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

• Published in: Cell 2023-11, Vol.186 (24), p.5375-5393.e25
• Main Authors: Deng, Liwen, Costa, Flavia, Blake, Kimbria J., Choi, Samantha, Chandrabalan, Arundhasa, Yousuf, Muhammad Saad, Shiers, Stephanie, Dubreuil, Daniel, Vega-Mendoza, Daniela, Rolland, Corinne, Deraison, Celine, Voisin, Tiphaine, Bagood, Michelle D., Wesemann, Lucia, Frey, Abigail M, Palumbo, Joseph S., Wainger, Brian J., Gallo, Richard L., Leyva-Castillo, Juan-Manuel, Vergnolle, Nathalie, Price, Theodore J., Ramachandran, Rithwik, Horswill, Alexander R., Chiu, Isaac M.
• Format: Article
• Language: English
• Subjects: Animals; Humans; itch; Mice; microbe; PAR1; Peptide Hydrolases - metabolism; proteinase-activated receptor; pruriceptor; Pruritus - microbiology; Receptor, PAR-1 - metabolism; Staphylococcal Infections - microbiology; Staphylococcal Infections - pathology; Staphylococcus aureus; Staphylococcus aureus - enzymology; Staphylococcus aureus - pathogenicity; Staphylococcus aureus - physiology; V8 protease
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2023.10.019

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. [Display omitted] •S. aureus induces itch and scratch damage with epicutaneous skin exposure•V8 protease (SspA) is necessary and sufficient for itch during S. aureus exposure•S. aureus V8 activates mouse and human sensory neurons through PAR1•PAR1 deficiency or blockade abrogates S. aureus-induced itch and skin damage Itch evokes a desire to scratch, but the link between microbes and itch was unclear. Staphylococcus aureus, a bacterial pathogen, secretes a protease V8 that activates PAR1 expressed on neurons to drive itch and skin damage.