The role of respiratory syncytial virus G protein in immune cell infection and pathogenesis

Abstract

Severe respiratory syncytial virus (RSV) disease is a significant contributor to the global burden of disease in infants and children. The RSV attachment protein (G) has been shown to be critical in invading airway epithelial cells through its CX3C motif interacting with the host receptor CX3CR1. The ubiquitous expression of this receptor on immune cells may explain their susceptibility to RSV infection. The RSV G protein may enhance disease severity through reprogramming of normal cellular functionality leading to inhibition of antiviral responses. While existing preventives targeting the RSV fusion (F) protein are highly effective, there are no RSV therapeutics based on the G protein to limit RSV pathogenesis. Monoclonal antibodies targeting the RSV G protein administered as post-infection therapeutics in mice have been shown to improve the antiviral response, reduce viral load and limit disease severity. Further research is required to better understand how RSV infection of immune cells contributes to pathogenesis for the development of more targeted and efficacious therapeutics.

Keywords: G protein; Infection; Pathogenesis; RSV; Therapeutics.

Fig. 1

Organisation of the RSV genome and G protein. The RSV genome consists of 10 genes with overlapping M2 and L genes encoding 11 proteins. These are the non-structural proteins 1 and 2 (NS), nucleocapsid protein (N), phosphoprotein (P), matrix protein (M2.1, M2.2), small hydrophobic protein (SH), G protein, fusion protein (F), M2.1 and M2.2 proteins and the large polymerase subunit L (L). For the RSV G protein, the cytosolic tail (CT), transmembrane domain (TMD), mucin-like regions I and II (MLR), central conserved domain (CCD), CX3C motif and heparin binding domain (HBD) are depicted.

Fig. 2

Infection of immune cells by RSV. This likely occurs through the interaction between the CX3C motif of the RSV G protein and CX3CR1 which is ubiquitously expressed on immune cells. RSV infection of immune cells reduces the antiviral response which promotes severe disease through increased pulmonary inflammation and increased viral load.

Fig. 3

Blocking RSV infection of immune cells by anti-G protein monoclonal antibodies. Blocking the interaction between CX3C and CX3CR1 allows CX3CL1 to bind more efficiently and promote antiviral inflammatory responses. This results in increased IFN-α and IFN-γ production, reduced Th2 cytokines (IL-4, IL-5 and IL-13) which reduces pulmonary inflammation, viral load and disease severity.