A generic cell-based biosensor converts bacterial infection signals into chemoattractants for immune cells.

IF 8.2 2区 医学 Q1 ENGINEERING, BIOMEDICAL
Sushobhan Sarker, Mario Köster, Omkar Desai, Muhammad Imran Rahim, Sabrina Herrmann, Sara Behme, Meike Stiesch, Hansjörg Hauser, Dagmar Wirth
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Abstract

Bacterial infections are a major challenge to human health. Although various potent antibiotics have emerged in the last decades, current challenges arise from an increasing number of multi-drug-resistant species. Infections associated with implants represent a particular challenge since they are usually diagnosed at an advanced state, and are difficult to treat with antibiotics due to the formation of protecting biofilms. In this study, we designed and explored a synthetic biology-inspired, cell-based bio-sensor/actor for the detection and counteraction of bacterial infections. The system is generic as it senses diverse types of infections and acts by enhancement of the endogenous immune system. The strategy is based on genetically engineered sensor/actor cells that can sense type I interferons (IFNs), which are released by immune cells at the early stages of infections. IFN signalling activates a synthetic circuit to induce reporter genes with a sensitivity of only 5 pg/ml of IFN and leads to a therapeutic protein output of 100ng/ml, resulting in theranostic cells that visualize and fight infections. Robustness and resilience were achieved by the implementation of a positive feedback loop. We show that diverse gram-positive and gram-negative implant-associated pathogenic bacteria activate the cascade in co-culture systems in a dose-dependent manner. Finally, we show that this system can be used to secrete chemoattractants facilitating the infiltration of immune cells in response to bacterial triggers. Together, the system is not only universal to bacterial infections but at the same time hypersensitive allowing the sensing of infections at initial stages.

一种基于细胞的通用生物传感器可将细菌感染信号转化为免疫细胞的趋化诱导剂。
细菌感染是人类健康面临的一大挑战。虽然在过去几十年中出现了各种强效抗生素,但目前的挑战来自于越来越多的多重耐药菌种。与植入物相关的感染是一个特殊的挑战,因为这些感染通常在晚期才被诊断出来,而且由于会形成保护性生物膜,很难使用抗生素进行治疗。在这项研究中,我们设计并探索了一种受合成生物学启发、基于细胞的生物传感器/反应器,用于检测和应对细菌感染。该系统具有通用性,可感知各种类型的感染,并通过增强内源性免疫系统发挥作用。该战略以基因工程传感器/反应器细胞为基础,这些细胞能够感知免疫细胞在感染早期释放的 I 型干扰素(IFN)。IFN 信号可激活合成电路,诱导报告基因,对 IFN 的敏感度仅为 5 pg/ml,从而产生 100ng/ml 的治疗蛋白输出,形成可视化和抗感染的治疗细胞。通过实施正反馈循环,实现了稳健性和复原力。我们的研究表明,在共培养系统中,多种革兰氏阳性和革兰氏阴性植入相关致病菌以剂量依赖的方式激活了级联。最后,我们还展示了这一系统可用于分泌趋化诱导剂,促进免疫细胞对细菌诱因的渗透。总之,该系统不仅对细菌感染具有普遍性,同时还具有超灵敏性,可在感染初期进行感知。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Biofabrication
Biofabrication ENGINEERING, BIOMEDICAL-MATERIALS SCIENCE, BIOMATERIALS
CiteScore
17.40
自引率
3.30%
发文量
118
审稿时长
2 months
期刊介绍: Biofabrication is dedicated to advancing cutting-edge research on the utilization of cells, proteins, biological materials, and biomaterials as fundamental components for the construction of biological systems and/or therapeutic products. Additionally, it proudly serves as the official journal of the International Society for Biofabrication (ISBF).
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