BREAKING! Chinese Study Indicates That Hepatitis In Children Could Be Due To Autoimmune T Cell Response Triggered By SARS-CoV-2 ORF1ab A1061S Mutation!

SARS-CoV-2-Pediatric Hepatitis: A new study by researchers from the the University of Chinese Academy of Sciences, Shanghai-China and the Guangzhou Laboratory-China indicates that the current caseloads of children developing hepatitis could be due to past or present infections with particular variants of the SARS-CoV-2 virus that contains the A1061S mutation on the ORF1ab proteins which is able to trigger an autoimmune T cell response via epitope mimicry that ends up attacking and destroying liver tissues.


 
The WHO or 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 debate.
 
The SARS-CoV-2-Pediatric Hepatitis study team performed genomic sequence alignment analysis of the genome of SARS-Cov-2 (Wuhan-hu-1) to the human genome reference.
 
Detailed sequence analysis revealed that the SARS-CoV-2 ORF1ab^1056-1173 presented high identities with the human protein PAPR14^53-176(3Q6Z_A).
 
Upon carefully searching the fully sequenced SARS-CoV-2 genomes deposited in GISAID (https://www.gisaid.org/), the study team detected 170 SARS-CoV-2 variants with mutation in ORF1ab¹⁰⁶¹, where alanine (A) was substituted by serine (S).
 
Interestingly, 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.
 
Importantly, 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%.
 
Hence the preliminary study findings 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.
 
The study team anticipates that these study findings will alert the research and medical communities to pay more attention to rare mutations beyond the spike proteins.
 
The study findings were published on a preprint server and are currently being peer reviewed. https://www.biorxiv.org/content/10.1101/2022.05.16.491922v2
 
It should be noted that T cell responses are critically important to eliminate virus infection and also for SARS-CoV-2.
 
Typically, the elimination of virus finally results in a persistent T cell-pools that processing diverse T cell receptor (TCR) repertoires to virus related antigens, thus leaving a protection for the secondary infections by the same virus.
 
In most cases, these T cells are kept in check and d o not attack human tissues. However, in some cases, virus infection led to immune disorders and caused autoimmune diseases, which were related to the disturbed peripheral tolerance.
 
In the cases of SARS-CoV-2 infections, severe immune perturbations have been noted. https://pubmed.ncbi.nlm.nih.gov/32726150/
 
This raises thus the possibilities that impaired peripheral T cell tolerance could have occurred.
 
The stud team hypothesized that virus mutations might generate new antigens that mimicked self-peptides and elicited an autoimmune response in appropriate inflammatory microenvironments, and thus associated with the emerging of hepatitis of unknown cause.
 
In order to test the hypothesis above, the study team made a whole-genome alignment of SARS-CoV-2 76 (wh-hu-1) to the human reference genome with PSI-blast in default parameters. Among all the SARS-CoV-2 proteins aligned, only a hit in ORF1ab (ORF1ab^1056-1173 ) was found, which presented high identity with a sequence in human PARP14 (PARP14^53-176, sequence ID: 3Q6Z_A).
 
Interestingly, the most identical peptide was located in a motif with 7 amino acids residuals, in which only a differential amino acid was found in ORF1ab¹⁰⁶¹ comparing to PARP14⁵⁸.
 
In addition, PAPR14^62-75(sequence ID: 3Q6Z_A) also shared high identity with ORF1ab^1065-1078.
 
It has been found that since the debut of the first sequence of SARS-CoV-2 (wuhan-hu-1) in December 2019, the virus has undergone numerous mutations.
 
The accumulation of mutations in the genome of SARS-CoV-2 will affect functional properties and may alter infectivity, disease severity or interactions with host immunity.
 
It is reasonable to speculate that there might be some SARS-CoV-2 variants with mutations occurring in ORF1ab^1056-1062, thus resulting in an increased identity to human PARP14^53-59 (3Q6Z_A).
 
In order to test that hypothesis, the study team downloaded the proteins of SARS-CoV-2 92 variants deposited on GISAID.
 
Detailed sequence analysis was focused on the amino acid sequence from 1055 to 1077 of the ORF1a protein. Among all the SARS-CoV-2 protein sequences (10,541,935 in total, by May 10^th 2022), 170 possessed an alanine (A) to serine (S) substitution on the site 1061 of ORF1ab.
 
Noteworthily, this alteration made the core amino acid sequences identical to that of human PARP14^53-59 (3Q6Z_A).
 
Subsequent analysis revealed that SARS-CoV-2 ORF1ab^VVVNASN variants has been recorded in 15 countries across 5 continents. The variants varied by countries with an overall frequency of 0.00161% worldwide.
 
Consistent with the firstly reported cases of hepatitis of unknown origin, SARS-CoV-2 ORF1ab^VVVNASN variants was mostly detected in the UK (135) and the USA (18).
 
In addition to ORF1ab^A1061S substitution, several other mutations that would potentially increase the sequence identity were also identified. For example, ORF1ab^G1073A have been emerging at a relative high frequency. This mutation led a 11-amino acid motif in ORF1ab (LKHGGGVAAAL) to be more similar in chemical properties, comparing to human PARP14 (LKHYGGLAAAL).
 
Also, the 170 variants bearing A1061S mutation in ORF1ab were also annotated to the Variants of Concern (VOC) and most of mutational variants are found within SARS-CoV-2 Delta lineage.
 
Although the Omicron variants were causing the most of the infections globally, an Israel research group has warned that Delta variants were still undergoing circulating in parallel to Omicron variants and might still maintain its circulation in future. https://pubmed.ncbi.nlm.nih.gov/35504376/
 
HLA prediction suggested potential overlaps of HLA in binding human and virus peptides T cells recognized peptides presented by specific array of HLA molecules. Thus, HLA overlapping was a pre-determinant for cross T cell reactivities induced by epitope mimicry.
 
The study team used an online HLA binding prediction tool (https://tools.iedb.org/mhcii/) to predict peptide binding abilities by a default array of 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.
 
The study team selected a total of 23 amino acid surrounding the identical 7-amino acid of ORF1ab^A1061S and PARP14 as inputs respectively.
 
As anticipated, the study team found that the peptide VVNASNELK in human PARP14 and VVNASNVYK in ORF1ab ^A1061S could be presented by a same HLA-A*11:01 molecule with comparable high-affinity.
 
Importantly, OFR1ab^A1061S mutation showed increased binding ability of this peptide to HLA-A*11:01 molecule, as comparing to its wuhan-hu-1 counterpart.
 
The study findings suggest that both the self- and virus- peptides with high 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 activated by virus peptides mimicry and led to autoimmune responses.
 
The HLA132 A*11:01 is one of the most prevalent HLAs across the world, suggesting virus 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 damage. https://pubmed.ncbi.nlm.nih.gov/9107563/
 
The study team hence found a mutation in SARS-CoV-2 ORF1ab may lead to increased identity between pathogen peptides with human proteins, providing a computational evidence for understanding the leading cause of SARS-CoV-2 associated autoimmune diseases, and also provided a new thought on the outbreaks of pediatric hepatitis of unknown cause under a background of the ongoingSARS-CoV-2 pandemic.
 
The outbreak of hepatitis of unknown cause was currently restricted to children under 16 years old. It should be noted that in children, their thymus output is kept in stack, T cell repertoires are continuously making, and peripheral tolerance are under establishing. https://pubmed.ncbi.nlm.nih.gov/32169378/
 
The disturbance of systematic and local immune microenvironment by SARS-CoV2 infection was likely to affect the establishment of normal T cell tolerances, thus possibly explained the preference of children to this type of hepatitis.
 
The study team noted some mutations will increase the sequence identity between ORF1ab^1065-1078 and PAPR14^62-75 (3Q6Z_A). Most of the variants bearing A1061S substitution were in Delta lineage, and it should be noted that Delta variants are still circulating in parallel with Omicron variants.
 
Professor Dr Yu Wang from the Shanghai Institute of Nutrition and Health at the University of Chinese Academy of Sciences-Shanghai told Thailand Medical News, “Mutations in these sites should call for our great concerns. However, our results are still preliminary and we only aimed to discussing a possible association of SARS-CoV-2 infection with children acute hepatitis of unknown cause. Further experimental validation of this hypothesis presented here is urgently needed to figure out the nature of hepatitis of unknown cause.”
 
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