The Lipid Mediator Protectin D1 Inhibits Influenza Virus Replication and Improves Severe Influenza

Abstract

Influenza A viruses are a major cause of mortality. Given the potential for future lethal pandemics, effective drugs are needed for the treatment of severe influenza such as that caused by H5N1 viruses. Using mediator lipidomics and bioactive lipid screen, we report that the omega-3 polyunsaturated fatty acid (PUFA)-derived lipid mediator protectin D1 (PD1) markedly attenuated influenza virus replication via RNA export machinery. Production of PD1 was suppressed during severe influenza and PD1 levels inversely correlated with the pathogenicity of H5N1 viruses. Suppression of PD1 was genetically mapped to 12/15-lipoxygenase activity. Importantly, PD1 treatment improved the survival and pathology of severe influenza in mice, even under conditions where known antiviral drugs fail to protect from death. These results identify the endogenous lipid mediator PD1 as an innate suppressor of influenza virus replication that protects against lethal influenza virus infection.

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.…”

“…These soluble lipid mediators originate from membrane glycerophospholipids (GPLs) via phospholipase activity, and (to some extent), are metabolized in peroxisomes. For example, ␤ -oxidation in the peroxisome is crucial for the retroconversion of DHA, the precursor of the lipid mediator protectin D1, which prevents nuclear export of infl uenza virus RNAs; protectin D1 production is directly inhibited by infl uenza virus ( 15 ). The role of peroxisomes during infl uenza virus replication is further evident by interaction between infl uenza virus nonstructural protein 1 (NS1) and multifunctional protein 2 (MFP2/HSD17B4), an antiviral protein essential for peroxisomal ␤ -oxidation ( 17 ).…”

Influenza virus-induced lung injury: pathogenesis and implications for treatment

“…Similarly, strategies that promote immune resolution or tissue regeneration, e.g. inhibitors of T-cell co-stimulators, resolvins, lipoxins, inhibitors of the CD200 receptor and immunomodulatory antibiotics or glitazones [93,99,[199][200][201] may accelerate regeneration in patients with severe disease. Further research is needed to identify cells and pathways that can be specifically targeted over the course of the infection and to develop clinically useful biomarkers that can identify the subset of patients in whom these targeted therapies will be most effective.…”