# Phospholipid-Protein Interactions Regulating Viral Infection

> **NIH NIH R01** · NATIONAL JEWISH HEALTH · 2020 · $311,056

## Abstract

Recent work has revealed an unexpected role for the anionic phospholipid, palmitoyl-oleoyl-
phosphatidylglycerol (POPG) as an antagonist of multiple Toll-like receptors, and a potent inhibitor of
Respiratory Syncytial Virus (RSV) and Influenza A virus (IAV) infection. The emerging view is that POPG
functions as a decoy ligand for multiple Toll-like receptors (TLRs 1,2,3,4 and 6) and competitively blocks their
engagement by native ligands present on microbes. Likewise, the phospholipid competitively inhibits
recognition of the cell surface attachment ligands for RSV and IAV and thereby prevents the viruses from
binding to the plasma membrane and infecting epithelial cells. Currently, the general features of POPG action
against TLRs and viruses are clearly understood from in vitro and in vivo studies, but the specific molecular
mechanisms of action have not been elucidated. In this proposal we will focus upon the physical interactions
of POPG and related phospholipids with Toll-like receptor 3 (TLR3) and the recently emergent pandemic H1N1
(pH1N1) virus. The goals are to define the structural features of phospholipids, TLR3 and the envelope
proteins of pH1N1 that are essential for the lipid-protein interactions and the subsequent inhibition of biological
effects. To accomplish these goals we will pursue three Specific Aims. In Aim 1 we will examine the
elements of lipid structure required to inhibit TLR3 activation and IAV infection by using a library of POPG
analogs. In Aim 2, we will identify the phospholipid binding site on TLR3 and determine its relationship to the
double stranded RNA binding sites on the molecule. In Aim 3, we will identify the POPG binding site(s) on
pH1N1 envelope protein(s) and determine its relationship to the sialic acid binding domain of the H1 protein.
From these studies we expect to define specific molecular interactions and mechanisms by which POPG and
structurally related molecules suppress IAV infection and the TLR3-dependent inflammatory processes that
follow viral infection. This information will provide new pharmacological insights for preventing and treating
IAV infections and reducing the pathological consequences of the inflammatory sequelae. There is significant
potential for this work to identify novel lipids that will function as antagonists of newly emergent and highly
virulent strains of IAV.

## Key facts

- **NIH application ID:** 9969456
- **Project number:** 5R01GM118819-04
- **Recipient organization:** NATIONAL JEWISH HEALTH
- **Principal Investigator:** Mari Numata-Nakamura
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $311,056
- **Award type:** 5
- **Project period:** 2017-09-19 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9969456

## Citation

> US National Institutes of Health, RePORTER application 9969456, Phospholipid-Protein Interactions Regulating Viral Infection (5R01GM118819-04). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9969456. Licensed CC0.

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