Project Summary The long-term goal is to provide new rat models for the study of pathogenesis and evaluation of vaccines and antiviral therapies for viruses like SARS-CoV-2 that use human ACE2 for entry into host cells. We have shown that the virus does not infect wild type laboratory rats. Therefore, we used genetic engineering approaches to generate a new rat strain (F344-Tg(CAG-ACE2)057) that expresses human ACE2. We have confirmed that the rats expressing human ACE2 are highly susceptible to viral challenge, showing severe signs of infection frequently leading to death within 6-8 days post-infection. The specific objectives of this proposal are to further characterize the F344-Tg(CAG-ACE2)057 rat strain by using inhalation exposure to test if there is evidence of post-acute sequelae of COVID-19 in this model and to investigate the effects of genetic background and comorbidities on infection susceptibility. The expected outcomes of these studies are the validation of the ACE2- expressing rat strain as a new animal model for the study of long-COVID and demonstration that infection susceptibility is modulated by different genetic backgrounds, including one with known COVID comorbidities (i.e., obesity). The expectation is that these studies will show that the rats appropriately recapitulate human disease following infection with SARS-CoV-2 and offer advantages over existing mouse models due to inherent advantages of rats over mice based on larger size, genetics and physiology more similar to humans and behavioral attributes. Importantly, this model will be available through the Rat Resource and Research Center to facilitate ready distribution to interested investigators. The availability of a new animal model will advance the understanding of COVID-19 and SARS-CoV-2 pathogenesis as well as accelerate the development of vaccines and antiviral therapies.