Mechanisms of immunomodulation by mammalian and viral decoy receptors: insights from structures

Félix, Jan; Savvides, Savvas N.

doi:10.1038/nri.2016.134

Cited by 58 publications

(52 citation statements)

References 206 publications

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“…8). Fusion proteins comprising receptor ectodomains and decoy receptors foster attractive binding properties to serve as effective therapeutics61, as exemplified in the targeting of IL-1 (Rilonacept) or TNFα (Etanercept) for the treatment of CAPS-syndrome and rheumatoid arthritis, respectively62. Indeed, we are currently performing in vivo studies to assess the antagonistic potency of such fusion proteins.…”

Section: Discussionmentioning

confidence: 99%

Structure and antagonism of the receptor complex mediated by human TSLP in allergy and asthma

et al. 2017

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The pro-inflammatory cytokine thymic stromal lymphopoietin (TSLP) is pivotal to the pathophysiology of widespread allergic diseases mediated by type 2 helper T cell (Th2) responses, including asthma and atopic dermatitis. The emergence of human TSLP as a clinical target against asthma calls for maximally harnessing its therapeutic potential via structural and mechanistic considerations. Here we employ an integrative experimental approach focusing on productive and antagonized TSLP complexes and free cytokine. We reveal how cognate receptor TSLPR allosterically activates TSLP to potentiate the recruitment of the shared interleukin 7 receptor α-chain (IL-7Rα) by leveraging the flexibility, conformational heterogeneity and electrostatics of the cytokine. We further show that the monoclonal antibody Tezepelumab partly exploits these principles to neutralize TSLP activity. Finally, we introduce a fusion protein comprising a tandem of the TSLPR and IL-7Rα extracellular domains, which harnesses the mechanistic intricacies of the TSLP-driven receptor complex to manifest high antagonistic potency.

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Section: Discussionmentioning

confidence: 99%

Structure and antagonism of the receptor complex mediated by human TSLP in allergy and asthma

et al. 2017

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“…Molecular mimicry, manifested by structural similarity between viral and endogenous host proteins, allow viruses to harness or disrupt cellular functions including nucleic acid metabolism and modulation of immune responses. Yet, while examples of this latter strategy pepper the literature 2-4 , most have focused on human infecting viruses 5,6 and a systematic analysis of pathogen-encoded molecular mimics has not been performed.…”

Section: Introductionmentioning

confidence: 99%

A sweep of earth’s virome reveals host-guided viral protein structural mimicry; with implications for human disease

Lasso

Shapira

2020

Preprint

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19Viruses deploy an array of genetically encoded strategies to coopt host machinery and support viral 20 replicative cycles. Molecular mimicry, manifested by structural similarity between viral and endogenous 21 host proteins, allow viruses to harness or disrupt cellular functions including nucleic acid metabolism and 22 modulation of immune responses. Here, we use protein structure similarity to scan for virally encoded 23 structure mimics across thousands of catalogued viruses and hosts spanning broad ecological niches and 24 taxonomic range, including bacteria, plants and fungi, invertebrates and vertebrates. Our survey identified 25 over 6,000,000 instances of structural mimicry, the vast majority of which (>70%) cannot be discerned 26 through protein sequence. The results point to molecular mimicry as a pervasive strategy employed by 27 viruses and indicate that the protein structure space used by a given virus is dictated by the host proteome. 28Interrogation of proteins mimicked by human-infecting viruses points to broad diversification of cellular 29 pathways targeted via structural mimicry, identifies biological processes that may underly autoimmune 30 disorders, and reveals virally encoded mimics that may be leveraged to engineer synthetic metabolic circuits 31 or may serve as targets for therapeutics. Moreover, the manner and degree to which viruses exploit 32 molecular mimicry varies by genome size and nucleic acid type, with ssRNA viruses circumventing 33 limitations of their small genomes by mimicking human proteins to a greater extent than their large dsDNA 34 counterparts. Finally, we identified over 140 cellular proteins that are mimicked by CoV, providing clues 35 about cellular processes driving the pathogenesis of the ongoing COVID-19 pandemic.36 37 42 structure-informed prediction algorithms have allowed discovery of such interactions across all fully 43 sequenced human infecting viruses 1 . Molecular mimicry, manifested by structural similarity between viral 44 and endogenous host proteins, allow viruses to harness or disrupt cellular functions including nucleic acid 45 metabolism and modulation of immune responses. Yet, while examples of this latter strategy pepper the 46 literature 2-4 , most have focused on human infecting viruses 5,6 and a systematic analysis of pathogen-encoded 47 molecular mimics has not been performed. 49The vast genomic landscape occupied by viruses hampers the discovery of evolutionary relationships 50 between viral proteins and their hosts. As is well known however, since 3-dimensional (3D) protein 51 structure is much better conserved than sequence, structural information can be used to interrogate 52 3 evolutionary relationships 1,7 as well as uncover virus-encoded structural mimics that cannot be detected by 53 sequence relationships (see Methods). Here, we use protein structure similarity to identify virally encoded 54 mimics of host proteomes. Briefly, we first employ sequence-based methods to identify proteins that have 55 similar structures to queried viral ...

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“…Common elements frequently targeted by various viruses and employing different strategies include the antiviral interferon IFN response, the inflammatory response or the antigen presentation pathways [2]. A relevant strategy found mostly in different families of large dsDNA viruses such as herpesviruses and poxviruses is the use of viral secreted proteins targeting cytokines, the soluble mediators of the immune response [4]. 2 of 15 These viral proteins in general act by binding to their ligands, thus blocking the recognition and/or activation of their cognate receptors.…”

Section: Introductionmentioning

confidence: 99%

Addition of a Viral Immunomodulatory Domain to Etanercept Generates a Bifunctional Chemokine and TNF Inhibitor

Alejo

Sánchez

Amu

et al. 2019

JCM

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The inhibition of tumor necrosis factor (TNF) through the use of either antibodies or soluble receptors is a highly effective strategy for the clinical control of chronic inflammatory conditions such as rheumatoid arthritis. Different viruses have similarly exploited this concept by expressing a set of specifically tailored secreted TNF decoy receptors to block host inflammatory responses. Poxviruses have been shown to encode at least two distinct molecules, termed Cytokine response modifier D (CrmD) and CrmB, in which a TNF inhibitor is combined with a chemokine inhibitor on the same molecule. The ectromelia virus CrmD protein was found to be a critical determinant of virulence in vivo, being able to control local inflammation to allow further viral spread and the establishment of a lethal infection. Strikingly, both the TNF and the chemokine inhibitory domains are required for the full activity of CrmD, suggesting a model in which inhibition of TNF is supported by the concomitant blockade of a reduced set of chemokines. Inspired by this model, we reasoned that a similar strategy could be applied to modify the clinically used human TNF receptor (etanercept), producing a generation of novel, more effective therapeutic agents. Here we show the analysis of a set of fusion proteins derived from etanercept by addition of a viral chemokine-binding protein.A bifunctional inhibitor capable of binding to and blocking the activity of TNF as well as a set of chemokines is generated that is active in the prevention of arthritis in a murine disease model.

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Mechanisms of immunomodulation by mammalian and viral decoy receptors: insights from structures

Cited by 58 publications

References 206 publications

Structure and antagonism of the receptor complex mediated by human TSLP in allergy and asthma

Structure and antagonism of the receptor complex mediated by human TSLP in allergy and asthma

A sweep of earth’s virome reveals host-guided viral protein structural mimicry; with implications for human disease

Addition of a Viral Immunomodulatory Domain to Etanercept Generates a Bifunctional Chemokine and TNF Inhibitor

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