Investigating the neurological immune response to long COVID SARS-CoV-2 infection in K18-hACE2 transgenic mouse model

Abstract

Since the onset of the coronavirus pandemic, considerable research has been conducted to explore the impact of SARS-CoV-2 infection on the human immune system and the body. However, less attention has been given to investigating "long COVID," defined by the CDC as persisting symptoms lasting at least three months post-infection. Therefore, current research has focused on understanding the effects of SARS-CoV-2 infection on the brain's immune response and behavioral or cognitive functions. Existing literature has proven angiotensin-converting enzyme 2 (ACE2) involvement in SARS-CoV-2 infection. Interestingly, this host entry receptor also plays a role in the upregulation of B1R expression associated with inflammation. Thus, our study aims to understand the benefit of oppressing the B1R during prolonged COVID-19 infection. Therefore, the hypothesis is that SARS-CoV-2 infection induces B1R expression in the brain, driving glial cell activation and cognitive and neuropsychiatric symptoms. We used our lab-established long COVID mouse model to test our hypothesis, including the K18-hACE2 transgenic mouse model infected at 4x10³ TCID SARS-CoV-2. The design involved testing with the B1R antagonist, SSR240612, in thirty-two mice divided appropriately into four groups evaluating glial cell activation, B1R expression, cognitive function, and behavior. Our study observed a 10% increase in survival rates among groups infected with SARS-CoV-2 when treated with a B1R antagonist. Cognitive trends indicated that B1R antagonists protected against deficits induced by 4x10³ TCID50 dose. Our findings also support existing research indicating elevated B1R expression following SARS-CoV-2 infection. Furthermore, analysis of glial cells suggests activation during SARS-CoV-2 infection. These results indicate that the B1R Antagonist SSR240612 plays a role in glial cells' neurological and immune response to inflammation and changes in behavior induced by mild SARS-CoV-2 infection.