Intracellular Staphylococcus aureus triggers pyroptosis and contributes to inhibition of healing due to perforin-2 suppression

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 m...

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Bibliographic Details
Published in:The Journal of clinical investigation 2021-12, Vol.131 (24)
Main Authors: Pastar, Irena, Sawaya, Andrew P, Marjanovic, Jelena, Burgess, Jamie L, Strbo, Natasa, Rivas, Katelyn E, Wikramanayake, Tongyu C, Head, Cheyanne R, Stone, Rivka C, Jozic, Ivan, Stojadinovic, Olivera, Kornfeld, Eran Y, Kirsner, Robert S, Lev-Tov, Hadar, Tomic-Canic, Marjana
Format: Article
Language:English
Subjects:
Adult
Aged
Animals
Care and treatment
Cellular proteins
Complications and side effects
Diabetic foot
Diabetic Foot - genetics
Diabetic Foot - immunology
Diabetic Foot - microbiology
DNA-Binding Proteins - genetics
DNA-Binding Proteins - immunology
Epidermis - immunology
Epidermis - microbiology
Female
Genetic aspects
Health aspects
Humans
Interleukin-1beta - genetics
Interleukin-1beta - immunology
Male
Membrane Proteins - genetics
Membrane Proteins - immunology
Mice
Mice, Knockout
Middle Aged
Physiological aspects
Pore Forming Cytotoxic Proteins - genetics
Pore Forming Cytotoxic Proteins - immunology
Pyroptosis - genetics
Pyroptosis - immunology
Staphylococcal Infections - genetics
Staphylococcal Infections - immunology
Staphylococcus aureus - immunology
Staphylococcus aureus infections
Wound healing
Wound Healing - genetics
Wound Healing - immunology
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Summary: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.
ISSN:1558-8238
0021-9738
1558-8238
DOI:10.1172/JCI133727