Intracellular Staphylococcus Aureus Triggers Pyroptosis and Contributes to Inhibition of Healing Due to Perforin-2 Suppression

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2021 Nov 3

PMID 34730110

Citations 29

Authors

Irena Pastar

Andrew P Sawaya

Jelena Marjanovic

Jamie L Burgess

Natasa Strbo

Katelyn E Rivas

Tongyu C Wikramanayake

Cheyanne R Head

Rivka C Stone

Ivan Jozic

Olivera Stojadinovic

Eran Y Kornfeld

Robert S Kirsner

Hadar Lev-Tov

Marjana Tomic-Canic

Affiliations

Soon will be listed here.

Abstract

Impaired wound healing associated with recurrent Staphylococcus aureus infection and unresolved inflammation are hallmarks of nonhealing diabetic foot ulcers (DFUs). Perforin-2, an innate immunity molecule against intracellular bacteria, limits cutaneous infection and dissemination of S. aureus in mice. Here, we report the intracellular accumulation of S. aureus in the epidermis of DFUs with no clinical signs of infection due to marked suppression of perforin-2. S. aureus residing within the epidermis of DFUs triggers AIM2 inflammasome activation and pyroptosis. These findings were corroborated in mice lacking perforin-2. The effects of pyroptosis on DFU clinical outcomes were further elucidated in a 4-week longitudinal clinical study in patients with DFUs receiving standard care. Increased AIM2 inflammasome and ASC-pyroptosome coupled with induction of IL-1β were found in nonhealing DFUs compared with healing DFUs. Our findings revealed that perforin-2 suppression, intracellular S. aureus accumulation, and associated induction of pyroptosis contribute to healing inhibition and prolonged inflammation in patients with DFUs.

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