Contribution of Dendritic Cells in Protective Immunity against Respiratory Syncytial Virus Infection

Abstract

Respiratory syncytial virus (RSV) is a major cause of severe respiratory disease in infants and the elderly. The socioeconomic burden of RSV infection is substantial because it leads to serious respiratory problems, subsequent hospitalization, and mortality. Despite its clinical significance, a safe and effective vaccine is not yet available to prevent RSV infection. Upon RSV infection, lung dendritic cells (DCs) detecting pathogens migrate to the lymph nodes and activate the adaptive immune response. Therefore, RSV has evolved various immunomodulatory strategies to inhibit DC function. Due to the capacity of RSV to modulate defense mechanisms in hosts, RSV infection results in inappropriate activation of immune responses resulting in immunopathology and frequent reinfection throughout life. This review discusses how DCs recognize invading RSV and induce adaptive immune responses, as well as the regulatory mechanisms mediated by RSV to disrupt DC functions and ultimately avoid host defenses.

Keywords: dendritic cells; immunomodulation; respiratory syncytial virus.

Figure 1

The structure of respiratory syncytial virus (RSV). The RSV genome is 15.2 kb of nonsegmented negative-sense RNA encoding 11 viral proteins. Viral envelope of RSV contains three transmembrane glycoproteins: attachment glycoprotein (G), fusion protein (F), and small hydrophobic protein (SH). Matrix proteins (M) are present on the inner side of the viral envelope. Viral RNA is tightly encapsidated by nucleoproteins (N) and the large proteins (L), phosphoproteins (P), and M2-1 proteins that mediate viral RNA transcription. M2-2 protein regulates viral RNA synthesis.

Figure 2

Innate sensors involved in RSV recognition, and immunomodulation strategies of RSV. Upon RSV infection, Toll-like receptors (TLR)2/6, TLR3, TLR4, TLR7, retinoic acid-inducible gene-I (RIG-I), and nucleotide-binding oligomerization domain (NOD2) are responsible for recognizing RSV pathogen-associated molecular patterns (PAMPs) in dendritic cells (DCs). The recognition of PAMPs by pattern recognition receptors (PRRs) activates downstream signaling pathways, which trigger DC activation and cytokine production. To avoid host immune responses, RSV has evolved various immunomodulatory strategies that inhibit DC functions. RSV proteins, specifically proteins G, NS1/NS2, and N, contribute to immunomodulation of RSV.

Figure 3

Lung dendritic cell subsets. Lung DCs are classified into conventional DC1s (cDC1s), cDC2s, and plasmacytoid DCs (pDCs). Each DC subset is widely distributed throughout the lungs and migrates to the lung-draining lymph node when they recognize RSV to initiate protective immune responses. cDC1s preferentially activate CD8⁺ T cells that mediate viral clearance, and cDC2s are responsible for Th2-mediated immune responses and RSV-mediated pulmonary diseases. pDCs are the main source of type I interferons (IFNs) and play an essential role in RSV-specific cytotoxic T lymphocyte (CTL) priming and regulation of disease severity. * Human-specific marker.