The Role of Mcl-1 inS. aureus-Induced Cytoprotection of Infected Macrophages

Abstract

As a facultative intracellular pathogen, Staphylococcus aureus invades macrophages and then promotes the cytoprotection of infected cells thus stabilizing safe niche for silent persistence. This process occurs through the upregulation of crucial antiapoptotic genes, in particular, myeloid cell leukemia-1 (MCL-1). Here, we investigated the underlying mechanism and signal transduction pathways leading to increased MCL-1 expression in infected macrophages. Live S. aureus not only stimulated de novo synthesis of Mcl-1, but also prolonged the stability of this antiapoptotic protein. Consistent with this, we proved a crucial role of Mcl-1 in S. aureus-induced cytoprotection, since silencing of MCL1 by siRNA profoundly reversed the cytoprotection of infected cells leading to apoptosis. Increased MCL1 expression in infected cells was associated with enhanced NFκB activation and subsequent IL-6 secretion, since the inhibition of both NFκB and IL-6 signalling pathways abrogated Mcl-1 induction and cytoprotection. Finally, we confirmed our observation in vivo in murine model of septic arthritis showing the association between the severity of arthritis and Mcl-1 expression. Therefore, we propose that S. aureus is hijacking the Mcl-1-dependent inhibition of apoptosis to prevent the elimination of infected host cells, thus allowing the intracellular persistence of the pathogen, its dissemination by infected macrophages, and the progression of staphylococci diseases.

Bacteria tracking by in vivomagnetic resonance imaging

“…For many bacterial pathogens and particularly for S. aureus, the intracellular persistence is increasingly recognized as an important infection and immune evasion strategy that causes chronic and therapy-refractory infections [45]. It has been demonstrated that S. aureus can invade and survive in different cell types, including professional phagocytes [46]. The use of iron labeled bacteria allowed us to track the surviving bacterial population in macrophages.…”

The Janus Face of a-Toxin: A Potent Mediator of Cytoprotection in Staphylococci-Infected Macrophages

“…We have shown recently that IL-6 plays a role in S. aureus -mediated Mcl-1 expression in hMDMs [13]. To determine the role of α-toxin in this process, macrophages were stimulated with Newman or its Δ hla mutant strain.…”

“…The increase of Mcl-1 expression, which occurrs shortly after infection and is sustained at high levels long after the engulfment of live S. aureus , is in stark contrast to the effects induced by E. coli , heat killed staphylococci or latex beads. This strongly argues that Mcl-1 expression is specifically induced and maintained by factors released by viable intracellular staphylococci [13]. Furthermore, only α-toxin-positive S. aureus strains are able to survive phagocytosis by macrophages beyond 24h post-infection [7], suggesting that this toxin may function as an effector molecule.…”

“…8) [13]. As such, the fact that cytochalasin D had differing effects on NFκB activation and MCL1 expression induced by α-toxin-producing and deficient strains, is perhaps the most compelling result in favour of a role for intracellular receptors in S. aureus -mediated signalling.…”

“…Recently, we showed that live intracellular staphylococci induce cytoprotection in human macrophages to promote survival of infected cells without bacterial eradication, allowing the pathogen to silently persist and remain invisible to the immune system [7,12]. Moreover, we proposed that the pathogen induces a prosurvival signalling pathway through the induction of expression of antiapoptotic factors, including myeloid cell leukemia-1 (Mcl-1), an antiapoptotic protein of the Bcl-2 family [13]. In this context, the physiological significance of α-toxin interaction with detection systems associated with innate immunity for the survival of S. aureus in infected macrophages has not yet been elucidated.…”