RAPID: Understanding SARS-CoV2 transmission through a novel continuous monitoring system

RAPID：通过新型连续监测系统了解 SARS-CoV2 的传播

• 批准号: 2031794
• 负责人: Bapi Pahar
• 金额: $ 20万
• 依托单位: Tulane University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2021-10-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2031794&HistoricalAwards=false
• 关键词: RAPID; Understanding; SARS; CoV2; transmission

The coronavirus SARS-CoV-2 (severe acute respiratory syndrome–coronavirus-2), which is the cause of COVID-19, has a higher transmission rate compared to previous limited epidemics related to similar coronaviruses that are known to be transmitted by respiratory secretions, droplets, direct or indirect contacts. A recent study documented that SARS-CoV-2 can remain viable for several hours on various surfaces such as stainless steel, plastic, glass, and cardboards, suggesting that transmission can also happen through contaminated surfaces. Controversies remain whether SARS-CoV-2 can be transmitted through aerosols. Therefore, it is important to understand how soon an infected person starts shedding the virus, and how soon he or she transmits the infection to another person who is in direct or indirect contact with them. To address these major questions, this project will utilize a novel non-invasive monitoring system that can provide important information about the disease progression and new insights on disease staging, outcomes, and transmissions using a mouse model that has been engineered to have the human receptor that is key to allowing the virus to enter cells lining human airways. The monitoring system can continuously capture disease related data such as body temperature, head-body distance, activity patterns and breathing sounds. The data obtained will be used to identify meaningful patterns associated with disease onset and progression. To determine the difference between direct contact (DC) and indirect contact (IC), infected and uninfected animal groups will be housed in the same cage (DC) or in adjoining cages separated by a permeable partition (IC). This novel information will open the door for further studies where a greater number of experimental factors can be investigated, enabling more humane endpoints. Furthermore, the novel SARS-CoV-2 - mouse transmission models can be applied to other contagious diseases. The goal of this proof-of-principle project is to generate novel information about the SARS-CoV-2 transmission rate, frequencies and, disease progression through direct or indirect contact (DC or IC) in murine models. Results obtained are expected to provide fundamental insight into how soon an infected person starts shedding the virus, and how soon he or she transmits the infection to another person who is in direct or indirect contact with them. The project’s goal will be accomplished using hACE2 (human angiotensin-converting enzyme 2) transgenic mice expressing the ACE2 receptor and a non-invasive and continuous monitoring system (CMS) designed for multi-sensor data collection that can capture several external phenotypes, including body temperature, head-body distance, activity patterns, breathing sounds, and others to characterize infectious disease progression. Algorithms have been developed for time-series decomposition and classification that can identify meaningful patterns associated with disease staging. The project hypothesizes that the novel CMS can be used to better characterize the SARS-CoV-2 transmission time, frequencies, and to study disease progression variability between DC and IC mice-to-mice transmission models. The hypothesis will be tested with two specific aims. The FIRST aim is to quantify the SARS transmission time, frequencies, and resulting disease progression dynamics in a DC mice-to-mice transmission model. This aim will be achieved by infecting one of the two housed hACE2 transgenic mice per cage with SARS-CoV-2, after which the animals will be continuously monitored for 21 days. Real time data analysis will be used to determine disease onset (viral transmission) for other uninfected hACE2 mice, which are housed in the same cage and have DC with the infected mice. The SECOND Aim will quantify the SARS transmission time, frequencies, and disease progression in an IC mice-to-mice transmission model. This aim will be accomplished by housing uninfected hACE2 mice in cages with a permeable partition separating them from infected hACE2 mice. In both aims, the morality rate will be quantified. Tissues will be collected from euthanized animals to measure tissue viral loads, tissue pathogenesis by histology, and to detect tissue viral antigens by immunohistochemistry (IHC) staining.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

引起新冠肺炎的冠状病毒SARS-CoV-2(严重急性呼吸综合征-冠状病毒-2)的传播率高于以往与类似冠状病毒相关的有限流行，已知的类似冠状病毒通过呼吸道分泌物、飞沫、直接或间接接触传播。最近的一项研究证明，SARS-CoV-2可以在不锈钢、塑料、玻璃和纸板等各种表面上存活数小时，这表明传播也可以通过受污染的表面发生。SARS-CoV-2是否可以通过气雾剂传播仍存在争议。因此，重要的是要了解感染者多久开始脱离病毒，以及他或她多快将感染传染给与他们有直接或间接接触的另一个人。为了解决这些主要问题，该项目将利用一种新型的非侵入性监测系统，该系统可以提供有关疾病进展的重要信息，并使用小鼠模型提供关于疾病分期、结果和传播的新见解，该模型已被设计为具有人类受体，该受体是允许病毒进入人类呼吸道内细胞的关键。该监测系统可以持续捕获与疾病相关的数据，如体温、头与身体的距离、活动模式和呼吸声。获得的数据将被用来确定与疾病发生和进展相关的有意义的模式。为了确定直接接触(DC)和间接接触(IC)之间的区别，感染和未感染的动物群体将被关在同一笼子(DC)或由可渗透隔板(IC)隔开的相邻笼子中。这一新颖的信息将为进一步研究打开大门，在那里可以调查更多的实验因素，从而实现更人性化的终点。此外，新的SARS-CoV-2小鼠传播模型还可以应用于其他传染病。这个原则证明项目的目标是通过直接或间接接触(DC或IC)在小鼠模型中产生关于SARS-CoV-2传播率、频率和疾病进展的新信息。预计所获得的结果将提供基本的洞察，了解感染者多快开始摆脱病毒，以及他或她多快将感染传播给与他们有直接或间接接触的另一个人。该项目的目标将通过使用表达ACE2受体的hACE2(人类血管紧张素转换酶2)转基因小鼠和一个非侵入性连续监测系统(CMS)来实现，该系统专为多传感器数据收集而设计，可以捕获几种外部表型，包括体温、头-身体距离、活动模式、呼吸声等，以表征传染病的进展。已经开发了用于时间序列分解和分类的算法，可以识别与疾病分期相关的有意义的模式。该项目假设新型CMS可以用于更好地表征SARS-CoV-2传播时间和频率，并研究DC和IC小鼠到小鼠传播模型之间的疾病进展变异性。这一假设将通过两个具体目标进行检验。第一个目标是量化SARS在DC小鼠到小鼠传播模型中的传播时间、频率和导致的疾病进展动力学。这一目标将通过每笼两只hACE2转基因小鼠中的一只感染SARS-CoV-2来实现，之后将对这些动物进行21天的持续监测。实时数据分析将被用来确定其他未感染的hACE2小鼠的疾病发病(病毒传播)，这些小鼠被关在同一个笼子里，与受感染的小鼠有DC。第二个目标将量化SARS在IC鼠对鼠传播模型中的传播时间、频率和疾病进展。这一目标将通过将未感染的hACE2小鼠与感染的hACE2小鼠隔离在笼子中来实现。在这两个目标中，道德率都将被量化。将从被安乐死的动物身上收集组织，以测量组织病毒载量，通过组织学检测组织致病机制，并通过免疫组织化学(IHC)染色检测组织病毒抗原。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。