The Human Immune Response to Respiratory Syncytial Virus Infection

Abstract

Respiratory syncytial virus (RSV) is an important etiological agent of respiratory infections, particularly in children. Much information regarding the immune response to RSV comes from animal models and in vitro studies. Here, we provide a comprehensive description of the human immune response to RSV infection, based on a systematic literature review of research on infected humans. There is an initial strong neutrophil response to RSV infection in humans, which is positively correlated with disease severity and mediated by interleukin-8 (IL-8). Dendritic cells migrate to the lungs as the primary antigen-presenting cell. An initial systemic T-cell lymphopenia is followed by a pulmonary CD8⁺ T-cell response, mediating viral clearance. Humoral immunity to reinfection is incomplete, but RSV IgG and IgA are protective. B-cell-stimulating factors derived from airway epithelium play a major role in protective antibody generation. Gamma interferon (IFN-γ) has a strongly protective role, and a Th2-biased response may be deleterious. Other cytokines (particularly IL-17A), chemokines (particularly CCL-5 and CCL-3), and local innate immune factors (including cathelicidins and IFN-λ) contribute to pathogenesis. In summary, neutrophilic inflammation is incriminated as a harmful response, whereas CD8⁺ T cells and IFN-γ have protective roles. These may represent important therapeutic targets to modulate the immunopathogenesis of RSV infection.

Keywords: immunology; respiratory syncytial virus.

FIG 1

Summary of the human immune response to RSV and potential novel therapeutic targets. The roles of major cell types (neutrophils, dendritic cells, macrophages, CD8⁺ T cells, and B cells) are summarized, in addition to key antibody, cytokine, chemokine, and other immune molecule responses. Major transcriptional changes (in peripheral blood) of immune-related pathways are shown. The deleterious role of neutrophilic inflammation and the protective role of CD8⁺ T-cell-mediated viral clearance are emphasized. Finally, we highlight areas where novel therapeutic interventions could potentially modulate the immune response in favor of the host. ↑, immune cell recruitment to the respiratory tract; *, association with increased disease severity.

FIG 2

Mechanisms of RSV T-cell interference as a potential immune evasion strategy. RSV infection is associated with an initial systemic T-cell lymphopenia that is quantitatively associated with disease severity. RSV may interfere with T-cell responses by inducing apoptosis (CD4⁺ and CD8⁺ T cells) (A), inducing increased expression of the programmed cell death 1 (PD-1) protein, which is inhibitory to activated T cells (CD8⁺ T cells) (B), and promoting activation of the mammalian target of rapamycin (mTOR) pathway, thus preventing memory CD8⁺ T-cell formation (C).