CX3C chemokine mimicry by respiratory syncytial virus G glycoprotein

Abstract

Chemokines are chemoattractant proteins that are divided into subfamilies based upon cysteine signature motifs termed C, CC, CXC and CX3C. Chemokines have roles in immunity and inflammation that affect cell trafficking and activation of T cells as well as cells of the innate immune system. We report here CX3C chemokine mimicry for the G glycoprotein of respiratory syncytial virus (RSV) and show binding to CX3CR1--the specific receptor for the CX3C chemokine fractalkine--and induction of leukocyte chemotaxis. We also show that CX3CR1 facilitates RSV infection of cells. Thus, G glycoprotein interaction with CX3CR1 probably plays a key role in the biology of RSV infection.

Potent High-Affinity Antibodies for Treatment and Prophylaxis of Respiratory Syncytial Virus Derived from B Cells of Infected Patients

“…interaction with the fractalkine receptor, CX3CR1, a key mediator of cell trafficking to the infected lung (15,21). Consistent with these findings, human polymorphisms showing reduced activity of either TLR4 (27) or CX3CR1 (28) were significantly overrepresented in studies of infants with severe RSV disease.…”

“…For the treatment setting, however, there is a complex interaction between the virus and the host immune response (15), suggesting that properties other than affinity and in vitro potency may also be critical to the in vivo response. For example, the substantially higher affinity of motavizumab than of palivizumab has not provided a major improvement in efficacy (6,7).…”

“…CellSpot single-cell phenotyping and ELISA assays RSV G protein from strain A2 (Ga), RSV G protein from strain B1 (Gb), and RSV F proteins were purified from virus-infected cells as previously described (15). These native proteins (50 g) were conjugated to customdyed 280-nm-diameter latex beads (35) in 50 mM borate buffer (pH 8.5) overnight, followed by addition of 3 mg/ml sodium cyanoborohydride at 25°C for 2 h. BSA (Sigma-Aldrich) solution was added to the suspension to a final concentration of 1%; the beads were washed in the same buffer and stored in 50 mM borate/1% BSA, 0.05% Tween 20 at 4°C.…”

“…Based on these characteristics, the F protein was considered an attractive target for mAb therapy as a successor to polyclonal RSV-neutralizing serum therapy (Respigam). Despite high variability in the G protein ectodomain (12), there are two conserved regions: an alternative initiation site that results in a secreted soluble form of the protein (13); and a central cysteine-noose region (14,15). RSV actively subverts the host immune response (16 -18), and the G protein has drawn increasing attention for its role in enhancing RSV disease (16, 19 -26).…”

New Generation Live Vaccines against Human Respiratory Syncytial Virus Designed by Reverse Genetics

“…The secreted form may induce oversensitization of T helper subset 2 lymphocytes, a response implicated in immune-mediated pathology (35). The G protein also contains a CX3C motif that appears to mimic the activity of the chemokine fractalkine (36). This mimicry has the potential to alter leukocyte trafficking, although exactly how this affects RSV biology remains to be defined.…”