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J Biol Chem. 2019 Feb 7. pii: jbc.AW118.003229. doi: 10.1074/jbc.AW118.003229. [Epub ahead of print]

Phospholipid regulation of innate immunity and respiratory viral infection.

Author information

1
Department of Medicine, Program in Cell Biology, National Jewish Health, United States.
2
NATIONAL JEWISH HEALTH, United States.

Abstract

Toll-like receptors (TLRs) coupled to intracellular signaling cascades function as central elements of innate immunity that control transcription of numerous pro-inflammatory genes. Two minor anionic phospholipids present in the pulmonary surfactant complex, palmitoyl-oleoyl-phosphatidylglyerol (POPG) and phosphatidylinositol (PI), antagonize the cognate ligand activation of TLRs 2 and 4.  The lipids block recognition of activating ligands by the TLRs, either directly, or via the TLR4 co-receptors, CD14 and MD2.  Antagonism of TLR activation results in inhibition of the initiating step of the pro-inflammatory signaling pathways.  Evidence for this mechanism of action comes from direct binding studies between CD14 and MD2 with POPG and PI.  Additional evidence for this mechanism of antagonism also comes from monitoring the reduction of protein phosphorylation events that characterize the intracellular signaling by activated TLRs.  The pathogenesis of Respiratory Syncytial Virus (RSV) and Influenza A Virus (IAV) have been linked to TLR4 activation and we examined the action of POPG and PI, as potential antagonists of the pathology of these viruses.  Surprisingly, POPG and PI dramatically curtail infection, in addition to inhibiting inflammatory sequelae associated with RSV and IAV infections.  The mechanism of action by the lipids is disruption of virus particle binding to host cell plasma membrane receptors, required for viral uptake. The antagonism of activation of TLRs and virus binding to the alveolar epithelium by resident constituents of the pulmonary surfactant system suggests that POPG and PI function in homeostasis, to prevent inflammatory processes that result in reductions in gas exchange within the alveolar compartment.

KEYWORDS:

antiviral agent; immunology; inflammation; innate immunity; phospholipids; pulmonary surfactant; signaling; toll receptor; viral entry; virology

PMID:
30733339
DOI:
10.1074/jbc.AW118.003229
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