RSV F binds TLR4:LY96:CD14

Stable Identifier
R-HSA-9836227
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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RSV F binds TLR4:LY96:CD14
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Respiratory syncytial virus (RSV) fusion glycoprotein (F) is synthesized as an inactive precursor that is proteolytically cleaved into covalently linked F2 and F1 polypeptides to become fusion competent (González-Reyes et al. 2001). The N-terminal fragment of F1, which includes the fusion peptide, interacts with human lymphocyte antigen 96 (LY96 or MD2), a co-receptor of Toll-like receptor 4 (TLR4) (Rallabhandi et al. 2012).

This Reactome event shows interaction between the virion-bound F protein and the host TLR4:MD2 complex leading to the production of pro-inflammatory cytokines via the MyD88-dependent or independent pathways.

Multiple lines of evidence indicate that F protein binding activates TLR4 signaling, although the precise mechanism is not known (Kurt-Jones et al. 2000; Rallabhandi et al. 2012). Yuan et al. 2018 showed colocalization of RSV (strain Long) F protein with TLR4 but a decrease of TLR4 expression after infection. Increased TLR4 expression upon RSV infection has also been reported (Monick et al. 2003; Gagro et al. 2004). The consensus is also lacking with respect to which form of F protein (virion-associated or purified protein) activates TLR4 signaling (Rallabhandi P et al. 2012; Marr and Turvey 2012; Lizundia et al. 2008).

Functional TLR4 signaling is required to mount an immune response against RSV. Polymorphisms in the TLR4 and CD14 genes have been associated with severity of RSV infection (Tal et al. 2004; Inoue et al. 2007). Lack of CD14 function leads to impaired TLR4-mediated immune responses in human peripheral blood mononuclear cells (PBMCs) in response to viral F (Kurt-Jones et al. 2000; Besteman et al. 2022), and the CD14-deficient patients develop recurrent RSV bronchiolitis (Besteman et al. 2022). TLR4 knockout mice show persistent RSV infection, impaired cytotoxicity of NK cells, decreased pulmonary CD14+ cell infiltration (Haynes et al. 2001) and reduced expression of inflammatory cytokines (Kurt-Jones et al. 2000; Haynes et al. 2001). Macrophages from LY96-deficient mice fail to express interleukin 1β (IL-1β) upon F protein treatment (Rallabhandi P et al. 2012). Intact TLR4/MyD88 signaling is required for optimal RSV immune response in mice and protection against RSV (Cyr et al. 2009). Intense TLR4 signaling can result in a more severe disease. The interaction of the RSV F protein with TLR4 receptor on the surface of neutrophils may promote release of neutrophil extracellular traps, which may exacerbate inflammation of the airways (Funchal et al. 2015). MEG3 lncRNA, which suppresses TLR4 signaling, has a protective effect against RSV disease severity (Tao et al. 2018). RSV infection can lead to increased TLR4 expression (Monick et al. 2003; Gagro et al. 2004). Increased level of TLR4 may sensitize airway epithelium to bacterial endotoxin LPS (lipopolysaccharide), leading to exacerbated airway inflammation (Monick et al. 2003), possibly through LPS-induced IL6 production in RSV-infected epithelial cells (Xie et al. 2009). In infected infants, LPS exposure and TLR4 genotype influence disease phenotypes (Caballero et al. 2015).

It is unlikely that the binding of F protein to the TLR4 receptor complex contributes to RSV entry into host cells or that the activation of TLR4 signaling requires viral internalization. While a mouse study has shown that TLR4/Myd88/p38 MAPK signaling cascade may aid in viral internalization (Marchant et al. 2010), other studies have not confirmed this. RSV-mediated, TLR4-dependent NF-kappa-B activation in alveolar macrophages is independent of viral replication (Haeberle et al. 2002). RSV can infect B lymphocytes, but this infection and upregulation of B lymphocyte activation markers is independent of TLR4 (Rico et al. 2010). Infection of macrophages by RSV is TLR4-independent, but differentiation of RSV-infected macrophages into so-called alternatively activated macrophages is dependent on TLR4 signaling (Shirey et al. 2010; Nikonova et al. 2018).

Literature References
PubMed ID Title Journal Year
35429403 Recurrent Respiratory Syncytial Virus Infection in a CD14-Deficient Patient

Besteman, SB, Phung, E, Raeven, HHM, Amatngalim, GD, Rumpret, M, Crabtree, J, Schepp, RM, Rodenburg, LW, Siemonsma, SG, Verleur, N, van Slooten, R, Duran, K, van Haaften, GW, Beekman, JM, Chang, LA, Meyaard, L, van der Bruggen, T, Berbers, GAM, Derksen, N, Nierkens, S, Morabito, KM, Ruckwardt, TJ, Kurt-Jones, EA, Golenbock, D, Graham, BS, Bont, LJ

J Infect Dis 2022
11062499 Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virus

Kurt-Jones, EA, Popova, L, Kwinn, L, Haynes, LM, Jones, LP, Tripp, RA, Walsh, EE, Freeman, MW, Golenbock, DT, Anderson, LJ, Finberg, RW

Nat Immunol 2000
18669608 Host species-specific usage of the TLR4-LPS receptor complex

Lizundia, R, Sauter, KS, Taylor, G, Werling, D

Innate Immun 2008
29427996 Respiratory syncytial virus prolifically infects N2a neuronal cells, leading to TLR4 and nucleolin protein modulations and RSV F protein co-localization with TLR4 and nucleolin

Yuan, X, Hu, T, He, H, Qiu, H, Wu, X, Chen, J, Wang, M, Chen, C, Huang, S

J Biomed Sci 2018
15048726 The role of Toll-like receptor 4 versus interleukin-12 in immunity to respiratory syncytial virus

Ehl, S, Bischoff, R, Ostler, T, Vallbracht, S, Schulte-Mönting, J, Poltorak, A, Freudenberg, M

Eur J Immunol 2004
22872782 Respiratory syncytial virus fusion protein-induced toll-like receptor 4 (TLR4) signaling is inhibited by the TLR4 antagonists Rhodobacter sphaeroides lipopolysaccharide and eritoran (E5564) and requires direct interaction with MD-2

Rallabhandi, P, Phillips, RL, Boukhvalova, MS, Pletneva, LM, Shirey, KA, Gioannini, TL, Weiss, JP, Chow, JC, Hawkins, LD, Vogel, SN, Blanco, JC

mBio 2012
22535679 Role of human TLR4 in respiratory syncytial virus-induced NF-κB activation, viral entry and replication

Marr, N, Turvey, SE

Innate Immun 2012
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Output
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Authored
Shamovsky, V  (2023-05-24)
Reviewed
Bergeron, HC  (2023-11-03)
Created
Shamovsky, V  (2023-05-24)
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