title: Inhibitory influence of the hexapeptidic sequence SLIGRL on influenza A virus infection in mice.
abstract: Proteinase-activated receptor 2 (PAR(2)) is widely expressed in the respiratory tract and is an integral component of the host antimicrobial defense system. The principal aim of this study was to investigate the influence of a PAR(2)-activating peptide, SLIGRL, on influenza A virus (IAV)-induced pathogenesis in mice. Intranasal inoculation of BALB/c mice with influenza A/PR/8/34 virus caused time-dependent increases in the number of pulmonary leukocytes (recovered from bronchoalveolar lavage fluid), marked airway histopathology characterized by extensive epithelial cell damage, airway hyper-responsiveness to the bronchoconstrictor methacholine, and elevated levels of inflammatory chemokines (keratinocyte-derived chemokine and macrophage inflammatory protein 2) and cytokines (interferon-γ). It is noteworthy that these IAV-induced effects were dose-dependently attenuated in mice treated with a PAR(2)-activating peptide, SLIGRL, at the time of IAV inoculation. However, SLIGRL also inhibited IAV-induced increases in pulmonary leukocytes in PAR(2)-deficient mice, indicating these antiviral actions were not mediated by PAR(2). The potency order obtained for a series of structural analogs of SLIGRL for anti-IAV activity (IGRL > SLIGRL > LSIGRL >2-furoyl-LIGRL) was also inconsistent with a PAR(2)-mediated effect. In further mechanistic studies, SLIGRL inhibited IAV-induced propagation in ex vivo perfused segments of trachea from wild-type or PAR(2)(-/-) mice, but did not inhibit viral attachment or replication in Madin-Darby canine kidney cells and chorioallantoic membrane cells, which are established hosts for IAV. In summary, SLIGRL protected mice from IAV infection independently of PAR(2) and independently of direct inhibition of IAV attachment or replication, potentially through the activation of endogenous antiviral pathways within the mouse respiratory tract.
authors.affiliation: School of Medicine and Pharmacology, University of Western Australia, Nedlands, Western Australia.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Betts
authors.forename: Tracy S
authors.initials: TS
authors.lastname: Mann
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Henry
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D002460:Cell Line; D016207:Cytokines / Q000276:immunology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D009980:Influenza A virus / Q000187:drug effects* / Q000472:pathogenicity / Q000502:physiology; D007958:Leukocyte Count; D007962:Leukocytes / Q000166:cytology; D008168:Lung / Q000187:drug effects / Q000648:ultrastructure / Q000821:virology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008855:Microscopy, Electron, Scanning; D009842:Oligopeptides / Q000008:administration & dosage / Q000627:therapeutic use*; D009976:Orthomyxoviridae Infections / Q000188:drug therapy* / Q000378:metabolism / Q000821:virology; D044464:Receptor, PAR-2 / Q000235:genetics / Q000378:metabolism*; D012129:Respiratory Function Tests; D014132:Trachea / Q000187:drug effects / Q000648:ultrastructure / Q000821:virology; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D016207:Cytokines; D009842:Oligopeptides; D044464:Receptor, PAR-2; C099570:seryl-leucyl-isoleucyl-glycyl-arginyl-leucine