G protein binds CX3CR1 on host cell surface

Stable Identifier
R-HSA-9836468
Type
Reaction [binding]
Species
Homo sapiens
Related Species
Human respiratory syncytial virus A
Compartment
plasma membrane, extracellular region, viral capsid, virion membrane
ReviewStatus
5/5
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G protein binds CX3CR1 on host cell surface
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During the initial infection steps, G protein of the respiratory syncytial virus (RSV) acts as the main attachment factor. The G protein possesses a CX3C motif (amino acid residues 182-186 of G protein), present in the natural ligand of the host CX3CR1 receptor, fractalkine, which enables G protein binding to the CX3CR1 receptor (Tripp et al. 2001, Chirkova et al. 2015). Mutations in the CX3C motif of G protein attenuate RSV infection in cotton rats and primary human airway epithelial cells (Ha et al. 2019). In pediatric lung, CX3CR1 was found to be expressed at both mRNA and protein levels in epithelial cells that line the airways. The epithelial cells of the upper airways in pediatric patients also expressed CX3CR1. Infection of primary pediatric human lung epithelial (PHLE) cells by RSV was impaired when PHLE cells were pre-incubated with an anti-CX3CR1 antibody (Anderson et al. 2020). More specifically, CX3CR1was shown to be expressed in the motile cilia of differentiated human airway epithelial cells, where it co-localizes with RSV particles (Jeong et al. 2015; Johnson et al. 2015). CX3CR1 was also shown to be the main human RSV receptor in cotton rats (Green et al. 2021). While RSV is infective in the absence of G protein, the attachment to host cells and viral replication are significantly reduced (Jeong et al. 2015). In a mouse model, antibodies that block interaction between G protein and CX3CR1 reduce lung RSV titers and lung inflammation (Zhang et al. 2010; Johnson et al. 2015). CX3CR1 is expressed in ciliated cells of the primary human airway epithelium culture (HAEC), with expression level varying between cells and between individual HAECs (Chirkova et al. 2015). CX3CR1 enables RSV to infect neonatal-specific regulatory B cells, which may contribute to high viral load and disease severity in infants (Zhivaki et al. 2017).

Besides binding to CX3CR1, G protein also binds to glycosaminoglycans (GAGs), such as heparan sulfate (HS), unbranched disaccharide polymers linked to extracellular portion of transmembrane proteins, known as heparan sulfate proteoglycans (HSPGs), on the host cell surface (Tripp et al. 2001). While GAGs were shown to be important for in vitro infection of cultured host cells, it is unknown how important they are for infection of RSV target cells in vivo (Zhang et al. 2002, Chirkova et al. 2015; Johnson et al. 2015), as heparan sulfate is not detectable on the surface of ciliated airway epithelial cells (Johnson et al. 2015).

In addition to being involved in the viral entry into ciliated epithelial cells of the airways, association of RSV with CX3CR1 is likely involved in immune response to RSV, including innate immune response to RSV infection (Johnson et al. 2011). CX3CR1-positive cells of the immune system are a major component of the cytotoxic response to RSV infection, and the CX3C motif of the viral G protein may reduce the antiviral T cell response to RSV infection (Harcourt et al. 2006). In the unsuccessful formalin-inactivated RSV vaccine that led to enhanced pulmonary disease after live RSV infection, the enhanced secondary inflammatory response was dependent on the presence of CX3C motif in the G protein (Haynes et al. 2003). G protein binding to CX3CR1 is associated with reduced leukocyte migration and chemotaxis, as shown in human peripheral blood mononuclear cells (Tripp et al, 2001; Chirkova et al, 2013), mouse bronchoalveolar, mediastinal lymph node and spleen leukocytes (Harcourt et al, 2006), as well as suppression of cilium-related genes and induction of nucleolin expression (Anderson et al, 2021). A common polymorphism in CX3CR1, CX3CR1 T280M, decreases affinity of CX3CR1 for its ligand fractalkine and is associated with an increased risk of severe RSV bronchiolitis in children (Amanatidou et al. 2006). While mast cells express CX3CR1, they are not efficiently infected by RSV and RSV does not efficiently induce their degranulation unless RSV-infected airway epithelial cells are present (Shirato and Taguchi 2009).
Literature References
PubMed ID Title Journal Year
26658574 Respiratory Syncytial Virus Uses CX3CR1 as a Receptor on Primary Human Airway Epithelial Cultures

Ioannidis, I, Flano, E, Oomens, AG, Teng, MN, Johnson, SM, McNally, BA, Walsh, EE, Peeples, ME

PLoS Pathog 2015
24089561 Respiratory syncytial virus G protein CX3C motif impairs human airway epithelial and immune cell responses

Boyoglu-Barnum, S, Trau, SP, Oomens, AG, Malik, FM, Gaston, KA, Anderson, LJ, Chirkova, T

J Virol 2013
11477410 CX3C chemokine mimicry by respiratory syncytial virus G glycoprotein

Tripp, RA, Murphy, PM, Anderson, LJ, Zheng, H, Haynes, LM, Jones, LP

Nat Immunol 2001
31726465 CX3CR1 as a respiratory syncytial virus receptor in pediatric human lung

Chu, CY, Wang, Q, Misra, RS, Bhattacharya, S, Pryhuber, GS, Ren, Y, Anderson, CS, Walsh, EE, Mariani, TJ, Donlon, K, Mereness, JA

Pediatr Res 2020
26107373 CX3CR1 Is Expressed in Differentiated Human Ciliated Airway Cells and Co-Localizes with Respiratory Syncytial Virus on Cilia in a G Protein-Dependent Manner

Kishko, M, Parrington, M, Piepenhagen, PA, Kleanthous, H, DiNapoli, JM, Zhang, L, Almond, J, Groppo, RP, Delagrave, S, Jeong, KI

PLoS One 2015
33731455 CX3CR1 Engagement by Respiratory Syncytial Virus Leads to Induction of Nucleolin and Dysregulation of Cilia-related Genes

Qiu, X, Anderson, CS, Walsh, EE, Mariani, TJ, Slaunwhite, CG, Anderson, LJ, Chirkova, T

J Virol 2021
16424189 Respiratory syncytial virus G protein and G protein CX3C motif adversely affect CX3CR1+ T cell responses

Harcourt, J, Jones, LP, Alvarez, R, Tripp, RA, Henderson, C, Anderson, LJ

J Immunol 2006
26297201 CX3CR1 is an important surface molecule for respiratory syncytial virus infection in human airway epithelial cells

Stobart, CC, Oomens, AGP, Boyoglu-Barnum, S, Ziady, AG, Hartert, TV, Lin, S, Meng, J, Moore, ML, Gaston, KA, Anderson, LJ, Chirkova, T, Cotton, CU

J Gen Virol 2015
28228284 Respiratory Syncytial Virus Infects Regulatory B Cells in Human Neonates via Chemokine Receptor CX3CR1 and Promotes Lung Disease Severity

Miatello, J, Schandene, L, Descamps, D, Zhivaki, D, Dériaud, E, Riffault, S, Tissières, P, Lemercier, B, Beitz, B, Lo-Man, R, Mascart, F, Morva, A, Hervé, PL, Lim, A, Schwartz, O, Lorin, V, Vidalain, PO, Lemoine, S, Porcheray, F, Mouquet, H, Fix, J, Eléouët, JF, Casartelli, N, Zhang, X, Ripaux-Lefevre, M, Rameix-Welti, MA

Immunity 2017
Participants
Input
Output
Participates
as an event of
This event is regulated
Positively by
Regulator
HSPGs [plasma membrane] (Homo sapiens)
Disease
Authored
Orlic-Milacic, M  (2023-05-28)
Reviewed
Bergeron, HC  (2023-11-03)
Created
Orlic-Milacic, M  (2023-05-28)
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