S. aureus drives itch and scratch-induced skin damage through a V8 protease-PAR1 axis

Liwen Deng; Flavia Costa; Kimbria J Blake; Samantha Choi; Arundhasa Chandrabalan; Muhammad Saad Yousuf; Stephanie Shiers; Daniel Dubreuil; Daniela Vega-Mendoza; Corinne Rolland; Celine Deraison; Tiphaine Voisin; Michelle D Bagood; Lucia Wesemann; Abigail M Frey; Joseph S Palumbo; Brian J Wainger; Richard L Gallo; Juan-Manuel Leyva-Castillo; Nathalie Vergnolle; Theodore J Price; Rithwik Ramachandran; Alexander R Horswill; Isaac M Chiu

doi:10.1016/j.cell.2023.10.019

S. aureus drives itch and scratch-induced skin damage through a V8 protease-PAR1 axis

Cell. 2023 Nov 22;186(24):5375-5393.e25. doi: 10.1016/j.cell.2023.10.019.

Authors

Liwen Deng¹, Flavia Costa², Kimbria J Blake¹, Samantha Choi¹, Arundhasa Chandrabalan³, Muhammad Saad Yousuf⁴, Stephanie Shiers⁴, Daniel Dubreuil⁵, Daniela Vega-Mendoza⁶, Corinne Rolland⁷, Celine Deraison⁷, Tiphaine Voisin¹, Michelle D Bagood⁸, Lucia Wesemann¹, Abigail M Frey¹, Joseph S Palumbo⁹, Brian J Wainger⁵, Richard L Gallo⁸, Juan-Manuel Leyva-Castillo⁶, Nathalie Vergnolle⁷, Theodore J Price⁴, Rithwik Ramachandran³, Alexander R Horswill², Isaac M Chiu¹⁰

Affiliations

¹ Department of Immunology, Harvard Medical School, Boston, MA 02215, USA.
² Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
³ Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario N6A 5C1, Canada.
⁴ Department of Neuroscience and Center for Advanced Pain Studies, University of Texas at Dallas, Richardson, TX 75080, USA.
⁵ Departments of Neurology and Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
⁶ Division of Immunology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
⁷ IRSD, Université de Toulouse, INSERM, INRAe, ENVT, Université Toulouse III-Paul Sabatier (UPS), Toulouse, France.
⁸ Department of Dermatology, University of California, San Diego, La Jolla, CA 92093, USA.
⁹ Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH, USA.
¹⁰ Department of Immunology, Harvard Medical School, Boston, MA 02215, USA. Electronic address: isaac_chiu@hms.harvard.edu.

Abstract

Itch is an unpleasant sensation that evokes a desire to scratch. The skin barrier is constantly exposed to microbes and their products. However, the role of microbes in itch generation is unknown. Here, we show that Staphylococcus aureus, a bacterial pathogen associated with itchy skin diseases, directly activates pruriceptor sensory neurons to drive itch. Epicutaneous S. aureus exposure causes robust itch and scratch-induced damage. By testing multiple isogenic bacterial mutants for virulence factors, we identify the S. aureus serine protease V8 as a critical mediator in evoking spontaneous itch and alloknesis. V8 cleaves proteinase-activated receptor 1 (PAR1) on mouse and human sensory neurons. Targeting PAR1 through genetic deficiency, small interfering RNA (siRNA) knockdown, or pharmacological blockade decreases itch and skin damage caused by V8 and S. aureus exposure. Thus, we identify a mechanism of action for a pruritogenic bacterial factor and demonstrate the potential of inhibiting V8-PAR1 signaling to treat itch.

Keywords: PAR1; Staphylococcus aureus; V8 protease; itch; microbe; proteinase-activated receptor; pruriceptor.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Comment

MeSH terms

Animals
Humans
Mice
Peptide Hydrolases* / metabolism
Pruritus* / microbiology
Receptor, PAR-1* / metabolism
Staphylococcal Infections* / microbiology
Staphylococcal Infections* / pathology
Staphylococcus aureus* / enzymology
Staphylococcus aureus* / pathogenicity
Staphylococcus aureus* / physiology

Substances

Peptide Hydrolases
Receptor, PAR-1

Abstract

Publication types

MeSH terms

Substances

Grants and funding