@article{15514870d4c741beada196b486fdeeff,
title = "Intracellular Staphylococcus aureus triggers pyroptosis and contributes to inhibition of healing due to perforin-2 suppression",
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.",
author = "Irena Pastar and Sawaya, {Andrew P.} and Jelena Marjanovic and Burgess, {Jamie L.} and Natasa Strbo and Rivas, {Katelyn E.} and Wikramanayake, {Tongyu C.} and Head, {Cheyanne R.} and Stone, {Rivka C.} and Ivan Jozic and Olivera Stojadinovic and Kornfeld, {Eran Y.} and Kirsner, {Robert S.} and Hadar Lev-Tov and Marjana Tomic-Canic",
note = "Funding Information: This work was supported by NIH R01NR015649 (to MTC and NS), NIH U01DK119085-02S1 (to RSK, RCS, and MTC), and Frost Endowed Investigator fund (to MTC). We dedicate this work to the late Eckhard Podack, without whom studies of P-2 would not be possible. We are grateful to E. Thomas, G. Plano, A. Barrientos, R.W. Keane, and J.P. Vaccari for generously sharing laboratory resources and equipment. We also thank Alan Burgess and Ashley Rosa for technical support and our lab members for their continuous support and constructive criticism. Funding Information: Authorship note: IP and APS contributed equally to this work. Conflict of interest: RSK is a consultant for M{\"o}lnlycke and has pending patent application US 2020/0100711 A1. HLT is a consultant for Next Science Inc. and Pfizer Inc. MTC{\textquoteright}s research is supported by Organogenesis Inc. Copyright: {\textcopyright} 2021, American Society for Clinical Investigation. Submitted: September 23, 2019; Accepted: October 27, 2021; Published: December 15, 2021. Reference information: J Clin Invest. 2021;131(24):e133727. https://doi.org/10.1172/JCI133727. Publisher Copyright: {\textcopyright} 2021, American Society for Clinical Investigation.",
year = "2021",
month = dec,
day = "1",
doi = "10.1172/JCI133727",
language = "English (US)",
volume = "131",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "24",
}