Airway epithelial cells are the primary target for human respiratory syncytial virus (hRSV) and other inhaled pathogens (Zhang et al., 2002). In response to RSV infection, airway epithelial cells initiate both inflammatory responses and antiviral immune responses to effectively eliminate the virus (reviewed by Espinoza, Bueno et al., 2014; Lay et al., 2016; Hu et al., 2020; Ouyang et al., 2022). Pattern recognition receptors (PRRs), including Toll-like receptors (TLRs) and retinoic acid-inducible gene-I-like receptors (RLRs), detect viral components such as RSV genomic RNA and trigger the production of pro-inflammatory cytokines, chemokines, and type I interferons (Liu et al. 2007; reviewed by Espinoza et al., 2014; Hu et al., 2020; Ouyang et al., 2022). Additionally, airway epithelial cells recruit other innate immune cells including polymorphonuclear leukocytes (PMNs), macrophages, and natural killer cells to establish an antiviral environment and facilitate the resolution of inflammation within the lungs (Miura 2019). The impact of RSV infection on the host cell transcriptome and proteome is reviewed by Hu et al., 2020. The adaptive immune response controls RSV infection by secreting antibodies (Jones et al., 2018; Fong et al., 2023) or by cytotoxic T lymphocytes (CTLs) that recognize and eliminate RSV-infected cells (Lukens et al., 2010; De et al., 2023). RSV evolved strategies to evade or subvert these host responses, allowing an infection to be established and persist within the host (reviewed by Espinoza, Bohmwald et al., 2014; Lay et al., 2016; Hu et al., 2020; Brasier 2020; Stephens & Varga 2020; Ouyang et al., 2022; van Royen et al., 2022). For example, the NS1 and NS2 proteins target the signaling molecules involved in the innate immune response suppressing PRR-induced IFN production and IFN-mediated signaling pathways (reviewed by Sedeyn et al., 2019; Thornhill & Verhoeven, 2020). Viral SH has been implicated in inhibiting apoptotic pathway, a type of non-inflammatory cell death that limits viral propagation (Li et al., 2015). At the same time, Triantafilou et al. (2013) have reported that viral SH promotes an inflammatory necrotic cell death to release the cell content. Further, the binding of RSV G protein to leukocytes involves the host CX3C chemokine receptor 1 (CX3CR1) and results in blocking signaling and trafficking of CX3CR1-expressing Th1 immune cells to the lungs, facilitating RSV infection (Harcourt et al., 2006). The hRSV NS2 protein induces cell shedding into large airways causing an acute airway obstruction in an animal model of RSV infection through an unknown mechanism (Liesman et al., 2014).

Several host factors contribute to the pathogenesis of RSV infection and its long-term effects, including age, prematurity, underlying respiratory conditions such as chronic lung disease including cystic fibrosis, deficiencies in specific immune components or dysregulated immune responses (reviewed by Carvajal et al., 2019). In some cases, an exaggerated immune response to RSV infection can affect the host's ability to control viral infection leading to immunopathology. For example, elevated production of Th2-type cytokines (IL-4, IL-5 and IL-13) in response to RSV infection leads to airway hyperreactivity and increased risk of developing asthma after hRSV infection (Vu et al., 2019; Dong et al., 2023; reviewed by Norlander & Peebles 2020; Manti & Piedimonte 2022). The outcome of RSV infection depends on a complex interplay between the immune responses induced by the host and the strategies developed by RSV to subvert these responses.

This Reactome module describes molecular mechanisms by which specific RSV components modulate innate and adaptive immune responses, programmed cell death, and host gene expression.