Lipidomic Profiling of Influenza Infection Identifies Mediators that Induce and Resolve Inflammation

Abstract

Summary Bioactive lipid mediators play a crucial role in the induction and resolution of inflammation. To elucidate their involvement during influenza infection, LC/MS lipidomic profiling of 141 lipid species was performed on a mouse influenza model using two viruses of significantly different pathogenicity. Infection by the low pathogenicity strain, X31/H3N2, induced a pro-inflammatory response followed by a distinct anti-inflammatory response; infection by the high pathogenicity strain, PR8/H1N1, resulted in overlapping pro- and anti-inflammatory states. Integration of the large-scale lipid measurements with targeted gene expression data demonstrated that 5 lipoxygenase metabolites correlated with the pathogenic phase of the infection whereas 12/15-lipoxygenase metabolites were associated with the resolution phase. Hydroxylated linoleic acid, specifically the ratio of 13- to 9-HODE, was identified as a potential biomarker for immune status during an active infection. Importantly, some of the findings from the animal model were recapitulated in studies of human nasopharyngeal lavages obtained during the 2009–2011 influenza seasons.

HLA-B27, but Not HLA-B7, Immunodominance to Influenza Is ERAP Dependent

“…3C) (18). As expected, the cytokine level of flu-infected animals was higher than that of its naive controls, confirming previous results (21,22). There was a significant (p , 0.001) difference in the levels of IL-1a, IL-6, and MIP-1a produced in the lung of B27/ERAP +/+ and B27/ERAP 2/2 Tg mice (Fig.…”

Lipidomics identifies a requirement for peroxisomal function during influenza virus replication

“…Consistent with impaired peroxisomal ␤ -oxidation, we observed an enrichment in C26:0 but a decrease in C24:1 fatty acids in SPL species ( Fig. 1G ) (25)(26)(27); this provided further support for an important role of fatty acyl metabolism during infl uenza infection ( 15,16 ).…”

“…Host cell lipid metabolism and plasma membrane microdomains are implicated in the biogenesis of virus envelopes. Several studies have dissected the lipid inventory of purifi ed infl uenza virions ( 9, 10 ), whereas others have demonstrated the requirements for de novo fatty acid and sphingolipid biosynthesis and unique cholesterol compositions for virus production at budding sites (11)(12)(13)(14).In addition to the importance of host cell lipid metabolism for the biogenesis of infl uenza virus envelopes, recent fi ndings suggest a major role for soluble lipid mediators in antiviral responses against infl uenza virus infection in vivo ( 15,16 ). These soluble lipid mediators originate from membrane glycerophospholipids (GPLs) via phospholipase activity, and (to some extent), are metabolized in peroxisomes.…”

“…In addition to the importance of host cell lipid metabolism for the biogenesis of infl uenza virus envelopes, recent fi ndings suggest a major role for soluble lipid mediators in antiviral responses against infl uenza virus infection in vivo ( 15,16 ). These soluble lipid mediators originate from membrane glycerophospholipids (GPLs) via phospholipase activity, and (to some extent), are metabolized in peroxisomes.…”

Liberating Chiral Lipid Mediators, Inflammatory Enzymes, and LIPID MAPS from Biological Grease

“…For example, we studied the effects of fish oil consumption on Lyme disease progression (174). In this research, novel eicosanoid mediators were found, including anti-inflammatory mediators that differentiate the pathogenicity of influenza strains in mouse and in human lavages (175). Lipidomic analysis of cells supplemented with small amounts of the fish oil-derived -3 fatty acids, eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), clarified their effects on the inflammatory eicosadome in inhibiting COX-1 more than COX-2 and shunting arachidonate to LOX physiologically (176).…”