Revisiting respiratory syncytial virus's interaction with host immunity, towards novel therapeutics

Abstract

Every year there are > 33 million cases of Respiratory Syncytial Virus (RSV)-related respiratory infection in children under the age of five, making RSV the leading cause of lower respiratory tract infection (LRTI) in infants. RSV is a global infection, but 99% of related mortality is in low/middle-income countries. Unbelievably, 62 years after its identification, there remains no effective treatment nor vaccine for this deadly virus, leaving infants, elderly and immunocompromised patients at high risk. The success of all pathogens depends on their ability to evade and modulate the host immune response. RSV has a complex and intricate relationship with our immune systems, but a clearer understanding of these interactions is essential in the development of effective medicines. Therefore, in a bid to update and focus our research community's understanding of RSV's interaction with immune defences, this review aims to discuss how our current knowledgebase could be used to combat this global viral threat.

Keywords: Immunity; Interferon; RSV; Therapeutics.

Fig. 1

RSV structure. The RSV genome encodes for 10 genes, giving rise to 11 proteins. The non-structural proteins, NS1 and NS2, are not present in the viron, but are expressed in high levels on infection of the host cell

Fig. 2

The RSV Life Cycle. (1) The virion initially binds to the host cell through its G protein and membrane fusion is mediated by the F protein, which anchors into the membrane of the target cell and then folds on itself to bring the viral and host membranes into contact, resulting in membrane fusion. (2) The genome of the virus is used for protein synthesis, with large amounts of NS1/2 and sG protein produced shortly after infection. These proteins protect the replicating virus from the host immune defences. (3) The viral genome is replicated and structural proteins are produced. (4) The surface glycoproteins are synthesised in the Golgi body and deposited in the host membrane. (5) Assembly of the new virion takes place in the cytoplasm, before budding through the host cell membrane, picking up its surface glycoproteins as part of this process. sG protein is also released

Fig. 3

TLR & IFN signalling. (1) Toll-like Receptor 3 & 8 detect intracellular pathogens by detecting dsRNA and ssRNA, respectively. Once initiated, signalling cascades activate transcription factors, (2) which upregulate anti-viral IFNs (Type I, II and III) and pro-inflammatory cytokines. (3) IFNs act on the infected and neighbouring cells by binding the Interferon receptors (e.g. IFNAR). (4) Change in receptor conformation allows the receptor-associated kinases, Tyk and Jak1, to trans-phosphorylate, which in turn phosphorylate receptor subunits, providing docking sites for STAT proteins. (5) Receptor-associated STATs become phosphorylated, dissociate from the receptor and form homo- or hetero-dimers. The IFN-α-activated STAT1:STAT2 dimer binds IRF9, forming a complex that translocates to the nucleus and stimulates the expression of Interferon Sensitive Genes (ISGs). RSV NS proteins have been shown to inhibit IFN signal transduction by impairing STAT activation

Fig. 4

The RSV F protein facilitates the fusion of the viral and host membranes. The stable form of the F protein anchors its hydrophobic N-terminus into the membrane of the target cell. The extended form of the F protein is not stable and the coils of the Heptad repeat A (blue) and Heptad repeat B (green) domains fold together. This overcomes the hydration force, to allow the viral capsid to fuse with the cell