Staphylococcus aureus subvert autophagy for induction of caspase-independent host cell death.
Staphylococcus aureus is a common bacterial etiology of serious infectious diseases. S. aureus can invade various types of non-professional phagocytes to produce host cell death. We show here that shortly after invasion of HeLa cells S. aureus transit to autophagosomes was characterized by double membranes and co-localization with LC3. S. aureus were not able to replicate and produce cell death in autophagy-deficient atg5-/- mouse embryonic fibroblasts. S. aureus-containing autophagosomes do not acidify nor do they acquire lysosome-associated membrane protein-2, indicating that S. aureus inhibits autophagosome maturation and fusion with lysosomes. Eventually, S. aureus escape from autophagosomes into the cytoplasm, which results in caspase-independent host cell death. S. aureus strains deficient for agr, a global regulator of S. aureus virulence, were not targeted by autophagy and did not produce host-cell death. Autophagy induction by rapamycin restored both replication and cytotoxicity of agr-deficient S. aureus strains, indicating that an agr-regulated factor(s) is required for autophagy-mediated cytotoxicity. The results of this study suggest that rapid induction of autophagy is essential for S. aureus replication, escape into the cytoplasm, and host cell killing.
Schnaith
Annabelle
A
Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, 50935 Cologne, Germany.
Kashkar
Hamid
H
Leggio
Sonja A
SA
Addicks
Klaus
K
Krönke
Martin
M
Krut
Oleg
O
D000818:Animals; D001343:Autophagy; D000071187:Autophagy-Related Protein 5; D001426:Bacterial Proteins / Q000378:metabolism; D020169:Caspases / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D013203:Staphylococcal Infections / Q000378:metabolism / Q000473:pathology; D013211:Staphylococcus aureus; D015534:Trans-Activators / Q000378:metabolism
C502778:ATG5 protein, human; C095698:Agr protein, Staphylococcus aureus; C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D001426:Bacterial Proteins; D008869:Microtubule-Associated Proteins; D015534:Trans-Activators; D020169:Caspases