The Long-COVID Syndrome: Neoantigens as Driving Force for the Onset of Autoimmune Diseases

In the fifth year of the pandemic, SARS-CoV-2 variants continue to unveil new insights into particular mechanism of human immunology but also new clues on the interaction of SARS-CoV-2 proteins with host proteins. Nearly all yet known SARS-CoV-2 variants had the ability to cause a post-infection disease termed the Long COVID (LC) syndrome. The LC syndrome encompasses various autoimmune diseases ranging from localized organ damage to systemic effects like the myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The complexity of these diverse disease conditions is challenging for physicians. Several studies indicate that SARS-CoV-2 infections may trigger the production of functional autoantibodies (fAAB’s), a fact that could well explain the yet known post-infection disease conditions. Therefore, the human target proteome of both SARS-CoV-2 viral proteases, NSP3/MPro and NSP5/3CLPro, was investigated. Based on these results, SARS-CoV-2 proteases target ~6,500 human proteins, while well-known common viruses were ranging only between 2 to less than 100 proteins. Thus, the capability of SARS-CoV-2 to generate reactogenicity against these neoantigens in infected cells is outstanding. Here, the hypothesis is posed that the neoantigen production during a SARS-CoV-2 infection is the major cause for the onset of the LC syndrome, which is currently affecting ~10% of all infected individuals worldwide.