Mutation of Respiratory Syncytial Virus G Protein's CX3C Motif Attenuates Infection in Cotton Rats and Primary Human Airway Epithelial Cells.

Binh Ha,Thomas J Mariani,Tatiana Chirkova,He Ying Sun,Marina S Boukhvalova,Christopher S Anderson,Edward E Walsh,Larry J Anderson

doi:10.3390/vaccines7030069

Abstract

Despite being a high priority for vaccine development, no vaccine is yet available for respiratory syncytial virus (RSV). A live virus vaccine is the primary type of vaccine being developed for young children. In this report, we describe our studies of infected cotton rats and primary human airway epithelial cells (pHAECs) using an RSV r19F with a mutation in the CX3C chemokine motif in the RSV G protein (CX4C). Through this CX3C motif, RSV binds to the corresponding chemokine receptor, CX3CR1, and this binding contributes to RSV infection of pHAECs and virus induced host responses that contribute to disease. In both the cotton rat and pHAECs, the CX4C mutation decreased virus replication and disease and/or host responses to infection. Thus, this mutation, or other mutations that block binding to CX3CR1, has the potential to improve a live attenuated RSV vaccine by attenuating both infection and disease pathogenesis.

Highlights

The respiratory syncytial virus (RSV) was first isolated in the 1950s [1,2] and it was quickly recognized as an important cause of acute lower respiratory tract illness in young children
We have shown that the RSV G protein is an important contributor to RSV disease, likely through its CX3C chemokine motif binding to the corresponding chemokine receptor, CX3CR1 [18,19,20,21,22,23,24,25,26]
Since disruption of the CX3C motif in the r19FCX4C virus was associated with decreased infectivity and disease in the cotton rat as well as the BALB/c mouse in an earlier study [25], we investigated the effect of this mutation in the primary human airway epithelial cells (pHAECs) model of human infection

Summary

Introduction

The respiratory syncytial virus (RSV) was first isolated in the 1950s [1,2] and it was quickly recognized as an important cause of acute lower respiratory tract illness in young children. The RSV infects most children by two years of age and causes repeat infections with disease throughout life [3] with compromised cardiac, pulmonary, and immune systems and in older age is associated with serious complications of infection [4,5]. Though the burden of RSV has made it a high priority for vaccine and antiviral drug development [12], no vaccine or effective antiviral drug is yet available. Immune prophylaxis is available and effective for preventing serious complications of RSV infection in high-risk young children

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Conclusion