Abstract
Community-acquired (CA) Staphylococcus aureus cause various diseases even in healthy individuals. Enhanced virulence of CA-strains is partly attributed to increased production of toxins such as phenol-soluble modulins (PSM). The pathogen is internalized efficiently by mammalian host cells and intracellular S. aureus has recently been shown to contribute to disease. Upon internalization, cytotoxic S. aureus strains can disrupt phagosomal membranes and kill host cells in a PSM-dependent manner. However, PSM are not sufficient for these processes. Here we screened for factors required for intracellular S. aureus virulence. We infected escape reporter host cells with strains from an established transposon mutant library and detected phagosomal escape rates using automated microscopy. We thereby, among other factors, identified a non-ribosomal peptide synthetase (NRPS) to be required for efficient phagosomal escape and intracellular survival of S. aureus as well as induction of host cell death. By genetic complementation as well as supplementation with the synthetic NRPS product, the cyclic dipeptide phevalin, wild-type phenotypes were restored. We further demonstrate that the NRPS is contributing to virulence in a mouse pneumonia model. Together, our data illustrate a hitherto unrecognized function of the S. aureus NRPS and its dipeptide product during S. aureus infection.
Highlights
Staphylococcus aureus is a notorious human pathogen that can cause a variety of diseases and causes a dramatic disease burden and death toll especially in the hospital setting [1,2]
Staphylococcus aureus is a notorious microbe that causes a variety of diseases in man ranging from skin abscesses to blood poisoning
Whereas such non-ribosomal peptides often act as antibiotics or in interspecies competition, we show that the production of phevalin enhances intracellular survival of S. aureus and increases killing of host cells, and is involved in lung infection
Summary
Staphylococcus aureus is a notorious microbe that causes a variety of diseases in man ranging from skin abscesses to blood poisoning. Human host, break out of membrane enclosures, and subsequently kill the cells from within. For these processes the bacterium usually employs an arsenal of partially unknown toxic proteins and peptides. We thereby found that S. aureus uses a small cyclic dipeptide, phevalin, to interfere with host processes that would lead to destruction of the pathogen. Phevalin is not formed by ribosomes, but by a multidomain peptide assembly line Whereas such non-ribosomal peptides often act as antibiotics or in interspecies competition, we show that the production of phevalin enhances intracellular survival of S. aureus and increases killing of host cells, and is involved in lung infection. Since we show that phevalin targets the host cell, this implies signaling across the domains of life—between bacteria and human cells
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