FPR2: A Novel Promising Target for the Treatment of Influenza

Abstract

The Formyl-peptide receptor-2 (FPR2) is a seven transmembrane G protein-coupled receptor, which plays an important role in sensing of bacteria and modulation of immune responses. FPR2 is also used by viruses for their own profit. Annexin A1, one of the multiple ligands of FPR2, is incorporated in the budding virus membrane of influenza A viruses (IAV). Thereby, once IAV infect a host cell, FPR2 is activated. FPR2-signaling leads to an increase in viral replication, a dysregulation of the host immune response and a severe disease. Conversely, experiments using FPR2 antagonists in a preclinical model of IAV infections in mice showed that blocking FPR2 protects animals from lethal infections. Thus, FPR2 represents a very attractive host target against influenza. In this review we will give an overview on the pathogenesis of influenza with a focus on the role of FPR2 and we will discuss the advantages of using FPR2 antagonists to treat the flu.

Keywords: FPR2; antiviral agents; formyl peptide receptor; human; inflammation mediators; influenza.

Figure 1

Model of how FPR2 promotes harmful inflammation in a time scale manner. At early stages post-infection, Annexin A1 incorporated into IAV, activates FPR2 leading to (i) an anti-inflammatory state, which impairs host immune response and provides the mean for IAV to replicate. In addition (ii), FPR2-signaling activates the ERK pathway, further increasing IAV replication. Altogether, IAV replication fosters PRR activation, leading to a dysregulated and excessive innate immune response. During the time course of infection, infected cells undergo apoptosis, leading to the release of mitochondrial formylated peptides. In addition, proteases are released in a large amount by leucocytes that are recruited to the site of infection. Those proteases cleave Annexin A1 incorporated into IAV. FPR2, which is then activated by formylated peptides and cleaved Annexin A1 turns pro-inflammatory. This further contributes at later stages post-infection to increased inflammation and IAV pathogenesis.

Figure 2

Model of the contribution of FPR2 in influenza virus pathogenesis and effect of FPR2 antagonists. Cellular Annexin A1 incorporated in the envelope of IAV, activates FPR2 during virus absorption to the host cell. FPR2-signaling through the ERK pathways increases infectious virus production (1) contributing to a proinflammatory state via the recognition of viral RNA by PRRs. In addition, FPR2-signaling also directly promotes a pro-inflammatory state (2), by enhancing the release of cytokines/chemokines and impairing the resolution of acute inflammation. Altogether, the excessive recruitment and activation of immune/inflammatory cells contributes to tissue damages and flu pathogenesis. Thereby, by inhibiting virus replication and preventing deleterious inflammation of the lungs, FPR2 antagonists emerge as a novel promising strategy to protect from influenza virus pathogenesis.