Sensing and responding to allergic response cytokines through a genetically encoded circuit

Chassin, Hélène; Geering, Barbara; Schukur, Lina; Auslander, David M.; Lang, Brian M.; Fussenegger, Martin

doi:10.1038/s41467-017-01211-1

Cited by 25 publications

(16 citation statements)

References 80 publications

(90 reference statements)

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“…Such circuits support the engineering of novel complex and multicellular systems that can sense and communicate 67 , and are essential for the development of personalized medicine and biomedical science. The pulsatile behavior of our circuit is an important requirement for numerous synthetic networks, including Boolean processing logic devices and closed-loop control capacity devices 25,26,67 , complex sensor–effector devices (so-called prosthetic gene networks) 68,69 for personalized medicine, and biosensors for reporting the presence of target analytes 62 . Furthermore, pulse-generating circuits have been proposed to achieve coordinated behavior in E. coli 23 .…”

Section: Discussionmentioning

confidence: 99%

A modular degron library for synthetic circuits in mammalian cells

Chassin

Müller²,

Tigges³

et al. 2019

Nat Commun

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Tight control over protein degradation is a fundamental requirement for cells to respond rapidly to various stimuli and adapt to a fluctuating environment. Here we develop a versatile, easy-to-handle library of destabilizing tags (degrons) for the precise regulation of protein expression profiles in mammalian cells by modulating target protein half-lives in a predictable manner. Using the well-established tetracycline gene-regulation system as a model, we show that the dynamics of protein expression can be tuned by fusing appropriate degron tags to gene regulators. Next, we apply this degron library to tune a synthetic pulse-generating circuit in mammalian cells. With this toolbox we establish a set of pulse generators with tailored pulse lengths and magnitudes of protein expression. This methodology will prove useful in the functional roles of essential proteins, fine-tuning of gene-expression systems, and enabling a higher complexity in the design of synthetic biological systems in mammalian cells.

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Section: Discussionmentioning

confidence: 99%

A modular degron library for synthetic circuits in mammalian cells

Chassin

Müller²,

Tigges³

et al. 2019

Nat Commun

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“…Utilising cytokine-centric ocular allergy research, development of a drug that directly inhibits cytokine signalling on the ocular surface, in the form of eye-drops or oral tablets, could be a universally beneficial alternative that is not subject to individual sensitivities. Similar technologies are currently being developed, with a study by Chassin et al in 2017 reporting the development of a lab-synthesised dual Th2 cytokine sensor (DCS) device modelled on mammalian cells [70]. This DCS device is potentially capable of detecting interaction levels between IL-4 and IL-13, and subsequently triggering the release of designed ankyrin repeat protein (DARPin) E2_79 when an allergic reaction is recognised [70].…”

Section: Results Of Previous Ocular Allergy Studiesmentioning

confidence: 99%

“…Similar technologies are currently being developed, with a study by Chassin et al in 2017 reporting the development of a lab-synthesised dual Th2 cytokine sensor (DCS) device modelled on mammalian cells [70]. This DCS device is potentially capable of detecting interaction levels between IL-4 and IL-13, and subsequently triggering the release of designed ankyrin repeat protein (DARPin) E2_79 when an allergic reaction is recognised [70]. DARPin E2_79 is then able to bind to IgE and thus dampen the degranulation of local immune cells that leads to physiological symptoms [70].…”

Section: Results Of Previous Ocular Allergy Studiesmentioning

confidence: 99%

“…This DCS device is potentially capable of detecting interaction levels between IL-4 and IL-13, and subsequently triggering the release of designed ankyrin repeat protein (DARPin) E2_79 when an allergic reaction is recognised [70]. DARPin E2_79 is then able to bind to IgE and thus dampen the degranulation of local immune cells that leads to physiological symptoms [70]. Alternatives to this method of inactivating the allergic pathway include anticytokine drugs that can be orally administered to prevent allergic flare-ups.…”

Section: Results Of Previous Ocular Allergy Studiesmentioning

confidence: 99%

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To See or Not to See: A Systematic Review of the Importance of Human Ocular Surface Cytokine Biosignatures in Ocular Allergy

Aydin

Gokhale

Azizoglu

et al. 2019

Cells

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Cytokines are key cell signalling proteins in a number of immune and homeostatic pathways of the human body. In particular, they mediate intracellular mechanisms of allergy on the ocular surface by triggering cellular responses that result in typical physiological ocular allergy symptoms, such as itchiness, watery eyes, irritation, and swelling. Given the recent research focus in optometry on the aetiology of corneal ectasia subtypes like keratoconus, there is an increasing need for the development of new clinical diagnostic methods. An increasing trend is evident among recent publications in cytokine studies, whereby the concentrations of cytokines in healthy and disease states are compared to derive a specific cytokine profile for that disease referred to as ‘biosignatures’. Biosignatures have diagnostic applications in ocular allergy as a cheap, non-invasive alternative to current techniques like IgE antibody testing and skin prick tests. Cytokine detection from tear samples collected via microcapillary flow can be analysed either by enzyme-linked immunosorbent assays (ELISA), multiplex magnetic bead assays, or immunoblot assays. Characterising patient hypersensitivities through diagnostic tests is the first step to managing exposure to triggers. Investigating cytokine biosignatures in ocular allergy and their links to physiology are imperative and will be the focus of this systematic review article.

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“…The inducing signals triggering the synthetic circuit can be of different types. Notably, for endogenous signals that are present in the body, the system can be autonomously detected [ 73 , 74 ]. This approach remains the long-term goal of synthetic immunology.…”

Section: Internal Induction By Endogenous Stimulimentioning

confidence: 99%

Toward Tightly Tuned Gene Expression Following Lentiviral Vector Transduction

Page

Fusil

Cosset

2020

Viruses

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Lentiviral vectors are versatile tools for gene delivery purposes. While in the earlier versions of retroviral vectors, transgene expression was controlled by the long terminal repeats (LTRs), the latter generations of vectors, including those derived from lentiviruses, incorporate internal constitutive or regulated promoters in order to regulate transgene expression. This allows to temporally and/or quantitatively control transgene expression, which is required for many applications such as for clinical applications, when transgene expression is required in specific tissues and at a specific timing. Here we review the main systems that have been developed for transgene regulated expression following lentiviral gene transfer. First, the induction of gene expression can be triggered either by external or by internal cues. Indeed, these regulated vector systems may harbor promoters inducible by exogenous stimuli, such as small molecules (e.g., antibiotics) or temperature variations, offering the possibility to tune rapidly transgene expression in case of adverse events. Second, expression can be indirectly adjusted by playing on inserted sequence copies, for instance by gene excision. Finally, synthetic networks can be developed to sense specific endogenous signals and trigger defined responses after information processing. Regulatable lentiviral vectors (LV)-mediated transgene expression systems have been widely used in basic research to uncover gene functions or to temporally reprogram cells. Clinical applications are also under development to induce therapeutic molecule secretion or to implement safety switches. Such regulatable approaches are currently focusing much attention and will benefit from the development of other technologies in order to launch autonomously controlled systems.

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Sensing and responding to allergic response cytokines through a genetically encoded circuit

Cited by 25 publications

References 80 publications

A modular degron library for synthetic circuits in mammalian cells

A modular degron library for synthetic circuits in mammalian cells

To See or Not to See: A Systematic Review of the Importance of Human Ocular Surface Cytokine Biosignatures in Ocular Allergy

Toward Tightly Tuned Gene Expression Following Lentiviral Vector Transduction

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