Staphylococcus aureus Subvert Autophagy for Induction of Caspase-independent Host Cell Death

Abstract

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.Staphylococcus aureus is the major cause of community-acquired and nosocomial infections such as pneumonia, endocarditis, osteomyelitis, and wound infections (1, 2). An important feature of S. aureus is the ability to invade the vascular system from local infection sites (3). Such dissemination includes passing across cellular barriers like the endothelial barrier, which leads to bacteremia and sepsis. Recent studies revealed the consistent ability of S. aureus to infect various types of non-professional phagocytic host cells such as keratinocytes, fibroblasts, endothelial cells, and epithelial cells (4 -6). Adherence to and invasion of non-professional phagocytic cells by S. aureus has been implicated in the pathogenesis of invasive and metastatic infections i.e. during hematogenous dissemination (7).We have recently shown that some but not all S. aureus strains are able to induce host cell death after invasion, which correlates with the virulence of a particular S. aureus strain (8). However, the exact molecular mechanisms leading to intracellular survival of S. aureus and death of host cells remained unclear. Although some investigators reported induction of caspase-dependent programmed cell death (apoptosis) involving tumor necrosis factor or CD95 signaling pathways, others observed necrosis of S. aureus-infected host cells induced by ␣-toxin (9 -11).In many cases microorganisms internalized by host cells are efficiently eliminated by host defense mechanisms. The microbial phagosome matures by sequential transient fusion events with early and late endosomal compartments, which are controlled by Rab GTPases (12). However, some pathogens like Mycobacteria tuberculosis, Legionella pneumophila, and Brucella abortus have evolved species-specific mec...

The autophagic pathway is a key component in the lysosomal dependent entry ofTrypanosoma cruziinto the host cell

“…[25][26][27] That is the case of Porphyromonas gingivalis, 26,27 Brucella abortus, 27 Coxiella burnetii, 28 Chlamydia 29 and Staphylococcus aureus. 30 The main difference between these two behaviors is not well understood to date, but is important to mention that some pathogens have the faculty to modulate the autophagic response in their own benefit. 31,32 In this work we have analyzed the possible connection between the parasite Trypanosoma cruzi and the host-cell autophagic pathway.…”

Differential impact of zinc deficiency on phagocytosis, oxidative burst, and production of pro-inflammatory cytokines by human monocytes

“…This was followed by addition of 20 ml of PBS containing 2 Â 10 7 bacteria transformed to express fluorescent proteins; either DSred-E. coli (strain BL21), 11 GFP-S. aureus (strain ATCC29213) 14 or GFP-S. pneumoniae (strain R6). 15 Additionally, redox sensitive pro-fluorophores were added, either DHR123 (1 mM) for DsRed-E. coli or DHE (2.5 mM) for bacteria expressing GFP, respectively.…”

Differential NF-κB pathways induction by Lactobacillus plantarum in the duodenum of healthy humans correlating with immune tolerance

“…Whereas pathogens induce mainly persistent inflammatory responses (9)(10)(11), commensal bacteria induce transient, noninflammatory responses. Commensal Lactobacillus species may stimulate the polarization of immune T cells toward regulatory T (Treg) cells (12).…”