Landscape of respiratory syncytial virus

Abstract

Respiratory syncytial virus (RSV) is an enveloped, negative-sense, single-stranded RNA virus of the Orthopneumovirus genus of the Pneumoviridae family in the order Mononegavirales. RSV can cause acute upper and lower respiratory tract infections, sometimes with extrapulmonary complications. The disease burden of RSV infection is enormous, mainly affecting infants and older adults aged 75 years or above. Currently, treatment options for RSV are largely supportive. Prevention strategies remain a critical focus, with efforts centered on vaccine development and the use of prophylactic monoclonal antibodies. To date, three RSV vaccines have been approved for active immunization among individuals aged 60 years and above. For children who are not eligible for these vaccines, passive immunization is recommended. A newly approved prophylactic monoclonal antibody, Nirsevimab, which offers enhanced neutralizing activity and an extended half-life, provides exceptional protection for high-risk infants and young children. This review provides a comprehensive and detailed exploration of RSV's virology, immunology, pathogenesis, epidemiology, clinical manifestations, treatment options, and prevention strategies.

Figure 1

Structure and genome of RSV virus. (A) Structure of RSV virus. (B) Genome structure of RSV, the six major antigenic sites of the F protein, and the location of G-HVR2. RSV: Respiratory syncytial virus.

Figure 2

The life cycle of the RSV. RSV can attach to cells by binding to receptors such as CX3CR1, IGF1R, EGFR, nucleolin, ICAM-1, TLR4-CD14, and cellular GAGs, followed by membrane fusion mediated by F-glycoproteins or by the macropinocytosis to complete entry. Viral replication, transcription, and translation occur in the cytoplasm, during which dense inclusion bodies are formed. A portion of the translated viral proteins are exported with the genome directly to the vicinity of the cell apical surface and are assembled with another portion that is transported to the endoplasmic reticulum and Golgi apparatus for further processing. Afterward, the virus can be released extracellularly by budding and infecting other cells or directly spreading to neighboring cells utilizing F proteins and cytoskeleton. CX3CR1: CX3C-chemokine receptor 1; EGFR: Epidermal growth factor; GAGs: Glycosaminoglycans; IGF1R: insulin-like growth factor-1 receptor; ICAM-1: Intercellular adhesion molecule-1; RSV: Respiratory syncytial virus; TLR4: Toll-like receptor 4.

Figure 3

Pathogenesis of RSV. RSV induces rounding and shedding of ciliated cells, and neutrophils release NETs in response to RSV infection. RSV infection of epithelial cells causes the release of TSLP, IL-33, HMGB1, and IL-25, activating ILC2 to produce the type 2 cytokines. Type 2 cytokines have many immunologic and physiologic effects, including promoting airway responsiveness and mucous cell metaplasia. TSLP can induce the dendritic cells to migrate to the lymph nodes, interacting with naïve CD4⁺ T cells, resulting in the Th2 polarization of CD4⁺ T cells. RSV can lead to apical junctional complex disruption, allowing the pathogens to invade and activate dendritic cells. Low IFN-I can suppress the DC response, leading to a Th2/Th17 response and a low Th1 response. Impaired Tfh activation may lead to poor B cell memory and inhibition of antibody production. Alveolar macrophages express IL-1β and TNF-α to activate inflammatory responses. All these events lead to poorly protective and dysregulated immune responses in infants. Chemokines facilitate the recruitment of immune cells from the periphery to the lung (e.g., eosinophils, monocytes, neutrophils, and NK cells), where they implement pathogenic mechanisms. CCL: Chemokine (C-C motif) ligand; CXCL: C-X-C motif chemokine ligand; DC: Dendritic cell; HMGB1: High mobility group box 1 protein; IFN: Interferon; IgE: Immunoglobulin E; IL: Interleukin; ILC2: Innate lymphoid 2 cells; NK: Natural killer; RSV: Respiratory syncytial virus; Tfh: Follicular helper T cell; Th: T helper cell; TSLP: Thymic stromal lymphopoietin; TSLPR: Thymic stromal lymphopoietin receptor.

Figure 4

Reported rates estimates of RSV-associated hospitalization (A) and RSV-associated mortality (B) by age group across modeling studies.^[106] The box top represents the upper IQR, the middle represents the median IQR, and the bottom represents the lower IQR. The top end of the whisker represents the highest value, excluding outliers (defined as any points with a longer distance than 1.5 times IQR from the box). The bottom end of the whisker represents the lowest value, excluding outliers. Dots represent outliers. ARI: Acute respiratory infection; IQR: Interquartile range; RSV: respiratory syncytial virus.

Figure 5

Heat maps of global monthly respiratory syncytial virus activity arranged by latitude.^[123] “+” indicates primary season onset. AAP: Annual average percentage, as a measurement of the strength of virus activity by the formula: $AA{P}_i=\frac{n_i}{{{\displaystyle \sum }}_1^{12}{n}_i}\times 100\text{\%}$, where i denotes the month and n denotes the number of cases.