virulent bacteria growth. Overall, we reveal here an innate immune barrier function of granzyme B by disrupting bacterial virulence to facilitate bacteria clearance by bystander immune and non-immune cells.
Highlights
Pathogenic, facultatively intracellular bacteria, such as Listeria, Salmonella, and Mycobacteria, are a global major health threat because they cause infections in human hosts leading to severe disease and death if untreated
SUMMARY Pathogenic bacteria secrete virulence factors that interact with the human host to establish infections
We show that granzyme B degrades multiple secreted virulence mediators from Listeria monocytogenes, Salmonella typhimurium, and Mycobacteria tuberculosis
Summary
Pathogenic, facultatively intracellular bacteria, such as Listeria, Salmonella, and Mycobacteria, are a global major health threat because they cause infections in human hosts leading to severe disease and death if untreated. To survive in the host, pathogenic bacteria evolved multiple secreted or externally exposed virulence mediators that allow specific interaction with the host cell. These factors orchestrate the major steps in a bacterial virulence strategy, which help with adherence, cellular invasion, and, the setup of a protective niche. The virulence strategy of Listeria monocytogenes responsible is characterized by various mechanisms, including forced uptake even in nonphagocytic cells, such as epithelial cells After uptake, they avoid lethal lysosomal degradation by a phagosomal escape mechanism, which is mainly promoted by their major virulence factor, listeriolysin O (LLO), supported by a few phospholipases. Listeria rapidly multiply and interact with the actin cytoskeleton to gain motility for cell-to-cell spreads (Cossart, 2011)
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