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.
Highlights
Methicillin-resistant Staphylococcus aureus (MRSA) refers to a group of Gram-positive cocci that have developed a resistance to most b-lactam antibiotics due to the expression of a penicillin-binding protein (PBP2a) [1]
CASP11 plays a role in inflammasome activation in response to MRSA, we evaluated cleavage of CASP1 and IL-1b in cell culture supernatants from WT and casp11À/À macrophages via Western blot analysis at 24 h post-infection (MOI 20:1)
The activation of the NLRP3 inflammasome has been shown in response to peptidoglycan or pore-forming toxins such as Hla, leukocidin AB (Leu AB), and Panton–Valentine leukocidin (PVL), leading to cleavage of CASP1, IL-1b/IL-18 secretion, and pyroptosis [21,22,44,45,46]
Summary
Methicillin-resistant Staphylococcus aureus (MRSA) refers to a group of Gram-positive cocci that have developed a resistance to most b-lactam antibiotics due to the expression of a penicillin-binding protein (PBP2a) [1]. While CASP11 deficiency has been shown to protect mice from LPS-induced endotoxemia due to reduced release of the inflammatory mediators IL-1a, IL-1b, and CXCL1/KC [5,9,12], the absence of CASP11 in the context of Gram-negative bacterial infections promotes bacterial replication and dissemination in mice [8,9,13,14]. Purified lipoteichoic acid (LTA), a cell wall component from Gram-positive bacteria, was reported to induce CASP11 activity via NLRP6 [15]. Unlike mice infected with Gram-negative bacteria, mice deficient of CASP11 exhibit improved survival and efficient bacterial clearance in response to a 2019 The Authors.
Sign-in/Register to view highlights & summary 
Published Version
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call