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Engineering Logical Inflammation Sensing Circuit for Modulating Gut Conditions

Merk, Liana N. and Shur, Andrey S. and Pandey, Ayush and Murray, Richard M. and Green, Leopold N. (2020) Engineering Logical Inflammation Sensing Circuit for Modulating Gut Conditions. . (Unpublished) https://resolver.caltech.edu/CaltechAUTHORS:20201111-100159834

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Abstract

The mammalian gut contains trillions of microbes that interact with host cells and monitor changes in the environment. Opportunistic pathogens exploit environmental conditions to stimulate their growth and virulence, leading to a resurgence of chronic disorders such as inflammatory bowel disease (IBD). Current therapies are effective in less than 30% of patients due to the lack of adherence to prescription schedules and overall, off-target effects. Smart microbial therapeutics can be engineered to colonize the gut, providing in situ surveillance and conditional disease modulation. However, many current engineered microbes can only respond to single gut environmental factors, limiting their effectiveness. In this work, we implement the previously characterized split activator AND logic gate in the probiotic E. coli strain Nissle 1917. Our system can respond to two input signals: the inflammatory biomarker tetrathionate and a second input signal, IPTG. We report 4-6 fold induction with minimal leak when both signals are present. We model the dynamics of the AND gate using chemical reaction networks, and by tuning parameters in silico, we identified perturbations that affect our circuit's selectivity. We anticipate that our results will prove useful for designing living therapeutics for spatial targeting and signal processing in complex environments.


Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription
https://doi.org/10.1101/2020.11.10.377085DOIDiscussion Paper
ORCID:
AuthorORCID
Pandey, Ayush0000-0003-3590-4459
Murray, Richard M.0000-0002-5785-7481
Green, Leopold N.0000-0001-5479-6970
Additional Information:The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. This version posted November 10, 2020. We thank William Poole and John Marken for technical guidance, as well as all other Murray lab members for insightful discussions. We thank Dr. Henry Schreiber and Prof. Sarkis Mazmanian for collaborating with us in ongoing microbiome studies with this project. Dr. Leo Green is supported by the Caltech NSF AGEP Fellowship and Rosen Fellowship. We thank Caltech CEMI for providing support for future directions of this work. Prof. Justin Bois has provided excellent discussions regarding data analysis and availability. Logic gate strains were provided by Martin Buck & Baojun Wan. Some figures were created with BioRender.com. The authors have declared no competing interest.
Group:Rosen Bioengineering Center
Funders:
Funding AgencyGrant Number
NSF Graduate Research FellowshipUNSPECIFIED
Donna and Benjamin M. Rosen Bioengineering CenterUNSPECIFIED
Record Number:CaltechAUTHORS:20201111-100159834
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20201111-100159834
Official Citation:Engineering Logical Inflammation Sensing Circuit for Modulating Gut Conditions. Liana N Merk, Andrey Shur, Ayush Pandey, Richard M Murray, Leopold N. Green. bioRxiv 2020.11.10.377085; doi: https://doi.org/10.1101/2020.11.10.377085
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:106610
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:11 Nov 2020 19:06
Last Modified:11 Nov 2020 19:06

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