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• W2023405034 abstract "Influenza is a leading cause of morbidity and mortality worldwide, with vaccines and antiviral drugs having limited efficacy thus far. Two recent studies in Cell apply lipidomics approaches to identify bioactive lipid mediators influencing host inflammation, viral replication, and disease progression. Influenza is a leading cause of morbidity and mortality worldwide, with vaccines and antiviral drugs having limited efficacy thus far. Two recent studies in Cell apply lipidomics approaches to identify bioactive lipid mediators influencing host inflammation, viral replication, and disease progression. Among viral respiratory pathogens, influenza virus causes the highest numbers of hospitalizations and deaths in humans. Not only are seasonal influenza viruses responsible for up to half a million deaths worldwide, but these numbers can significantly increase during pandemic years that occur every 10–50 years. Available vaccines only protect against antigenically related strains and have limited efficacy, especially in the elderly, a population at higher risk of severe influenza. There are limited choices of drugs for the treatment of severe influenza, and these drugs can easily generate resistance, as is the case with the viral neuraminidase inhibitor oseltamivir. A promising approach for the discovery of compounds for the treatment of influenza virus infections is targeting host factors that regulate viral replication and/or disease. In this respect, genomics and proteomics studies have given us a plethora of information on host genes and proteins whose regulation is associated with viral infection and pathogenesis (Korth et al., 2012Korth M.J. Tchitchek N. Benecke A.G. Katze M.G. Semin. Immunol. 2012; (Published online December 4, 2012)https://doi.org/10.1016/j.smim.2012.11.001Crossref PubMed Scopus (39) Google Scholar). In addition, siRNA screens have provided us with a list of host genes required for optimal influenza virus replication as well as restricting viral replication (Shaw, 2011Shaw M.L. Rev. Med. Virol. 2011; 21: 358-369Crossref PubMed Scopus (46) Google Scholar). Among host factors involved in viral replication and/or in pathogenesis, it is likely that some of them can be targeted for the treatment of influenza without significant side effects. However, very limited information has been available until now with respect to host factors different than coding genes and proteins involved in influenza disease. The recent studies in Cell from Morita et al., 2013Morita M. Kuba K. Ichikawa A. Nakayama M. Katahira J. Iwamoto R. Watanebe T. Sakabe S. Daidoji T. Nakamura S. et al.Cell. 2013; 153: 112-125Abstract Full Text Full Text PDF PubMed Scopus (336) Google Scholar and Tam et al. (Tam et al., 2013Tam V.C. Quehenberger O. Oshansky C.M. Suen R. Armando A.M. Treuting P.M. Thomas P.G. Dennis E.A. Aderem A. Cell. 2013; 154 (this issue): 213-227Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar, this issue) provide a comprehensive analysis of host lipid factors regulated during influenza virus infection that have an impact in viral replication, inflammation, and disease. Together, they point toward possible new treatment modalities based on key bioactive lipids involved in viral pathogenesis. Morita et al., 2013Morita M. Kuba K. Ichikawa A. Nakayama M. Katahira J. Iwamoto R. Watanebe T. Sakabe S. Daidoji T. Nakamura S. et al.Cell. 2013; 153: 112-125Abstract Full Text Full Text PDF PubMed Scopus (336) Google Scholar screened lipid metabolites for their impact in influenza virus replication in human respiratory cells. Among the identified compounds affecting virus replication, 10S 17S-dihydroxydocosahexaenoic acid, also known as protectin D1 (PD1), was found to be a potent inhibitor. Mechanistically, PD1 interferes with binding of specific host nuclear export factors to influenza virus RNAs, preventing viral RNA export from the nucleus to the cytoplasm. The authors also conducted a comprehensive analysis of changes in endogenous lipid mediators in lungs during infection with influenza virus in a mouse model. Interestingly, PD1 levels were reduced during infection, and the levels of reduction correlated with virulence and disease. Importantly, exogenous administration of PD1 ameliorated lung function during infection, reduced viral titers, and increased survival. Consistent with these data, ablation of the host enzyme 12/15-lipoxygenase (12/15-LOX) responsible for PD1 synthesis increased viral replication and disease. Tam et al., 2013Tam V.C. Quehenberger O. Oshansky C.M. Suen R. Armando A.M. Treuting P.M. Thomas P.G. Dennis E.A. Aderem A. Cell. 2013; 154 (this issue): 213-227Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar also conducted a comprehensive analysis of lipid mediators during influenza virus infection in mouse lungs, comparing two viruses of high and low virulence. This analysis was integrated with data on cytokine and chemokine profiles, virus replication, and transcriptomics. Interestingly, the authors also identified lipid metabolites derived from the 12/15-LOX pathway as differentially regulated by infection according to virulence. In the mouse, 12/15-LOX derived metabolites were elevated during resolution of infection with the less-virulent virus. Intriguingly, levels of 12-LOX generated metabolites also correlated with increasing clinical symptoms in nasal washes from influenza-virus-infected humans. Moreover, the ratios of two other lipid metabolites, the proinflammatory 9 HODE and the anti-inflammatory 13 HODE, were found to be predictive of the level of inflammation, at least in the mouse model. Although PD1 levels were not detected in the study by Tam et al., data from both studies are consistent with a protective role of 12/15 LOX-derived metabolites. More detailed studies will be needed in humans to validate the use of these metabolites for the treatment of influenza. However, the identification of lipid mediators that directly inhibit virus replication while at the same time promoting resolution of inflammation due to their anti-inflammatory properties provides the basis for an interesting new concept for the treatment of influenza. Other immunoregulatory molecules might indirectly increase viral replication by inhibiting antiviral inflammatory effectors, and a right balance between beneficial effects related to their anti-inflammatory properties and detrimental effects due to potential increased viral replication during reduced inflammation might be difficult to achieve. By combining direct antiviral activity with anti-inflammatory properties, bioactive lipid mediators such as PD1 are attractive candidates for the development of new drugs for the treatment of influenza and perhaps of other viral diseases characterized by high viral replication in the context of exacerbated proinflammatory responses (Figure 1). Because this strategy targets host factors involved in viral replication rather than viral proteins, it is unlikely to be easily overcome by the selection of resistant mutant viruses. The Lipid Mediator Protectin D1 Inhibits Influenza Virus Replication and Improves Severe InfluenzaMorita et al.CellMarch 7, 2013In BriefThe bioactive lipid protectin D1 inhibits influenza virus replication and when injected in mice improves outcomes even at late stages of infection Full-Text PDF Open ArchiveLipidomic Profiling of Influenza Infection Identifies Mediators that Induce and Resolve InflammationTam et al.CellJuly 03, 2013In BriefA large-scale lipidomics study identifies lipid regulators of inflammation during influenza infections in mice and humans and demonstrates that lipids provide a more dynamic view of the inflammatory response than either cytokine protein levels or immune response genes. Full-Text PDF Open Archive" @default.
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• W2023405034 title "Lessons from Lipids in the Fight against Influenza" @default.
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