Identification of nucleolin as a cellular receptor for human respiratory syncytial virus

Abstract

Human respiratory syncytial virus (RSV) causes a large burden of disease worldwide. There is no effective vaccine or therapy, and the use of passive immunoprophylaxis with RSV-specific antibodies is limited to high-risk patients. The cellular receptor (or receptors) required for viral entry and replication has yet to be described; its identification will improve understanding of the pathogenesis of infection and provide a target for the development of novel antiviral interventions. Here we show that RSV interacts with host-cell nucleolin via the viral fusion envelope glycoprotein and binds specifically to nucleolin at the apical cell surface in vitro. We observed decreased RSV infection in vitro in neutralization experiments using nucleolin-specific antibodies before viral inoculation, in competition experiments in which virus was incubated with soluble nucleolin before inoculation of cells, and upon RNA interference (RNAi) to silence cellular nucleolin expression. Transfection of nonpermissive Spodoptera frugiperda Sf9 insect cells with human nucleolin conferred susceptibility to RSV infection. RNAi-mediated knockdown of lung nucleolin was associated with a significant reduction in RSV infection in mice (P = 0.0004), confirming that nucleolin is a functional RSV receptor in vivo.

Siglec‐1 inhibits RSV‐induced interferon gamma production by adult T cells in contrast to newborn T cells

“…Sialoglycans are present on the gp120 envelope of HIV and mediate cell entry via Siglec‐1. Little is known about cellular receptors for RSV and nucleolin has been proposed as an important receptor for RSV fusion protein to allow cell entry of epithelial cells 25. Our data indicate that Siglec‐1 is not required for RSV infection of monocytes.…”

RNA-binding protein nucleolin in disease

“…Nucleolin was shown to be essential for entry of the human parainfluenza virus type 3 (HPIV3) during infection of lung epithelial cells, and functioned as a receptor for the respiratory syncytial virus (RSV). 67,68 The synthetic peptide HB-19, a specific antagonist that binds the C-terminal RGG domain of nucleolin, inhibited the attachment of human immunodeficiency virus (HIV) to cells, indicating that this domain of nucleolin could be functional during the process of HIV anchorage. 69 Nucleolin is also believed to participate in the infection of Hepatitis C virus (HCV), herpes simplex virus (HSV) type 1, white-spot syndrome virus (WSSV) and the Crimean-Congo hemorrhagic fever virus (CCHFV).…”

“…94 A receptor for human RSV, nucleolin reduction by RNA interference (RNAi)-mediated knockdown lowered RSV infection in mice. 68 …”

The Human Respiratory Syncytial Virus Matrix Protein Is Required for Maturation of Viral Filaments

“…F resembles the prototypic paramyxovirus fusion protein but can induce membrane fusion in the absence of G (26,39). F also appears to play a role in viral attachment, and nucleolin was recently identified as a cellular receptor for the F protein (57). M is a nonglycosylated phosphorylated protein of 256 amino acids and a structural component of the HRSV virion (19,27,52).…”