key: cord-0293692-xuug2eyn
authors: Wang, Yu; Liu, Yuexing
title: SARS-CoV-2 ORF1abA1061S potentiate autoreactive T cell responses via epitope mimicry: an explanation to hepatitis of unknown cause
date: 2022-05-23
journal: bioRxiv
DOI: 10.1101/2022.05.16.491922
sha: 209a11b4af7788bbcde6cc4b44c5025ee6f00309
doc_id: 293692
cord_uid: xuug2eyn

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 ORF1ab1056-1173 presented high identities with the human protein PAPR1453-176(3Q6Z_A). After searching the fully sequenced SARS-CoV-2 genomes deposited in GISAID (https://www.gisaid.org/), 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 ORF1ab1056-1062 identical to its counterpart in PARP1453-59(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 ORF1abVVVNASN 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 ORF1abVVVNASN 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.

cases of hepatitis of unknown, SARS-CoV-2 ORF1ab VVVNASN variants was mostly 1 0 1 detected in the UK (135) and the USA (18) (Fig. 1D ).

In addition to ORF1ab A1061S substitution, several other mutations that would 1 0 3

potentially increase the sequence identity were also identified. For example, 1 0 4

ORF1ab G1073A have been emerging at a relative high frequency ( Fig. 2A, table 1 ).

This mutation led a 11-amino acid motif in ORF1ab (LKHGGGVAAAL) to be more SARS-CoV-2 Delta lineage (Fig. 2B) . Although the Omicron variants were causing 1 1 0 most of the infections globally, an Israel research group has warned that Delta MHC-I molecules, allowing to evaluate the binding potential and usage overlaps of

HLA molecules by high similar peptides from human PARP14 and SARS-CoV2

ORF1ab. We selected a total of 23 amino acid surrounding the identical 7-amino acid 1 2 2

of ORF1ab A1061S and PARP14 as inputs respectively. As expected, we found that the could be presented by a same HLA-A*11:01 molecule with comparable high-affinity 1 2 5 (Fig. 2C) . Importantly, OFR1ab A1061S mutation showed increased binding ability of 1 2 6 this peptide to HLA-A*11:01 molecule, as comparing to its wuhan-hu-1 counterpart 1 2 7 (Fig. 2C) . These findings suggested both the self-and virus-peptides with high 1 2 8 sequence identity could be presented by a same HLA molecule, supporting that specific T-cell clones restricted to an HLA-A*11:01 molecules might be cross- antigen presentation by HLA-A*11:01 were generally applicable to the worldwide. Deregulated T cell responses are common triggers of various autoimmune diseases. Epitope mimicry of host proteins by pathogen is a common inducer in susceptible

individuals to induce biased immune response versus tolerance, leading to tissue

Here we found a mutation in SARS-CoV-2 ORF1ab may lead to 1 3 8 increased identity between pathogen peptides with human proteins, providing a The outbreak of hepatitis of unknown cause was currently restricted to children under Based on that, we anticipated that HLA genotyping may facilitate to uncovering the 1 4 9 real cause of hepatitis. be noteworthy that Delta variants were still circulating in parallel with Omicron However, our results were still preliminary and we only aimed to discussing a We thank GISAID for collecting and sharing the sequences of SARS-CoV-2 globally. processing. The authors declared no conflict of interest. This manuscript was not funded by any sponsors. All of the data was generated from 1 7 4 public available database and did not required ethics committee approval. 155599. genomes possessing A1601S mutation in SARS-CoV-2 OFR1ab VVVNAAN motif. binding predictions were made using the IEDB analysis resource NetMHCpan (ver. 

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