SARS-CoV-2 ORF1ab^A1061S potentiate autoreactive T cell responses via epitope mimicry: an explanation to hepatitis of unknown cause

The World Health Organization have recently announced outbreak news of acute, severe hepatitis of unknown cause in children under a Covid-19 pandemic. Whether it is associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is still under debating. Here, we performed genomic sequence alignment analysis of the genome of SARS-Cov-2 (Wuhan-hu-1) to the human genome reference. Sequence analysis revealed that the SARS-CoV-2 ORF1ab^1056-1173 presented high identities with the human protein PAPR14^53-176(3Q6Z_A). After searching the fully sequenced SARS-CoV-2 genomes deposited in GISAID (<ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="https://www.gisaid.org/">https://www.gisaid.org/</ext-link>), we detected 170 SARS-CoV-2 variants with mutation in ORF1ab¹⁰⁶¹, where alanine (A) was substituted by serine (S). This alteration made a 7-amino acid peptide (VVVNASN) in ORF1ab^1056-1062 identical to its counterpart in PARP14^53-59(3Q6Z_A). HLA prediction suggested that the peptides with high identities in PARP14 and ORF1ab could be presented by a same globally prevalent HLA-A*11:01 molecule. And in consistent with the first reported case of hepatitis of unknown, SARS-CoV-2 ORF1ab^VVVNASN variants were mostly identified as Delta lineages in UK by the late 2021, with an overall frequency of 0.00161%. Thus, our preliminary results raised a possibility that infection by SARS-CoV-2 ORF1ab^VVVNASN variant might elicit an autoimmune T cell response via epitope mimicry and is associated with the outbreak of unknown hepatitis. We anticipated that these findings will alert the human societies to pay more attention to rare mutations beyond the spike proteins.