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 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

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[12].

Here we 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 children hepatitis of unknown cause under a background of SARS-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 was kept in stack, T cell repertoires were continuously making, and peripheral tolerance was under establishing [13].

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. Based on that, we anticipated that HLA genotyping may facilitate to uncovering the real cause of hepatitis.

According to the fully sequenced genomes deposited in GISAID, the frequency of SARS-CoV-2 ORF1ab^VVVNASN variants was around 0.0000161. Among 517,648,631 confirmed SARS-CoV-2 cases by 15, May 2022 (https://covid19.who.int/), it was roughly estimated that 8334 people, irrespective of children or adults, might be subjected to risks of autoimmune T cell responses and possibly the hepatitis of unknown cause. However, other unknown factors may also participate to exacerbate disease morbidity and severity, and indeed we have 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 noteworthy that Delta variants were still circulating in parallel with Omicron variants[11].

Thus, mutations in these sites should call for our great concerns. However, our results were 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 was urgently needed to figure out the nature of hepatitis of unknown cause.