Pulmonary surfactant lipids inhibit infections with the pandemic H1N1 influenza virus in several animal models

Mari Numata,James R Mitchell,Jennifer L Tipper,Jeffrey D Brand,John E Trombley,Yoji Nagashima,Pitchaimani Kandasamy,Hong Wei Chu,Kevin S Harrod,Dennis R Voelker

doi:10.1074/jbc.ra119.012053

Abstract

The influenza A (H1N1)pdm09 outbreak in 2009 exemplified the problems accompanying the emergence of novel influenza A virus (IAV) strains and their unanticipated virulence in populations with no pre-existing immunity. Neuraminidase inhibitors (NAIs) are currently the drugs of choice for intervention against IAV outbreaks, but there are concerns that NAI-resistant viruses can transmit to high-risk populations. These issues highlight the need for new approaches that address the annual influenza burden. In this study, we examined whether palmitoyl-oleoyl-phosphatidylglycerol (POPG) and phosphatidylinositol (PI) effectively antagonize (H1N1)pdm09 infection. POPG and PI markedly suppressed cytopathic effects and attenuated viral gene expression in (H1N1)pdm09-infected Madin-Darby canine kidney cells. POPG and PI bound to (H1N1)pdm09 with high affinity and disrupted viral spread from infected to noninfected cells in tissue culture and also reduced (H1N1)pdm09 propagation by a factor of 102 after viral infection was established in vitro In a mouse infection model of (H1N1)pdm09, POPG and PI significantly reduced lung inflammation and viral burden. Of note, when mice were challenged with a typically lethal dose of 1000 plaque-forming units of (H1N1)pdm09, survival after 10 days was 100% (14 of 14 mice) with the POPG treatment compared with 0% (0 of 14 mice) without this treatment. POPG also significantly reduced inflammatory infiltrates and the viral burden induced by (H1N1)pdm09 infection in a ferret model. These findings indicate that anionic phospholipids potently and efficiently disrupt influenza infections in animal models.

Highlights

The influenza A (H1N1)pdm09 outbreak in 2009 exemplified the problems accompanying the emergence of novel influenza A virus (IAV) strains and their unanticipated virulence in populations with no pre-existing immunity
We previously reported that POPG and PI markedly inhibit respiratory syncytial virus (RSV) infection by binding the virus with high affinity and preventing attachment to epithelial cell surfaces [17, 18]
We examined the effects of POPG and PI upon MDCK cells challenged with (H1N1)pdm09

Summary

Introduction

The influenza A (H1N1)pdm outbreak in 2009 exemplified the problems accompanying the emergence of novel influenza A virus (IAV) strains and their unanticipated virulence in populations with no pre-existing immunity. Neuraminidase inhibitors (NAIs) are currently the drugs of choice for intervention against IAV outbreaks, but there are concerns that NAI-resistant viruses can transmit to high-risk populations These issues highlight the need for new approaches that address the annual influenza burden. POPG significantly reduced inflammatory infiltrates and the viral burden induced by (H1N1)pdm infection in a ferret model. These findings indicate that anionic phospholipids potently and efficiently disrupt influenza infections in animal models. It is noteworthy that neuraminidase inhibitorresistant variants of this virus appeared [7,8,9,10,11] along with other novel variant viruses [12] These issues demonstrate the need for new approaches to the annual influenza burden.

Objectives

Methods

Results

Conclusion