Protective Role for Protease-Activated Receptor-2 against Influenza Virus Pathogenesis via an IFN-γ-Dependent Pathway

Abstract

Protease-activated receptor-2 (PAR2), a receptor highly expressed in the respiratory tract, can influence inflammation at mucosal surfaces. Although the effects of PAR2 in the innate immune response to bacterial infection have been documented, knowledge of its role in the context of viral infection is lacking. We thus investigated the role of PAR2 in influenza pathogenesis in vitro and in vivo. In vitro, stimulation of PAR2 on epithelial cells inhibited influenza virus type A (IAV) replication through the production of IFN-γ. In vivo, stimulation of PAR2 using specific agonists protected mice from IAV-induced acute lung injury and death. This effect correlated with an increased clearance of IAV in the lungs associated with increased IFN- γ production and a decreased presence of neutrophils and RANTES release in bronchoalveolar fluids. More importantly, the protective effect of the PAR2 agonist was totally abrogated in IFN- γ-deficient mice. Finally, compared with wild-type mice, PAR2-deficient mice were more susceptible to IAV infection and displayed more severe lung inflammation. In these mice higher neutrophil counts and increased RANTES concentration but decreased IFN- γ levels were observed in the bronchoalveolar lavages. Collectively, these results showed that PAR2 plays a protective role during IAV infection through IFN-γ production and decreased excessive recruitment of inflammatory cells to lung alveoli.

Multiple roles of the coagulation protease cascade during virus infection

“…40,42,45 These results suggested that PAR2ko mice would be protected from IAV infection because they would express higher levels of IFN-b. Indeed, the Vogel group found that PAR2ko mice For personal use only.…”

“…40 Similarly, the Riteau group found that PAR2 activation suppressed CCL5 expression by A549 human epithelial cells after influenza A infection. 45 We found that murine embryonic CFs lacking PAR2 expressed higher levels of IFN-b and CCL5 expression after poly I:C stimulation compared with wild-type (WT) fibroblasts (Figure 4). 42 Taken together, these results indicate that PAR2 suppresses For personal use only.…”

“…The Riteau group also showed that administration of SLIGRL, a PAR2 agonist peptide, to WT mice increased survival after H1N1 infection. 45 However, a recent study showed that this peptide mediated PAR2-independent protection against IAV. 74 It is difficult to explain the different results found with IAV infection in PAR2ko mice ( Table 2).…”

“…70 In contrast to these studies, the Riteau group reported that H1N1 infected PAR2ko mice had a small increase in mortality compared with WT mice (Table 2). 45 The authors concluded that PAR2 protected mice by increasing IFN-g expression. The Riteau group also showed that administration of SLIGRL, a PAR2 agonist peptide, to WT mice increased survival after H1N1 infection.…”

Novel agonists & antagonists for protease-activated receptor 2 and C3a receptor

“…[109][110][111] Three major pathways are implicated in complement activation: classical, lectin and alternative pathways, as shown in figure 1.3. The classical and alternative pathways converged at C3, with two C3 convertases cleaving C3 to produce anaphylatoxin C3a and opsonin C3b, then C5 convertases cleaving C5…”