Innate immune and inflammatory responses to coronaviruses

Coronaviruses are a group of viruses well known for causing highly pathogenic respiratory and neurological infections. One method coronaviruses do this is by encoding in their genome a variety of genes capable of disrupting the innate immune response. The innate immune response is composed of immune cells that produce a multitude of factors directly capable of limiting viral infection. If the innate immune response is compromised, virus clearance is inhibited and risk of disease severity increases. I focused on characterizing a gene, the internal N gene “I”, in mouse coronaviruses (MHV) that was thought to limit the innate immune response. I found the I gene did inhibit the innate immune response, particularly interferon, a pathway of molecules excellent at limiting viral infection. Interestingly, I protein also acted as a component of the virion and aided in virion assembly. To understand the functional role of this gene, I constructed a virus lacking the I gene in MHV strain JHM. Mice infected with virus lacking the I gene were able to survive a lethal infection as viral replication and assembly of the virus were significantly reduced. Overall, this study provided an unappreciated role in CoV accessory proteins in virion formation.

SARS-CoV-2 is another coronavirus capable of disrupting the innate immune response. Infection with SARS-CoV-2 has led to people developing symptoms long term, called long Covid or post-acute sequelae of SARS-CoV-2 (PASC). PASC patients experience cognitive deficits including brain fog, fatigue, memory loss, and movement impairment in addition to increased risk of heart and lung damage. We developed a mouse model of PASC where mice have cognitive deficits including anti-social behavior and long-term lung damage. I determined that overactivation of the innate immune cells contribute to lung and brain alterations. Interestingly, I found the immune cell populations of monocytes and macrophages displayed characteristics like that seen in other neurological diseases such as Alzheimer’s disease. Overall, I developed a mouse model that recapitulates human PASC and can allow for therapeutic testing to prevent and limit PASC.