IGF1R is an entry receptor for respiratory syncytial virus

Griffiths, Cameron; Bilawchuk, Leanne M.; McDonough, John E.; Jamieson, Kyla C.; Elawar, Farah; Cen, Yuchen; Duan, Wenming; Lin, Cindy; Song, Haeun; Casanova, Jean‐Laurent; Ogg, Steven; Jensen, Lionel D.; Thienpont, Bernard; Kumar, Anil; Hobman, Tom C.; Proud, David; Moraes, Theo J.; Marchant, David

doi:10.1038/s41586-020-2369-7

Cited by 104 publications

(111 citation statements)

References 29 publications

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“…Although some recent studies show that RSV might be taken up via macropinocytosis, most studies have reported that the virus can utilize receptor mediated-endocytic uptake, indicating nucleolin as a potential receptor (8). Indeed, a recent article confirmed nucleolin as an important co-receptor for RSV entry both in vitro and in vivo (28). Although, nucleolin is primarily located in the nucleolus of cells, it can also be present in the cytoplasm as well as the plasma membrane, where it is reported to interact with the RSV F protein, which facilitates the viral binding (29).…”

Section: Discussionmentioning

confidence: 99%

“…Although, nucleolin is primarily located in the nucleolus of cells, it can also be present in the cytoplasm as well as the plasma membrane, where it is reported to interact with the RSV F protein, which facilitates the viral binding ( 29 ). Furthermore, RSV was shown to recruit nucleolin to the surface of cells thereby aiding its own uptake ( 28 ). Nucleolin contains RNA recognition motifs that have been reported to bind RNA, as well as single stranded DNA in some cases ( 30 ).…”

Section: Discussionmentioning

confidence: 99%

“…This suggests that pre-treatment with ssON inhibits RSV from binding to nucleolin and thereby prevents the virus from infecting cells. Nucleolin is implicated to take part in multicomplex interactions occurring during viral binding and uptake of a plethora of viruses, such as RSV, HIV-1 and HSV-2 ( 8 , 28 , 30 ). It remains to be further elucidated which viral families use nucleolin to enter target cells and whether ssON has the capacity to act as a broad-spectrum antiviral agent.…”

Section: Discussionmentioning

confidence: 99%

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Single-Stranded Oligonucleotide-Mediated Inhibition of Respiratory Syncytial Virus Infection

et al. 2020

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Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infections in young children. Currently, there is no RSV vaccine or universally accessible antiviral treatment available. Addressing the urgent need for new antiviral agents, we have investigated the capacity of a non-coding single-stranded oligonucleotide (ssON) to inhibit RSV infection. By utilizing a GFP-expressing RSV, we demonstrate that the ssON significantly reduced the proportion of RSV infected A549 cells (lung epithelial cells). Furthermore, we show that ssON’s antiviral activity was length dependent and that both RNA and DNA of this class of oligonucleotides have antiviral activity. We reveal that ssON inhibited RSV infection by competing with the virus for binding to the cellular receptor nucleolin in vitro. Additionally, using a recombinant RSV that expresses luciferase we show that ssON effectively blocked RSV infection in mice. Treatment with ssON in vivo resulted in the upregulation of RSV-induced interferon stimulated genes (ISGs) such as Stat1, Stat2, Cxcl10, and Ccl2. This study highlights the possibility of using oligonucleotides as therapeutic agents against RSV infection. We demonstrate that the mechanism of action of ssON is the inhibition of viral entry in vitro, likely through the binding of the receptor, nucleolin and that ssON treatment against RSV infection in vivo additionally results in the upregulation of ISGs.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Single-Stranded Oligonucleotide-Mediated Inhibition of Respiratory Syncytial Virus Infection

et al. 2020

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“…In subsequent studies, we showed that targeting nucleolin with the DNA aptamer, AS1411, originally developed as a cancer therapeutic, could not only reduce infection of cells in culture, but in two animal models with a corresponding reduction of lung inflammation [5]. Recently, it has also been shown that targeting a pathway that controls shuttling of nucleolin to the cell surface is a viable strategy to reduce RSV infection [6].…”

Section: Introductionmentioning

confidence: 99%

“…While attachment via the G protein is not absolutely required, as shown by the ability of ∆G RSV to infect cells [13], it does greatly improve the efficiency of infection and likely involves CX3CR1 [14]. Attachment and viral entry through RSV-F involve proteins such as IGFR1 and nucleolin [4,6].…”

Section: Introductionmentioning

confidence: 99%

Identification of RSV Fusion Protein Interaction Domains on the Virus Receptor, Nucleolin

Mastrangelo

Chin

Tan

et al. 2021

Viruses

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Nucleolin is an essential cellular receptor to human respiratory syncytial virus (RSV). Pharmacological targeting of the nucleolin RNA binding domain RBD1,2 can inhibit RSV infections in vitro and in vivo; however, the site(s) on RBD1,2 which interact with RSV are not known. We undertook a series of experiments designed to: document RSV-nucleolin co-localization on the surface of polarized MDCK cells using immunogold electron microscopy, to identify domains on nucleolin that physically interact with RSV using biochemical methods and determine their biological effects on RSV infection in vitro, and to carry out structural analysis toward informing future RSV drug development. Results of immunogold transmission and scanning electron microscopy showed RSV-nucleolin co-localization on the cell surface, as would be expected for a viral receptor. RSV, through its fusion protein (RSV-F), physically interacts with RBD1,2 and these interactions can be competitively inhibited by treatment with Palivizumab or recombinant RBD1,2. Treatment with synthetic peptides derived from two 12-mer domains of RBD1,2 inhibited RSV infection in vitro, with structural analysis suggesting these domains are potentially feasible for targeting in drug development. In conclusion, the identification and characterization of domains of nucleolin that interact with RSV provide the essential groundwork toward informing design of novel nucleolin-targeting compounds in RSV drug development.

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Do some viruses use growth hormone, prolactin and their receptors to facilitate entry into cells?

Wallis

2021

BioEssays

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The molecular evolution of pituitary growth hormone and prolactin in mammals shows two unusual features: episodes of markedly accelerated evolution and, in some species, complex families of related proteins expressed in placenta and resulting from multiple gene duplications. Explanations of these phenomena in terms of physiological adaptations seem unconvincing. Here, I propose an alternative explanation, namely that these evolutionary features reflect the use of the hormones (and their receptors) as viral receptors. Episodes of rapid evolution can then be explained as due to “arms races” in which changes in the hormone lead to reduced interaction with the virus, and subsequent changes in the virus counteract this. Placental paralogues of the hormones could provide decoys that bind viruses, and protect the foetus against infection. The hypothesis implies that the extensive changes introduced into growth hormone, prolactin and their receptors during the course of mammalian evolution reflect viral interactions, not endocrine adaptations.

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IGF1R is an entry receptor for respiratory syncytial virus

Cited by 104 publications

References 29 publications

Single-Stranded Oligonucleotide-Mediated Inhibition of Respiratory Syncytial Virus Infection

Single-Stranded Oligonucleotide-Mediated Inhibition of Respiratory Syncytial Virus Infection

Identification of RSV Fusion Protein Interaction Domains on the Virus Receptor, Nucleolin

Do some viruses use growth hormone, prolactin and their receptors to facilitate entry into cells?

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