Search

Caspase-3 and -7 are redundantly required to amplify the extrinsic and intrinsic apoptotic cascade in human leukemia., Apoptosis is a complex multi-step process driven by caspase-dependent proteolytic cleavage cascades. Dysregulation of apoptosis promotes tumorigenesis and limits the efficacy of chemotherapy. To assess the complex interactions among caspases during apoptosis, we disrupted caspase-8, -9, -3, -7, or -6 and combinations thereof, using CRISPR-based genome editing in living human leukemia cells. While loss of apical initiator caspase-8 or -9 partially blocked extrinsic or intrinsic apoptosis, respectively, only combined loss of caspase-3 and -7 fully inhibited both apoptotic pathways, with no discernible effect of caspase-6 deficiency alone or in combination. Caspase-3/7 double knockout cells exhibited almost complete inhibition of caspase-8 or -9 activation. Furthermore, deletion of caspase-3 and -7 decreased mitochondrial depolarization and cytochrome c release upon apoptosis activation. Thus, activation of effector caspase-3 or -7 sets off explosive feedback amplification of upstream apoptotic events, which is a key feature of apoptotic signaling essential for efficient apoptotic cell death.

Methicillin-resistant Staphylococcus aureus (MRSA) causes community and healthcare associated infections in all age groups and treatment can be difficult due to its resistance against methicillin and other antimicrobials. The disease spectrum ranges from superficial skin and soft tissue infections (SSTI) (1) to life-threatening invasive infections (2). Colonisation is age-dependent (3) and often precedes infection (1). Other risk factors for MRSA infections in children are not well established. We aimed to characterise paediatric MRSA infections to assess potential risk factors for transmission and infection in children in a single centre in Switzerland, a country with a very low prevalence of MRSA, at less than 1% (4). This article is protected by copyright. All rights reserved.