PT  - JOURNAL ARTICLE
AU  - Betts, Richard J.
AU  - Mann, Tracy S.
AU  - Henry, Peter J.
TI  - Inhibitory Influence of the Hexapeptidic Sequence SLIGRL on Influenza A Virus Infection in Mice
AID  - 10.1124/jpet.112.196485
DP  - 2012 Dec 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 725--735
VI  - 343
IP  - 3
4099  - http://jpet.aspetjournals.org/content/343/3/725.short
4100  - http://jpet.aspetjournals.org/content/343/3/725.full
SO  - J Pharmacol Exp Ther2012 Dec 01; 343
AB  - Proteinase-activated receptor 2 (PAR2) 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 PAR2-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 PAR2-activating peptide, SLIGRL, at the time of IAV inoculation. However, SLIGRL also inhibited IAV-induced increases in pulmonary leukocytes in PAR2-deficient mice, indicating these antiviral actions were not mediated by PAR2. 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 PAR2-mediated effect. In further mechanistic studies, SLIGRL inhibited IAV-induced propagation in ex vivo perfused segments of trachea from wild-type or PAR2(−/−) 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 PAR2 and independently of direct inhibition of IAV attachment or replication, potentially through the activation of endogenous antiviral pathways within the mouse respiratory tract.