Using silicon-based biosensors to detect host protein signatures capable of differentiating between bacterial and viral infection at point-of-care

使用硅基生物传感器检测宿主蛋白质特征，能够在护理点区分细菌和病毒感染

• 批准号: 2621331
• 金额: --
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2621331
• 关键词: Using; silicon; based; biosensors; detect

The World Health Organisation has predicted that the rise of antimicrobial resistance (AMR) will claim up to 10 million lives by the year 2050[1]. One of the key factors driving AMR emergence is the lack of a rapid diagnostic device capable of differentiating between bacterial and viral infection. A bacterial culture test is the current "gold standard", however it presents with various draw backs such as long time-to-positive results and risk of sample contamination[2]. This leads to clinicians either delaying antibiotic treatment as they wait for confirmation or overprescribing broad spectrum antibiotics in cases of severe infection. It is then unsurprising to learn that around 50% of antibiotics are inappropriately prescribed[3]. The ideal diagnostic device would be rapid and available at point-of-care with high sensitivity and specificity, however challenges with current diagnostics make these characteristics difficult to achieve. Primarily, they mostly rely on optical-based methods of detection which usually require bulky and expensive laboratory equipment and so often makes these assays unavailable at point-of-care[4]. Additionally, direct detection of the causative pathogen may not be possible as some pathogens are incredibly invasive or inaccessible, especially in cases of tuberculosis. Finally, confirmation of a bacterial infection does not rule out a causative viral infection and vice versa which is a very common dynamic in upper respiratory infections[5].Host protein signatures could bypass all these challenges and various host protein signatures have already been cited in literature. Oved et al. (2015) discovered a 3 host protein signature composed of C-reactive protein (CRP), TNF-related apoptosis-inducing ligand (TRAIL) and Interferon gamma-induced protein-10 (IP-10) which is able to accurately differentiate between bacterial and viral infection[6]. However, it is estimated that over 90% of discovered host biomarkers have not yet been applied successfully at point-of-care[7]. Combining host protein signatures with already leveraged complementary metal-oxide semiconductor technology (CMOS) (the leading technology used to manufacture everyday electronics) would make such devices incredibly cheap and scalable[8]. CMOS technology is also compatible with ion sensitive field effect transistors (ISFETs), which can be used to detect changes in surface charge due to antigen-antibody binding and hence detect and quantify host proteins in real time.Research questions:-What specific host protein signature is able to differentiate between bacterial and viral infection with high sensitivity and specificity? -How does the sensitivity and specificity of the immunoassay immobilised on-chip compare to the "gold standard" protein detection technique?-What techniques are required to immobilise primary antibodies onto an array of ISFET sensors? -What is the on-chip limit of detection for that specific protein signature?Aims:-This project aims to develop an immunoassay specific to a host protein signature capable of differentiation between bacterial and viral infection. -The specific immunoassay will then be translated onto a silicon-based biosensor and the on-chip limit of detection will be established. -Finally, the assay will be validated against clinical samples and used to provide quantitative data around the infection state of the patient. References [1] M. E. A. de Kraker, A. J. Stewardson, and S. Harbarth, "Will 10 Million People Die a Year due to Antimicrobial Resistance by 2050?," PLOS Medicine, vol. 13, no. 11, p. e1002184, Nov. 2016, doi: 10.1371/JOURNAL.PMED.1002184.[2] J. C. Craig et al., "The accuracy of clinical symptoms and signs for the diagnosis of serious bacterial infection in young febrile children: prospective cohort study of 15 781 febrile illnesses," BMJ (Clinical research ed.), vol. 340, no. 7754, p. 1015, May 2010, doi: 10.1136/BMJ.C1594.[3] C. Giuliano, C. R. Patel, and

世界卫生组织预测，到2050年，抗菌抗性（AMR）的兴起将夺走多达1000万生命[1]。推动AMR出现的关键因素之一是缺乏能够区分细菌和病毒感染的快速诊断装置。细菌培养试验是当前的“黄金标准”，但是它具有各种抽签，例如长时间的阳性结果和样品污染的风险[2]。这导致临床医生在严重感染的情况下等待确认或过度处方广谱抗生素时延迟抗生素治疗。因此，得知大约50％的抗生素是不适当的[3]并不令人惊讶。理想的诊断装置将很快，并且在护理点上具有高灵敏度和特异性，但是当前诊断的挑战使这些特征难以实现。主要是，它们主要依赖于基于光学的检测方法，这些检测方法通常需要笨重且昂贵的实验室设备，因此通常会使这些测定在护理点[4]。另外，由于某些病原体具有令人难以置信的侵入性或无法访问，尤其是在结核病的情况下，可能无法直接检测病原体。最后，对细菌感染的确认不能排除病毒感染，反之亦然，这是上呼吸道感染的一种非常普遍的动态[5]。HOST蛋白质特征可以绕过所有这些挑战，并且已经在各种宿主蛋白​​质特征中列出了所有这些挑战。文学。 Oved等。 （2015年）发现了一个由C反应蛋白（CRP）组成的3个宿主蛋白质特征，TNF相关的凋亡诱导配体（TRAIL）和Interferonγ诱导的蛋白-10（IP-10），能够准确区分细菌之间的细菌之间和病毒感染[6]。但是，据估计，超过90％的发现的宿主生物标志物尚未在护理点上成功应用[7]。将宿主蛋白质特征与已经杠杆互补的金属氧化物半导体技术（CMOS）（用于生产日常电子产品的领先技术）相结合，将使此类设备变得令人难以置信的便宜和可扩展性[8]。 CMOS技术还与离子敏感的场效应晶体管（ISFET）兼容，可用于检测由于抗原抗体结合而引起的表面电荷变化，因此在实时检测和量化宿主蛋白。签名能够以高灵敏度和特异性区分细菌感染和病毒感染？ - 与“金标准”蛋白检测技术相比，固定的免疫测定的灵敏度和特异性如何？ - 该特定蛋白质特征的芯片检测极限是什么？目的： - 该项目旨在开发针对能够分化细菌和病毒感染的宿主蛋白特异性特异性的免疫测定。 - 然后，特定的免疫测定将转换为基于硅的生物传感器，并将建立芯片上检测极限。 - 最后，该测定法将对临床样本进行验证，并用于提供围绕患者感染状态的定量数据。参考文献[1] M. E. A. De Kraker，A。J。Stewardson和S. Harbarth，“ 1000万人将因2050年抗菌抗药性而死亡，” Plos Medicine，第1卷。 13，否。 11，第1页。 E1002184，2016年11月，doi：10.1371/journal.pmed.1002184。[2] J. C. Craig等人，“临床症状和诊断出严重细菌感染的临床症状的准确性和年轻儿童的严重细菌感染的迹象：15 781 Febrile疾病的前瞻性队列研究，” BMJ（临床研究编辑），第1卷。 340，没有。 7754，p。 1015，2010年5月，doi：10.1136/bmj.c1594。[3] C. Giuliano，C。R。Patel和