Phosphatidylglycerol Suppresses Influenza A Virus Infection

Department of Medicine, Program in Cell Biology, National Jewish Health, Denver, CO 80206, USA.
American Journal of Respiratory Cell and Molecular Biology (Impact Factor: 3.99). 11/2011; 46(4):479-87. DOI: 10.1165/rcmb.2011-0194OC
Source: PubMed


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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    • "PG also protects the lungs from inflammation initiated by LPS exposure in vivo [33]. In addition, PG inhibits infection of airway epithelial cells by respiratory syncytial virus and influenza A in vitro and protects the lungs from the deleterious effects of these viruses in vivo [35], [36]. Finally, in eukaryotes PG is a precursor of cardiolipin [37], a key mitochondrial lipid that plays a role in mitochondrial function and energy production as well as apoptosis (reviewed in [38]). "
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    ABSTRACT: We have previously shown that liposomes composed of egg-derived phosphatidylglycerol (PG), with a mixed fatty acid composition (comprising mainly palmitate and oleate), inhibit the proliferation and promote the differentiation of rapidly dividing keratinocytes, and stimulate the growth of slowly proliferating epidermal cells. To determine the species of PG most effective at modulating keratinocyte proliferation, primary mouse keratinocytes were treated with different PG species, and proliferation was measured. PG species containing polyunsaturated fatty acids were effective at inhibiting rapidly proliferating keratinocytes, whereas PG species with monounsaturated fatty acids were effective at promoting proliferation in slowly dividing cells. Thus, palmitoyl-arachidonyl-PG (16∶0/20∶4), palmitoyl-linoleoyl-PG (16∶0/18∶2), dilinoleoyl-PG (18∶2/18∶2) and soy PG (a PG mixture with a large percentage of polyunsaturated fatty acids) were particularly effective at inhibiting proliferation in rapidly dividing keratinocytes. Conversely, palmitoyl-oleoyl-PG (16∶0/18∶1) and dioleoyl-PG (18∶1/18∶1) were especially effective proproliferative PG species. This result represents the first demonstration of opposite effects of different species of a single class of phospholipid and suggests that these different PG species may signal to diverse effector enzymes to differentially affect keratinocyte proliferation and normalize keratinocyte proliferation. Thus, different PG species may be useful for treating skin diseases characterized by excessive or insufficient proliferation.
    PLoS ONE 09/2014; 9(9):e107119. DOI:10.1371/journal.pone.0107119 · 3.23 Impact Factor
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    • "For cellular binding studies, HEp2 cells were grown in 24-well plates and RSV was adsorbed to the monolayers at varying MOIs (0, 1, 2, 5, and 10) for 2 hours at 18°C, either in the absence or presence of nPOPG, nPOPC, or liposome POPG (200 μg/mL of phospholipids). At 18°C, endocytosis by HEp2 cells is minimal, and this temperature allows viral binding to reach equilibrium within 2 hours.28 The cell monolayers were processed at 0°C for subsequent analysis by quantitative immunoblotting using a goat anti-RSV antibody (AbD Serotec, Raleigh, NC, USA). "
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    ABSTRACT: There is increasing interest in the application of nanotechnology to solve the difficult problem of therapeutic administration of pharmaceuticals. Nanodiscs, composed of a stable discoidal lipid bilayer encircled by an amphipathic membrane scaffold protein that is an engineered variant of the human Apo A-I constituent of high-density lipoproteins, have been a successful platform for providing a controlled lipid composition in particles that are especially useful for investigating membrane protein structure and function. In this communication, we demonstrate that nanodiscs are effective in suppressing respiratory syncytial viral (RSV) infection both in vitro and in vivo when self-assembled with the minor pulmonary surfactant phospholipid palmitoyloleoylphosphatidylglycerol (POPG). Preparations of nanodiscs containing POPG (nPOPG) antagonized interleukin-8 production from Beas2B epithelial cells challenged by RSV infection, with an IC50 of 19.3 μg/mL. In quantitative in vitro plaque assays, nPOPG reduced RSV infection by 93%. In vivo, nPOPG suppressed inflammatory cell infiltration into the lung, as well as IFN-γ production in response to RSV challenge. nPOPG also completely suppressed the histopathological changes in lung tissue elicited by RSV and reduced the amount of virus recovered from lung tissue by 96%. The turnover rate of nPOPG was estimated to have a halftime of 60-120 minutes (m), based upon quantification of the recovery of the human Apo A-I constituent. From these data, we conclude that nPOPG is a potent antagonist of RSV infection and its inflammatory sequelae both in vitro and in vivo.
    International Journal of Nanomedicine 04/2013; 8:1417-1427. DOI:10.2147/IJN.S39888 · 4.38 Impact Factor
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    • "Even though the latter administration is conducted under anesthesia and the bulk of the inoculum reaches the lower respiratory tract (Larson et al., 1976), it is likely that these large drops would be retained in the bronchioles where virus can be eliminated after binding to mucins (Rogers, 2003) or inactivated by a number of other innate soluble or cellular mechanisms. This may include inactivation by collectins such as surfactant protein D, alone or through activation of neutrophils (Hartshorn et al., 1994), inactivation by phosphatidylglycerol (Numata et al., 2012), or removal by macrophages (Wang et al., 2012). Our future studies will determine whether there is differential distribution of infected cells in the lower respiratory tract after inhalation and instillation challenge. "
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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 · 3.72 Impact Factor
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