Intracellular Staphylococcus aureus triggers pyroptosis and contributes to inhibition of healing due to perforin-2 suppression
Irena Pastar, … , Hadar Lev-Tov, Marjana Tomic-Canic
Irena Pastar, … , Hadar Lev-Tov, Marjana Tomic-Canic
Published November 2, 2021
Citation Information: J Clin Invest. 2021;131(24):e133727. https://doi.org/10.1172/JCI133727.
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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.

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

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Figure 4

Pyroptosis correlates with the healing outcome of DFUs.

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Pyroptosis correlates with the healing outcome of DFUs. (A) Western blot...
(A) Western blot and corresponding quantification plot (B, the ratio of week 4/week 0 (W4/W0) tissue levels for ASC) of ASC pyroptosome in healing (DFU-H; n = 3) and nonhealing DFUs (DFU-NH; n = 4); *P < 0.05. (C) AIM2 Western blot and corresponding quantification plot (D; the ratio of W4/W0 AIM2 tissue levels) in DFU-H (n = 3) and DFU-NH (n = 4). ASC pyroptosome and AIM2 levels decreased in DFU-H over time, whereas they persisted or increased in DFU-NH after 4 weeks (W4) of standard of care; **P < 0.01 (n = 4 per group). (E) Western blot of GsdmD in prospective DFU-H and DFU-NH. (F) Quantification of the ratio W4/W0 levels for GsdmD in DFU-H and DFU-NH. Activation of GsdmD was found to persist or increase in DFU-NH at W4. **P < 0.01 (n = 3 per group). (G) Quantification of S. aureus levels by qPCR in tissue from DFU-H and DFU-NH. **P < 0.01 (n = 5 per group).