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.
