Protease-activated receptor-1 impairs host defense in murine pneumococcal pneumonia: a controlled laboratory study

Marcel Schouten,Cornelis Van'T Veer,Marcel Levi,Tom Van Der Poll,Joris Jth Roelofs

doi:10.1186/cc11910

Abstract

IntroductionStreptococcus pneumoniae is the most common causative pathogen in community-acquired pneumonia. Protease-activated receptor-1 (PAR-1) is expressed by multiple cell types present in the lungs and can be activated by various proteases generated during acute inflammation. The cellular effect of PAR-1 activation partially depends on the specific protease involved. We here determined the role of PAR-1 in the host response during murine pneumococcal pneumonia.MethodsWild-type (WT) and PAR-1 knockout (KO) mice were infected intranasally with viable S. pneumoniae and observed in a survival study or euthanized at 6, 24 or 48 hours of infection.ResultsPAR-1 KO mice had a better survival early after infection compared to WT mice. Moreover, PAR-1 KO mice had lower bacterial loads in lungs and blood at 24 hours and in spleen and liver at 48 hours after infection. This favorable response was accompanied by lower lung histopathology scores and less neutrophil influx in PAR-1 KO mice.ConclusionPAR-1 impairs host defense during murine pneumococcal pneumonia.

Highlights

Streptococcus pneumoniae is the most common causative pathogen in community-acquired pneumonia
We show that in pneumococcal pneumonia, Protease activated receptor (PAR)-1 impairs host defense, as reflected by a reduced lethality and lower bacterial loads, lung histopathology scores and less pulmonary neutrophil influx in Protease-activated receptor-1 (PAR-1) KO mice
Our finding that PAR-1 deficiency improves survival early in severe murine pneumococcal pneumonia is in accordance with data by Niessen et al, who, using a PAR-1 antagonist, showed that functional PAR-1 reduces survival in polymicrobial sepsis induced by cecal ligation and puncture (CLP), a finding which was associated with dendritic cell-mediated sustainment of proinflammatory and procoagulant mechanisms [11]

Summary

Introduction

Streptococcus pneumoniae is the most common causative pathogen in community-acquired pneumonia. Protease-activated receptor-1 (PAR-1) is expressed by multiple cell types present in the lungs and can be activated by various proteases generated during acute inflammation. The cellular effect of PAR-1 activation partially depends on the specific protease involved. We here determined the role of PAR-1 in the host response during murine pneumococcal pneumonia. Streptococcus (S.) pneumoniae or the pneumococcus is the number one causative pathogen in communityacquired pneumonia (CAP) [1]. Worldwide S. pneumoniae is responsible for approximately ten million deaths annually, making pneumococcal pneumonia and sepsis a major health threat [3]. Protease-activated receptors (PARs) are G proteincoupled receptors that are abundantly expressed in the lungs [4,5,6]. A variety of proteases can activate PARs, including several proteases

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Conclusion