Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which is otherwise known as the coronavirus disease 2019 (COVID-19), continues to pose significant worldwide health and economic effects. There remains an urgent need to better comprehend the intricate relationship between SARS-CoV-2, infected host cells, and the pathophysiology of the disease.
Recent research suggests that transposable elements (TEs) play a crucial role in the host's response to COVID-19 and the development of illness. In a recent study, researchers assess the impact of SARS-CoV-2 infection on endogenous retroviruses of the LTR69 subfamily.
Study
In the present study, researchers examine the effect of SARS-CoV-2 on the expression profiles of TEs in virus-exposed or -infected cells.
To this end, the team investigated publicly available poly(A)-enriched messenger ribonucleic acid (mRNA)-seq data 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 employed to detect TEs with differential expression.
To examine the enhancer activity 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 A549-angiotensin-converting enzyme 2 (ACE2) cells. To determine whether any of the SARS-CoV-2-activated LTR69 repeats elicit regulatory influences, their potential enhancer activities were examined. Five representative candidates were inserted into enhancer reporter vectors.
To explore the mechanisms that may be involved in LTR69-Dup69 activation following SARS-CoV-2 infection, the viral nucleotide sequence was examined for binding sites associated with transcription factors known to be active in infected cells.
Findings
Solo-LTRs found in two human endogenous retroviruses (HERV) subfamilies, LTR103_Mam and LTR69, were considerably up-regulated by SARS-CoV-2 infection. Similarly, A549-ACE2 lung cells infected with SARS-CoV-2 and bronchoalveolar lavage fluid (BALF) obtained from non-deceased and deceased SARS-CoV-2 patients exhibited higher LTR69 expression. In contrast, there was no remarkable enhancement in LTR69 expression in SARS-CoV-2-infected Calu-3 cells or in peripheral blood mononuclear cells (PBMCs) of surviving COVID-19 patients.
The transcription start site (TSS) profile plot over LTR69 loci revealed enrichment of H3K27Ac marks in infected cells as compared to uninfected cells. No considerable enrichment of enhancer marks was observed on the LTR103_Mam loci.
Subsequent investigations were primarily focused on individual LTR69 loci, for which the MACS2 peak calling method detected a minimum of one significant H3K27Ac peak. There were 12 distinct peaks associated with H3K27Ac on 15 LTR69 loci following SARS-CoV-2 infection.
LTR12C_GBP2 boosted the expression of Gaussia luciferase relative to the vector control that lacked an LTR repeat. Dup69 had a comparable boosting impact, while the remaining LTR69 elements exhibited no remarkable modulatory impact or even lowered reporter gene expression.
Dup69 resides in an intron of protein tyrosine phosphatase receptor type N2 (PTPRN2), which is approximately 500 nucleotides upstream of a long non-coding RNA gene called ENSG00000289418, according to an examination of the respective gene locus. PTPRN2 encodes a tyrosine phosphatase receptor that is a significant autoantigen in type 1 diabetes.
In A549-ACE2 and Calu-3 cells, lncRNA expression rose by a factor of 25.2 and 3.6, respectively. In addition, PTPRN2 expression increased by an average of 4.1 times in A549-ACE2 cells following SARS-CoV-2 infection, whereas PTPRN2 mRNA was undetectable in Calu-3 cells.
Interestingly, a previous study discovered the up-regulation of PTPRN2 in whole blood samples of COVID-19 patients. Collectively, these results indicate that SARS-CoV-2 infection activates an LTR69 repeat that responded to interferon regulatory transcription factor (IRF)-3 and p65/RelA functions as an enhancer element and may influence the expression of nearby genes.
Several probable binding sites for nuclear factor kappa B (NF-κB) subunits, signal transducer and activator of transcription 1 (STAT1), and IRF3 were identified. Furthermore, p65/RelA and an active mutant of IRF3, but not STAT1, may augment the LTR69-mediated increase in reporter gene expression. Consistent with the activation of IRF3 and NF-κB upon innate sensing, synthetic double-stranded RNA analog polyI:C dramatically boosted LTR69_Dup69 activity.
Conclusion
The study findings showed the differential expression and activation of distinct mobile genetic elements in response to SARS-CoV-2 infection. Specifically, the team identified and validated the infection-induced upregulation of the LTR69 subfamily of endogenous retroviruses. LTR69-Dup69 was also found to possess enhancer activity and exhibit sensitivity to the transcription factors IRF3 and p65/RelA.
LTR69 is considered a TE that is activated in SARS-CoV-2-infected cells and can regulate host gene expression, thus contributing to the outcome of COVID-19. However, additional research is required to confirm this finding.
Source:
https://www.news-medical.net/news/20230328/COVID-19-activates-endogenous-retroviruses-within-our-genome.aspx