Dysregulated retroelements associated with autoimmunity in COVID-19

By Sam HancockApr 12 2022Reviewed by Benedette Cuffari, M.Sc.

The coronavirus disease 2019 (COVID-19) causes a wide variety of symptoms, with the vast majority of individuals suffering from a mild flu-like disease. Unfortunately, a subset of vulnerable individuals is at risk of experiencing more severe symptoms that can culminate in organ failures and death.

This risk of severe COVID-19 can be exacerbated by the disease’s autoimmune pathology, which can cause significant dysregulation of the immune system. In a recent BMC Genomic Data study, researchers investigate potential interactions between retro-elements shared between the human and coronavirus genomes.

Study: SARS-CoV-2 and human retroelements: a case for molecular mimicry? Image Credit: Immersion Imagery / Shutterstock.com

Background

Long interspersed nuclear elements (LINE) belong to the long terminal repeat negative retrotransposons in the human genome. Moreover, LINEs, which comprise about 20% of the human genome, can move and repeat themselves using reverse transcriptase and an endonuclease.

While most of these sequences are inactivated, viral infection has been known to reactivate these otherwise dormant sequences. Given the prevalence of coronaviruses, the researchers of the current study were interested in investigating the relationship and similarity between members of the coronavirus family and human retro-elements.

Study findings

The examined genomes harbored a large number of sequences identical to human retro-elements (RE), several of which were shared RE-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epitopes. The antibodies against some of these epitopes are correlated to the severity of the coronavirus disease 2019 (COVID-19), with RE expressed in healthy controls and deregulated in COVID-19 patients and infected cells.

Sequence alignment of human RE sequences and different CoV genomes were observed between human RE sequences and genomes from SARS-CoV-2, SARS-CoV-1, and the Middle East respiratory syndrome coronavirus (MERS-CoV), NL63, 229E, OC43, HKU1, bat CoV RA13591, bat CoV RATG13 and bat CoV RSSHC014. Any sequence over or equal to 18 base pairs (bp) of length was considered ineligible due to issues with downstream analysis.

The vast majority of RE-identical sequences at this level were observed in HKU1 (332), NL63 (206), and SARS-CoV-2 (191). RE and SARS-CoV-2 sequence data were also investigated using the LAST software to include single nucleotide polymorphisms, which revealed even more shared sequences.

RE-identical sequences were then compared to coding regions in the SARS-CoV-2 genome, thus revealing 70 identical amino acid sequences. Comparing these to peptide array results from epitope signatures in severe and mild COVID-19 patients, the researchers observed an overlap of human LINE1 proteins to SARS-CoV-2 epitopes from the ribonucleic acid (RNA) dependent RNA polymerase (Rdrp), which was present for epitopes with greater than two-fold increase in antibody levels in severe cases.

Antibodies for the RdRp polymerase epitope, which were identical to a LINE1 open reading frame 2p (ORF2p) endonuclease epitope, were 39-fold elevated in antibody levels in severe cases. Similar results were observed with antibodies targeting the shared RE epitopes from the 2-O-ribose methyltransferase and helicase. While many of the shared epitopes were not targeted by antibodies, some are known as T-cell epitopes.

COVID-19 patient data, SARS-CoV-2 infected lung cells, and SARS-CoV-2 infected macrophages were then analyzed to investigate any changes in RE expression after infection. All samples showed deregulation of human RE by significant margins.

Transcriptome data showed an upregulation of 2,035 RE and a downregulation of 3,144 RE, with LINE1 among the most deregulated. Data from infected epithelial lungs showed similar results, with 34 up and 29 downregulated RE.

Conclusions

The authors conclude that they have successfully revealed the presence of short RE-identical sequences in different coronavirus genomes, including SARS-CoV-2, and that some of the sequences correspond to epitopes correlating to COVID-19 severity. Additionally, RE was found to be expressed in COVID-19 patients and become dysregulated following infection with SARS-CoV-2, which can cause severe changes in LINE1 expression. Autoantibodies against LINE1 could further the autoimmune pathology reported in severe COVID-19 patients.