Host Responses to Respiratory Syncytial Virus Infection

Abstract

Respiratory syncytial virus (RSV) infections are a constant public health problem, especially in infants and older adults. Virtually all children will have been infected with RSV by the age of two, and reinfections are common throughout life. Since antigenic variation, which is frequently observed among other respiratory viruses such as SARS-CoV-2 or influenza viruses, can only be observed for RSV to a limited extent, reinfections may result from short-term or incomplete immunity. After decades of research, two RSV vaccines were approved to prevent lower respiratory tract infections in older adults. Recently, the FDA approved a vaccine for active vaccination of pregnant women to prevent severe RSV disease in infants during their first RSV season. This review focuses on the host response to RSV infections mediated by epithelial cells as the first physical barrier, followed by responses of the innate and adaptive immune systems. We address possible RSV-mediated immunomodulatory and pathogenic mechanisms during infections and discuss the current vaccine candidates and alternative treatment options.

Keywords: adaptive immunity; immune evasion; immunopathology; innate immunity; respiratory syncytial virus; vaccines.

Figure 1

Overview of the intracellular mechanisms in airway epithelial cells (AECs) after respiratory syncytial virus (RSV) entry. RSV enters ciliated AECs by binding to receptors on the surface of the cells (e.g., CX3CR1), followed by internalization of the virus particle into the cytoplasm. Following infection, intracellular pattern recognition receptors, like RIG-I or TLR3, sense viral ssRNA or dsRNA intermediates resulting in the activation of transcription factors like NK-κB or IRF3. Nuclear translocation of transcription factors leads to the expression of several antiviral mediators, like cytokines, chemokines, and receptors for antigen presentation. RIG-I: retinoic-acid-inducible protein I; TLR3: toll-like receptor 3; IRF3: interferon regulatory factor 3; IFN: interferon; TNF-α: tumor necrosis factor α; IL: interleukin; MHC-I: major histocompatibility complex I. Created with BioRender.com.

Figure 2

Schematic representation of the antiviral responses of innate and adaptive immune cells during RSV infection. Innate immune cells mediate the control of infection by direct interaction with the infected AECs, followed by their phagocytosis, or by direct interaction with virus particles, leading to the neutralization of the virus, e.g., by NETosis. Non-professional and professional antigen-presenting cells are responsible for the activation and recruitment of adaptive immune cells to the site of infection to further drive viral clearance. Regulation of immune responses is thereby crucial to avoid exaggerated, potentially immunopathogenic responses. IL: interleukin; IFN: interferon; TNF: tumor necrosis factor; GrB: granzyme B; BAFF: B cell-activating factor; APRIL: A proliferation-inducing ligand; MHC: major histocompatibility complex; MMP9: matrix metalloprotease 9. Created with BioRender.com.

Figure 3

Overview of immunopathogenic responses mediated by innate and adaptive immune cells during RSV infection. Changes in the innate and adaptive immune response can be a consequence of microenvironmental changes, genetic predispositions, or interaction with the virus. RSV can directly infect a variety of immune cells or indirectly alter their immune response, e.g., by the secretion of soluble G, characterized by phenotype changes in immune cells, or the excessive secretion of immunosuppressive or proinflammatory cytokines. TNF-α: tumor necrosis factor α; IFN: interferon; IL: interleukin; ECP: eosinophil cationic protein; MIP-1α: macrophage inflammatory protein-1α; MPO: myeloperoxidase. Created with BioRender.com.

Figure 4

Schematic overview of current vaccines and monoclonal antibody-based treatment options available for RSV. The mentioned vaccines and monoclonal antibodies are either licensed or currently in phase III clinical trials for the treatment of patients at risk. Created with BioRender.com.