Phosphatidylglycerol suppresses influenza A virus infection
ABSTRACT Influenza A virus (IAV) is a worldwide public health problem causing 500,000 deaths each year. Palmitoyl-oleoyl-phosphatidylglycerol (POPG) is a minor component of pulmonary surfactant, which has recently been reported to exert potent regulatory functions upon the innate immune system. In this article, we demonstrate that POPG acts as a strong antiviral agent against IAV. POPG markedly attenuated IL-8 production and cell death induced by IAV in cultured human bronchial epithelial cells. The lipid also suppressed viral attachment to the plasma membrane and subsequent replication in Madin-Darby canine kidney cells. Two virus strains, H1N1-PR8-IAV and H3N2-IAV, bind to POPG with high affinity, but exhibit only low-affinity interactions with the structurally related lipid, palmitoyl-oleoyl-phosphatidylcholine. Intranasal inoculation of H1N1-PR8-IAV in mice, in the presence of POPG, markedly suppressed the development of inflammatory cell infiltrates, the induction of IFN-γ recovered in bronchoalveolar lavage, and viral titers recovered from the lungs after 5 days of infection. These findings identify supplementary POPG as a potentially important new approach for treatment of IAV infections.
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ABSTRACT: Influenza continues to cause widespread disease and death during winter months. In preclinical studies to evaluate the potential efficacy of drugs and vaccines, influenza challenge virus is usually instilled into the noses of animals in the form of large liquid drops. Since inhalation of aerosolized influenza is commonly associated with human transmission, instillation of challenge virus raises uncertainty about the applicability of results. In order to compare the challenge methods, we established conditions to generate influenza aerosols with a mass median aerodynamic diameter (MMAD) of 1 μm that were delivered to mice in a nose-only inhalation system. In this report, we describe the system and compare the 50% lethal dose (LD(50)) of instilled and inhaled A/PR/8/34 (PR8) in BALB/c mice. The estimated LD(50) for inhaled virus was 8.7 plaque forming units (PFU) and the mean time to death was 7.7 days, whereas the estimated LD(50) for instilled virus was 51.6 PFU and the mean time to death was 8.2 days. Our results show that mice are more sensitive to inhaled virus than virus delivered by intranasal instillation. The murine nose-only inhalation model of influenza infection can be used to infect large numbers of animals simultaneously with well-characterized, homogenous PR8 bioaerosol in a controlled and reproducible manner. This model provides the means to evaluate the efficacy of drug and vaccine candidates against the relevant route of challenge, thereby providing data that may better predict clinical outcome.Frontiers in Cellular and Infection Microbiology 05/2012; 2:74. DOI:10.3389/fcimb.2012.00074 · 2.62 Impact Factor
- Expert Review of Respiratory Medicine 06/2012; 6(3):243-6. DOI:10.1586/ers.12.21
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ABSTRACT: Protease-activated receptor-2 (PAR2) is widely expressed in the respiratory tract and is an integral component of the host antimicrobial defence 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 characterised by extensive epithelial cell damage, airway hyperresponsiveness to the bronchoconstrictor methacholine, and elevated levels of inflammatory chemokines (KC, MIP-2) and cytokines (interferon-γ). Interestingly, 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 analogues of SLIGRL for anti-IAV activity (IGRL > SLIGRL > LSIGRL > f-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 MDCK 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 activation of endogenous antiviral pathways within the mouse respiratory tract.Journal of Pharmacology and Experimental Therapeutics 09/2012; 343(3). DOI:10.1124/jpet.112.196485 · 3.86 Impact Factor