Primary Human mDC1, mDC2, and pDC Dendritic Cells Are Differentially Infected and Activated by Respiratory Syncytial Virus

Abstract

Respiratory syncytial virus (RSV) causes recurrent infections throughout life. Vaccine development may depend upon understanding the molecular basis for induction of ineffective immunity. Because dendritic cells (DCs) are critically involved in early responses to infection, their interaction with RSV may determine the immunological outcome of RSV infection. Therefore, we investigated the ability of RSV to infect and activate primary mDCs and pDCs using recombinant RSV expressing green fluorescent protein (GFP). At a multiplicity of infection of 5, initial studies demonstrated ∼6.8% of mDC1 and ∼0.9% pDCs were infected. We extended these studies to include CD1c−CD141+ mDC2, finding mDC2 infected at similar frequencies as mDC1. Both infected and uninfected cells upregulated phenotypic markers of maturation. Divalent cations were required for infection and maturation, but maturation did not require viral replication. There is evidence that attachment and entry/replication processes exert distinct effects on DC activation. Cell-specific patterns of RSV-induced maturation and cytokine production were detected in mDC1, mDC2, and pDC. We also demonstrate for the first time that RSV induces significant TIMP-2 production in all DC subsets. Defining the influence of RSV on the function of selected DC subsets may improve the likelihood of achieving protective vaccine-induced immunity.

Respiratory Syncytial Virus G Protein CX3C Motif Impairs Human Airway Epithelial and Immune Cell Responses

“…4 and 5). Similar to our findings, previous studies showed the ability of RSV to induce production of these cytokines in isolated human pDCs and mDCs (73,74). However, our data show that these RSVinduced responses are impaired by the CX3C motif.…”

The plasmacytoid dendritic cell: at the cross-roads in asthma

“…The ability of clinical isolates of RSV (and metapneumovirus (MPV)) to attenuate TLR7/TLR9-induced IFN-I responses in pDCs has been consistently shown in human and murine models [104][105][106]. The infection of pDCs by RSV was implied when cell surface expression of the viral F protein was observed, which was later confirmed using green fluorescent protein-labelled RSV; although the fraction of infected pDCs was extremely low [103,107].…”

Limited Type I Interferons and Plasmacytoid Dendritic Cells during Neonatal Respiratory Syncytial Virus Infection Permit Immunopathogenesis upon Reinfection

“…In particular, several laboratories have demonstrated that type I IFNs (mainly IFN-␣ and IFN-␤) and their major producers, plasmacytoid dendritic cells (pDCs), are important in protection from RSV disease. It has been reported that RSV stimulates pDCs isolated from human peripheral blood mononuclear cells (13,14) or murine bone marrow-derived pDCs (15,16) to produce type I IFNs ex vivo. Furthermore, several publications have demonstrated that RSV infection of adult mice induces pulmonary type I IFNs in vivo (17,18) and that intranasal administration of recombinant IFN-␣ significantly reduces the lung viral load, inflammation, weight loss, and clinical illness scores of RSVinfected adult mice (19).…”