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Role of Lipids/Lipid Rafts in the Pathogenesis of Influenza

Influenza A virus is an enveloped virus with a lipid-bilayer membrane and three types of integral membrane proteins, namely hemagglutinin (HA), neuraminidase (NA) and M2. Beneath the lipid membrane is a protein matrix made of protein M1. A segmented genome, comprised of eight single-stranded RNAs packed into ribonucleoprotein (RNP) complexes, resides inside the virus....

Role of Lipids/Lipid Rafts in the Pathogenesis of Influenza

Pathway Summary

Influenza A virus is an enveloped virus with a lipid-bilayer membrane and three types of integral membrane proteins, namely hemagglutinin (HA), neuraminidase (NA) and M2. Beneath the lipid membrane is a protein matrix made of protein M1. A segmented genome, comprised of eight single-stranded RNAs packed into ribonucleoprotein (RNP) complexes, resides inside the virus.Lipid rafts are lipid microdomains enriched in sphingolipids and cholesterol. They play a critical role in many aspects of the influenza A virus life cycle, from viral entry and fusion with the endosomal membrane to virus assembly and budding. Influenza viruses bind via HA to sialic acid residues on the glycoproteins on the host cell surface. The glycoproteins are often embedded in lipid rafts. Once bound to the cell surface, the virus relies on endocytosis and a pH-dependent fusion mechanism to enter the cytoplasm. In the early steps of viral entry, cholesterol aids the HA-catalyzed fusion between viral and endosomal membranes. The viral protein M2 forms pH-gated proton channels in the viral lipid envelope, allowing proton conductance and acidification of viral interior leading to release of RNPs into the cytoplasm and later the nucleus.After viral replication and transcription, which takes place in the nucleus, RNPs are associated with M1 and exported to the cytoplasm. Other viral proteins such as NA and HA are transported via the Trans-Golgi network. HA and M2 also undergo palmitoylation. HA and NA use lipid rafts as a platform for apical transport and remain associated with lipid raft microdomains present on cellular membranes. Recent studies show that M2 is a cholesterol-binding protein and may play a critical role in virus budding. M1-RNP complexes bind to HA- and NA-enriched raft membranes as M1 has affinity for membrane rafts as well as to NA and HA cytoplasmic tails. Lipid raft associated viral assembly is followed by virus budding. Cholesterol is very important to this process. It has been demonstrated that cholesterol depletion results in an increase in viral budding while adversely affecting viral infectivity. Studies also show that influenza A virus acquires a lipid raft-containing envelope while budding.

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