Caspase‐11 counteracts mitochondrial ROS‐mediated clearance of Staphylococcus aureus in macrophages

Abstract

Methicillin‐resistant Staphylococcus aureus (MRSA) is a growing health concern due to increasing resistance to antibiotics. As a facultative intracellular pathogen, MRSA is capable of persisting within professional phagocytes including macrophages. Here, we identify a role for CASP11 in facilitating MRSA survival within murine macrophages. We show that MRSA actively prevents the recruitment of mitochondria to the vicinity of the vacuoles they reside in to avoid intracellular demise. This process requires CASP11 since its deficiency allows increased association of MRSA‐containing vacuoles with mitochondria. The induction of mitochondrial superoxide by antimycin A (Ant A) improves MRSA eradication in casp11−/− cells, where mitochondria remain in the vicinity of the bacterium. In WT macrophages, Ant A does not affect MRSA persistence. When mitochondrial dissociation is prevented by the actin depolymerizing agent cytochalasin D, Ant A effectively reduces MRSA numbers. Moreover, the absence of CASP11 leads to reduced cleavage of CASP1, IL‐1β, and CASP7, as well as to reduced production of CXCL1/KC. Our study provides a new role for CASP11 in promoting the persistence of Gram‐positive bacteria.

Pyroptotic and non‐pyroptotic effector functions of caspase‐11

“…We also showed that IL‐6, KC, and TNF‐α are drastically reduced in the absence of caspase‐11 33 . Additionally, caspase‐11 −/− mice showed reduction in the level of IL‐1α and KC in response to MRSA infection 60 . Consequently, directly targeting caspase‐11/‐5 may reduce inflammation and limit the deleterious effects of senescent cells that accumulate during disease and aging 55 …”

“…Using three different multiplicity of infections (MOIs), our group showed that caspase‐11 −/− macrophages promoted efficient clearance of methicillin‐resistant S aureus (MRSA) with increasing MOI. Further, lungs of caspase‐11 −/− mice exhibit reduced MRSA as compared to WT mice 60 . Thus, the in vivo and in vitro data suggest that the macrophage response against MRSA is more effective in the absence of caspase‐11.…”

“…Notably, macrophages lacking caspase‐11 exhibited higher MitoSOX fluorescence in response to MRSA than corresponding WT cells 60 . In addition, pharmacological inhibition of mitochondrial complex III in the electron transport chain (ETC) by antimycin A (Ant‐A) treatment, which raises mitochondrial superoxide production, augments the bactericidal capacity of caspase‐11 −/− macrophages against MRSA 60 . This suggests that the enhanced proximity to mitochondria contributes to MRSA elimination in response to Ant‐A‐induced mitochondrial superoxide generation in caspase‐11 −/− macrophages.…”

“…Even though caspase‐11‐mediated pyroptosis restricts bacterial growth by demolishing the bacterial niche, other studies have demonstrated a non‐pyroptotic role of caspase‐11 in clearing bacteria 30,60,91‐93 . When used at a physiological MOI (0.025‐0.05), L pneumophila helps discern important physiological processes in the cell.…”

“…Furthermore, measurement of mitochondrial superoxide production, using the MitoSOX Red reagent, showed that MRSA suppressed superoxide levels in WT macrophages. Notably, macrophages lacking caspase‐11 exhibited higher MitoSOX fluorescence in response to MRSA than corresponding WT cells 60 . In addition, pharmacological inhibition of mitochondrial complex III in the electron transport chain (ETC) by antimycin A (Ant‐A) treatment, which raises mitochondrial superoxide production, augments the bactericidal capacity of caspase‐11 −/− macrophages against MRSA 60 .…”