Features and Functions of ACE2 Autoantibodies that Developed after SARS-CoV-2 Infection

Introduction: The cause of the long-lasting effects of SARS-CoV-2 infection referred to as PASC are unknown. One possible mechanism for the manifestations of PASC could be the overactivation of the immune system that drives inflammation and cellular injury disrupting host tissue homeostasis.

Objective: Generation of ACE2 autoantibodies after SARS-CoV-2 infection could inhibit ACE2 function and lead to increased inflammation and tissue damage that could contribute to PASC.

Methods: In Aim1, we will isolate ACE2-specific B cells after SARS-CoV-2 infection and determine B cell receptor genetic features and convergent clonal evolution after SARS-CoV-2 infection and vaccination and recombinantly express these ACE2 autoantibodies. In Aim 2, we will determine the ACE2 autoantibody epitopes, antigen recognition kinetics, and effects on ACE2 function elicited after SARS-CoV-2 infection and vaccination. Finally, in Aim 3 we will determine if there are differences the levels of ACE2 autoantibodies in pediatric individuals recovered from SARS-CoV-2 infection compared with adults.

Results: We demonstrate that ACE2 autoantibody levels are increased in individuals with severe COVID-19 compared with those with mild infection or no prior infection. We identify epitopes near the catalytic domain of ACE2 targeted by these antibodies. Levels of autoantibodies targeting ACE2 and other immune factors could serve as determinants of COVID-19 disease severity, and represent a natural immunoregulatory mechanism in response to viral infection.

Conclusion/Discussion: These results demonstrate that SARS-CoV-2 infection can increase autoantibody levels to ACE2 and other immune factors. The levels of these autoantibodies are associated with COVID-19 disease severity.

Key Topics:

• Biomarker, in-depth phenotyping assays and in vitro studies using tissue and other biospecimens
• Chronic immune dysfunction
• Clinical manifestations of chronic viral infections, biological pathways, immune-autoimmune disorders, systems, organs, or diseases
• Studies of vascular injury, thrombosis, and other potential mechanisms of Long COVID
• Therapeutic targets and drug development