Immune-Modulation by the Human Respiratory Syncytial Virus: Focus on Dendritic Cells

Abstract

The human respiratory syncytial virus (hRSV) is the leading cause of pneumonia in infants and produces a significant burden in the elderly. It can also infect and produce disease in otherwise healthy adults and recurrently infect those previously exposed to the virus. Importantly, recurrent infections are not necessarily a consequence of antigenic variability, as described for other respiratory viruses, but most likely due to the capacity of this virus to interfere with the host's immune response and the establishment of a protective and long-lasting immunity. Although some genes encoded by hRSV are known to have a direct participation in immune evasion, it seems that repeated infection is mainly given by its capacity to modulate immune components in such a way to promote non-optimal antiviral responses in the host. Importantly, hRSV is known to interfere with dendritic cell (DC) function, which are key cells involved in establishing and regulating protective virus-specific immunity. Notably, hRSV infects DCs, alters their maturation, migration to lymph nodes and their capacity to activate virus-specific T cells, which likely impacts the host antiviral response against this virus. Here, we review and discuss the most important and recent findings related to DC modulation by hRSV, which might be at the basis of recurrent infections in previously infected individuals and hRSV-induced disease. A focus on the interaction between DCs and hRSV will likely contribute to the development of effective prophylactic and antiviral strategies against this virus.

Keywords: DC maturation; T cell activation; antigen presentation; dendritic cells (DCs); immune evasion; immunity; inflammation; recurrent infection.

Figure 1

hRSV virion structure. The hRSV genome is a negative-sense single-stranded RNA virus. Its genome is wrapped by the nucleoprotein (N). An RNA-dependent RNA polymerase (L) is associated to the viral genome in the virion. Also, within the virion is the viral phosphoprotein (P), which is required by the L polymerase for its function. Additionally, within the virion are the viral proteins M2-1 and M2-2, derived from a single mRNA, which modulate transcription of viral genes and genome replication by the L polymerase. Beneath the virus envelope is the matrix protein (M), which has been described to inhibit host gene translation in the nucleus of infected cells. Three proteins are immersed in the virus envelope: the small hydrophobic (SH) protein, which forms a viroporin, that transports cations, the attachment glycoprotein (G) and the fusion protein, which arranges as a trimer on the virion surface (F). The viral proteins NS1 and NS2 are non-structural and hence, are not found within the virion.

Figure 2

hRSV modulates dendritic cell function. (1) DC infection with hRSV can occur even in the presence of antibodies bound to the virus (opsonized virus), which enter DCs through Fcγ receptors (FcγRs). (2) hRSV is capable of inhibiting antiviral signaling pathways mediated by STAT-1 and STAT-2, likely through its NS proteins. (3) The G glycoprotein signals through L-/DC-SIGN and phosphorylates ERK1/2, which translates into the upregulation of surface expression of CD40, OX40L, and PD-L2, whereas it downregulates IFN-α secretion. (4) The hRSV NS1 and NS2 proteins interfere with type-I interferon secretion. (5) hRSV induces the secretion of proinflammatory cytokines by DCs. Some mDC subsets (BDCA-1⁺ and BDCA-3⁺) secrete IL-10. (6) hRSV induces autophagy and is processed by the autophagosome leading to cytokine release and lung inflammation. (7) hRSV differentially modulates the expression of interferon-stimulated genes (ISGs), through IFN-dependent and independent pathways. (8) hRSV induces the activity of demethylases to modulate gene expression, such as IFN-γ, preventing an antiviral response. (9) hRSV upregulates the expression of specific host microRNAs. (10) hRSV stimulates the expression of CD80 and CD86. Additionally, the virus upregulates PD-L1 and CD38 expression on the DC surface to modulate inflammation in the lungs.

Figure 3

hRSV modulates dendritic cell migration and induces inflammatory profiles in T cells. (1) Epithelial cells infected with hRSV produce TSLP, which elicits MHC-II, CD80, and CD86 expression in lung DCs. (2) hRSV-infected DCs fail to downmodulate the surface expression of the chemokine receptors CCR1, CCR2 and CCR5, which is needed for effective DC migration to lymph nodes. Additionally, CCR7, which favors DC migration to the LNs, is not upregulated on the surface of hRSV-infected DCs. (3) Nevertheless, during infection hRSV-infected DCs migrate to the LNs to interact with T cells. hRSV-infected DCs secrete IL-4, IL-6, and IL-10 and promote the differentiation of CD4⁺ helper T cells toward a Th2 phenotype. (4) The hRSV N protein expressed on the DC surface mediates impaired immunological synapse assembly. The signaling events led by host proteins that interact with N are unknown. (5) hRSV induces PD-L1 expression on the DC surface which signals negatively within inflammatory T cells.