COVID-19 activates endogenous retroviruses within our genome

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*Important note: bioRxiv It publishes preliminary scientific reports that have not been peer-reviewed and therefore should not be considered conclusive, directing clinical practice/health-related behaviour, or treated as hard information.

Coronavirus disease 2 (SARS-CoV-2) and severe acute respiratory syndrome, commonly known as coronavirus disease 2019 (COVID-19), continue to cause significant health and economic impacts worldwide. There is still an urgent need to better understand the complex relationship between SARS-CoV-2 and infected host cells and the pathophysiology of the disease.

Recent research indicates that transmissible elements (TEs) play an important role in the host response to COVID-19 and disease progression. In a recent study published in bioRxiv* Preprint server, researchers evaluate the impact of SARS-CoV-2 infection on endogenous retroviruses of the LTR69 subfamily.

Study: SARS-CoV-2 infection activates endogenous retroviruses of the LTR69 subfamily.  Image credit: Numstocker/Shutterstock.com

Stady: SARS-CoV-2 infection activates endogenous retroviruses of the LTR69 subfamily. Image credit: Numstocker/Shutterstock.com

about studying

In this study, the researchers examined the effect of SARS-CoV-2 on the expression profiles of TEs in cells exposed to or infected with the virus.

To this end, the team investigated publicly available data on poly(A)-enriched ribonucleic acid (mRNA) from cell lines and COVID-19 patients to determine the impact of COVID-19 on TE activity. Initially, data collected from SARS-CoV-2-infected and uninfected Calu-3 cells were used to detect TEs with differential expression.

To examine the activity of the enhancer of long terminal repeat (LTR)-103 and LTR69 in the absence and presence of SARS-CoV-2, the team analyzed publicly available ChIP-seq data associated with Histone H3 Lysine 27. acetylation (H3K27ac) in angiotensin-converting enzyme 2 (ACE2) A549 cells. To determine whether any of the SARS-CoV-2-activated LTR69 replicates regulatory effects, their potential reinforcing activities were examined. Five of the represented candidates were inserted into the enhanced reporter vector.

To investigate mechanisms that may be involved in the activation of LTR69-Dup69 after SARS-CoV-2 infection, viral nucleotide sequences of binding sites associated with transcription factors known to be active in infected cells were examined.

results

Single LTRs present in two endogenous retrovirus (HERV) subfamilies, LTR103_Mam and LTR69, were significantly upregulated by SARS-CoV-2 infection. Similarly, A549-ACE2 lung cells infected with SARS-CoV-2 and bronchoalveolar lavage fluid (BALF) obtained from non-morbid and deceased SARS-CoV-2 patients showed higher expression of LTR69. In contrast, there was no significant improvement in LTR69 expression in SARS-CoV-2-infected Calu-3 cells or in peripheral blood mononuclear cells (PBMCs) of surviving COVID-19 patients.

A transcription start site profile (TSS) plot on the LTR69 site revealed an enrichment of H3K27Ac markers in infected cells compared to uninfected cells. No significant enrichment of enhancer markers was observed in LTR103_Mam loci.

Subsequent investigations focused mainly on individual LTR69 sites, where the MACS2 peak calling method detected a minimum of one large H3K27Ac peak. There were 12 distinct H3K27Ac-associated peaks on 15 LTR69 loci after SARS-CoV-2 infection.

LTR12C_GBP2 enhanced the expression of Gaussia luciferase relative to vector control lacking an LTR repeat. Dup69 had a similar enhancing effect, while the remaining LTR69s showed no significant modulating effect or even decreased reporter gene expression.

Dup69 is located in an intron of the protein tyrosine phosphatase receptor type N2 (PTPRN2), which is approximately 500 nucleotides upstream of a long noncoding RNA gene called ENSG00000289418, as determined by an examination of the locus of the respective gene. PTPRN2 encodes a receptor tyrosine phosphatase that is an important autoexpressor in type 1 diabetes.

In A549-ACE2 and Calu-3 cells, lncRNA expression increased by factors of 25.2 and 3.6, respectively. In addition, PTPRN2 expression increased by 4.1-fold in A549-ACE2 cells after infection with SARS-CoV-2, while PTPRN2 mRNA was undetectable in Calu-3 cells.

Interestingly, a previous study detected up-regulation of PTPRN2 in whole blood samples of COVID-19 patients. Collectively, these results indicate that SARS-CoV-2 infection activates LTR69 repeat that responded to interferon regulatory transcription factor (IRF)-3 and p65/RelA functions as an enhancer and may influence the expression of nearby genes.

Several potential binding sites for nuclear factor kappa B (NF-κB), signal transducer and activator of transcription 1 (STAT1) and IRF3 subunits have been identified. Furthermore, p65/RelA and its active mutant of IRF3, but not STAT1, may further increase LTR69-mediated increase in reporter gene expression. Consistent with the activation of IRF3 and NF-κB upon innate sensing, the synthetic double-stranded RNA analog polyI:C significantly enhanced the activity of LTR69_Dup69.

conclusions

The results of the study demonstrated the differential expression and activation of distinct mobile genetic elements in response to SARS-CoV-2 infection. Specifically, the team identified and validated infection-induced regulation of the LTR69 subfamily of endogenous retroviruses. It was also found that LTR69-Dup69 possesses an enhancer activity and shows sensitivity to the transcription factors IRF3 and p65/RelA.

LTR69 is a TE that is activated in cells infected with SARS-CoV-2 and can regulate host gene expression, thus contributing to the outcome of COVID-19. However, more research is needed to confirm this finding.

*Important note: bioRxiv It publishes preliminary scientific reports that have not been peer-reviewed and therefore should not be considered conclusive, directing clinical practice/health-related behaviour, or treated as hard information.

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