Researchers from the University of Chinese Academy of Sciences in Shanghai and the Guangzhou Laboratory in China have found evidence that the current cases of children developing hepatitis may be linked to past or current infections with specific variants of the SARS-CoV-2 virus that contain the A1061S mutation on the ORF1ab proteins, which can trigger an autoimmune T cell response through epitope mimicry and ultimately attack the liver.
The World Health Organization has declared an outbreak of acute, severe hepatitis in children due to an unknown source in the midst of a COVID-19 pandemic. It’s still unclear whether it’s linked to the SARS-CoV-2 infection.
The SARS-CoV-2-Pediatric Hepatitis study group conducted a genomic sequence alignment analysis of the SARS-CoV-2 (Wuhan-hu-1) genome to the human genome reference.
SARS-CoV-2 ORF1ab1056-1173 has a lot of similarities with the human protein PAPR1453-176(3Q6Z A), according to detailed sequence analysis.
The study team discovered 170 SARS-CoV-2 variants with mutations in ORF1ab1061, where alanine (A) was replaced by serine (S), after carefully searching the completely sequenced SARS-CoV-2 genomes deposited in GISAID.
Surprisingly, this change made a 7-amino-acid peptide (VVVNASN) in ORF1ab1062 identical to its PARP1453-59(3Q6Z A) counterpart.
HLA prediction suggested that peptides with high identities in PARP14 and ORF1ab might be presented by the same HLA-A*11:01 molecule, which is widely distributed.
SARS-CoV-2 ORF1abVVVVNASN variants were largely identified as Delta lineages in the UK by late 2021, with an overall frequency of 0.00161 percent, in line with the first recorded case of unexplained hepatitis.
As a result of the preliminary findings, it’s possible that infection with the SARS-CoV-2 ORF1abVVVNASN variation elicits an autoimmune T cell response via epitope mimicry and is linked to an unexplained hepatitis outbreak.
The researchers hope that by publishing these findings, the academic and medical communities will be more aware of unusual mutations outside of spike proteins.
The findings of the study were posted on a preprint server and are currently undergoing peer review.
It should be underlined that T cell responses are necessary for both viral infection and SARS-CoV-2 infection.
Virus elimination typically results in persistent T cell pools that process multiple TCR repertoires to virus-related antigens, providing protection against subsequent infections by the same virus.
These T cells are usually kept in check and do not attack human tissue. In some cases, however, viral infection resulted in immunological disorders and autoimmune illnesses, which were linked to a disruption in peripheral tolerance.
Severe immunological disturbances have been observed in SARS-CoV-2 infections.
This raises the possibility that peripheral T cells may not have been able to tolerate their environment well.
The research team expected that virus mutations would produce new antigens that mirrored self-peptides and provoked an autoimmune response to appropriate inflammatory microenvironments, resulting in the emergence of hepatitis of unknown origin.
To test the notion, the researchers used PSI-blast with default parameters to align the complete genome of SARS-CoV-2 76 (wh-hu-1) to the human reference genome. Out of all the SARS-CoV-2 proteins that were aligned, only one hit was found in ORF1ab (ORF1ab1056–1173), which was very similar to a sequence in human PARP14 (PARP1453–176, sequence ID: 3Q6Z A).
Surprisingly, the most similar peptide was found in a motif with seven amino acid residues, with only one amino acid difference between ORF1ab1061 and PARP1458.
PAPR1462-75 (sequence ID: 3Q6Z A) also had a high degree of similarity with ORF1ab1065-1078.
SARS-CoV-2 (wuhan-hu-1) has undergone multiple changes since its first sequencing was published in December of this year.
Infectivity, illness severity, or interactions with host immunity may change as the SARS-CoV-2 genome accumulates mutations.
It’s fair to believe that some SARS-CoV-2 variants have mutations in ORF1ab1056-1062, resulting in a higher level of similarity to human PARP1453-59 (3Q6Z A).
To test this theory, the researchers used GISAID to download the proteins of SARS-CoV-2 92 variants.
In-depth sequencing analysis was concentrated on the portion of the ORF1a protein including the amino acid sequence from position 1055 to 1077. By May 10, 2022, 170 of the SARS-CoV-2 protein sequences (out of a total of 10,541,935) had an alanine (A) to serine (S) change at site 1061 of ORF1ab.
Intriguingly, this change made the primary sequences of the amino acids identical to the human PARP1453-59 (3Q6Z A) sequence.
After further investigation, it was discovered that SARS-CoV-2 ORF1abVVVNASN variations had been documented in 15 countries spread over five continents. The frequency of the variations varied by country, with a global average of 0.00161 percent.
SARS-CoV-2 ORF1abVVVVNASN variations were predominantly identified in the UK (135) and the USA (18), which is consistent with the first reported cases of hepatitis of unknown origin.
In addition to the ORF1abA1061S change, numerous other mutations that have been reported have the potential to increase the sequence identity. ORF1abG1073A, for example, has been appearing with increasing frequency. When compared to human PARP14 (LKHYGGLAAAL), this mutation caused an 11-amino acid motif in ORF1ab (LKHGGGVAAAL) to have greater chemical characteristics.
The 170 ORF1ab variations with the A1061S mutation were also added to the Variants of Concern (VOC) list, with the majority of mutational variants detected in the SARS-CoV-2 Delta lineage.
Although Omicron variants were responsible for the majority of illnesses worldwide, an Israeli research group warned that Delta variants were still spreading in parallel to Omicron variations and could continue to do so in the future.
T cells identified peptides provided by a distinct array of HLA molecules, indicating possible HLA overlaps in binding human and viral peptides. Thus, HLA overlapping was a prerequisite for epitope mimicry-induced cross T cell reactivities.
The researchers 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 them to assess the binding potential and HLA molecule usage overlaps by highly similar peptides from human PARP14 and SARS-CoV2 ORF1ab.
As inputs, the researchers chose a total of 23 amino acids surrounding the identical 7-amino acid of ORF1abA1061S and PARP14.
The researchers discovered that the peptide VVNASNELK in human PARP14 and VVNASNVYK in ORF1ab A1061S could both be presented by a single HLA-A*11:01 molecule with comparable high affinity, as expected.
In comparison to its Wuhan-hu-1 counterpart, the OFR1abA1061S mutation improved the peptide’s ability to attach to the HLA-A*11:01 molecule.
The findings reveal that a single HLA molecule might display both self-and viral peptides with high sequence identity, implying that virus peptide mimicry could cross-activate particular T-cell clones restricted to HLA-A*11:01 molecules, resulting in autoimmune responses.
HLA132 A11:01 is one of the most common HLAs in the world, implying that virus antigen presentation by HLA-A11:01 is universally applicable.
Many types of autoimmune disorders are characterized by abnormal T cell responses that have been dysregulated. In susceptible people, epitope mimicry of host proteins by pathogens is a common inducer of biased immune response vs tolerance, resulting in tissue damage.
So, the study team found that a mutation in SARS-CoV-2 ORF1ab may increase the similarity between pathogen peptides and human proteins. This provides computational evidence for understanding the main cause of SARS-CoV-2-related autoimmune diseases. It also gives us a new way of thinking about outbreaks of pediatric hepatitis with unknown causes that have been happening during the SARS-CoV-2 pandemic.
The unknown-cause hepatitis outbreak was currently limited to children under the age of 16. It’s worth noting that in children, thymus output is held in reserve, T cell repertoires are constantly evolving, and peripheral tolerance is still developing.
The disruption of the systemic and local immunological milieu caused by SARS-CoV2 infection is likely to have hampered the development of normal T cell tolerances, which could explain why children prefer this type of hepatitis.
Some alterations will improve the sequence identity between ORF1ab1065-1078 and PAPR1462-75 (3Q6Z A), according to the researchers. The majority of the variations with the A1061S alteration belonged to the Delta lineage, and Delta variants are still circulating alongside Omicron variants.
“Mutations in these sites should call for our great concerns,” said Professor Dr Yu Wang of the Shanghai Institute of Nutrition and Health at the University of Chinese Academy of Sciences-Shanghai. “However, our results are still preliminary and we only aimed to discuss a possible association of SARS-CoV-2 infection with children’s 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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