Protease-Activated Receptor 2 Facilitates Bacterial Dissemination in Pneumococcal Pneumonia

• Published in: The Journal of infectious diseases Vol. 217; no. 9; pp. 1462 - 1471
• Main Authors: van den Boogaard, Florry E, Brands, Xanthe, Duitman, JanWillem, de Stoppelaar, Sacha F, Borensztajn, Keren S, Roelofs, Joris J T H, Hollenberg, Morley D, Spek, C Arnold, Schultz, Marcus J, van ‘t Veer, Cornelis, van der Poll, Tom
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 11-04-2018
• Subjects: pneumococcal bacteremia; bacterial pneumonia; PARS; proteases
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1093/infdis/jiy010

Abstract
Streptococcus pneumoniae is the most common causative pathogen in community-acquired pneumonia. Protease-activated receptor 2 (PAR2) is expressed by different cell types in the lungs and can mediate inflammatory responses. We sought to determine the role of PAR2 during pneumococcal pneumonia. Pneumococcal pneumonia or sepsis was induced in wild-type and PAR2 knock-out (Par2−/−) mice by infection with viable S. pneumoniae. Par2−/− mice demonstrated improved host defense, a largely preserved lung barrier integrity, and reduced mortality during pneumococcal pneumonia. PAR2 deficiency did not influence bacterial growth after intravenous infection. Inhibition of the endogenous PAR2 activating proteases tissue factor/factor VIIa or tryptase did not impact on bacterial burdens during pneumonia. In a PAR2 reporter cell line it was demonstrated that S. pneumoniae-derived proteases are able to cleave PAR2. These results show that S. pneumoniae is able to cleave and exploit PAR2 to disseminate systemically from the airways.
PAR2 can mediate inflammatory responses. Par2−/−mice were protected from bacterial dissemination and mortality during pneumococcal pneumonia. Streptococcus pneumoniae-derived proteases were able to cleave PAR2. This suggests that S. pneumoniae is able to exploit PAR2 to disseminate systemically.