A recent study has found that infection with the SARS-CoV-2 virus can activate endogenous retroviruses (ERVs) of the LTR69 subfamily in human cells.
ERVs are remnants of ancient retroviral infections that have become integrated into the genome of their hosts. They make up a significant proportion of the human genome, and while most are thought to be inactive, some have been shown to retain their ability to express viral proteins and even generate infectious particles.
The LTR69 subfamily of ERVs has been linked to various diseases, including cancer, autoimmune disorders, and neurological conditions. The exact mechanisms by which they contribute to disease pathogenesis are not fully understood, but they are thought to have immunomodulatory effects and may activate inflammatory responses.
In the new study, researchers investigated whether SARS-CoV-2 infection could induce the expression of LTR69 ERVs in human cells. They found that infection with the virus led to a significant upregulation of LTR69 expression, both in vitro and in vivo.
Further analysis revealed that the LTR69 ERVs induced by SARS-CoV-2 were able to activate the expression of nearby genes, including those involved in the immune response and inflammation. This suggests that the activation of LTR69 ERVs may contribute to the dysregulated immune response seen in severe cases of COVID-19.
The researchers also found that treatment with the antiviral drug remdesivir, which is used to treat COVID-19, reduced the expression of LTR69 ERVs in infected cells. This suggests that targeting the expression of these retroviruses could be a potential therapeutic strategy for COVID-19.
The study provides important insights into the complex interactions between viruses and host genomes. It highlights the potential for viruses to activate latent retroviruses, which may have important implications for disease pathogenesis.
Overall, the findings suggest that the activation of LTR69 ERVs may contribute to the dysregulated immune response seen in severe cases of COVID-19.
Reference link : https://doi.org/10.1101/2023.03.21.533610;
In-depth analysis ….
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the COVID-19 pandemic, has caused unprecedented global health and socioeconomic impacts. With billions of infections and millions of reported deaths worldwide, there is a pressing need to better understand the complex interplay of SARS-CoV-2 with infected host cells and the pathogenesis of the disease.
Recent studies have suggested that repetitive DNA sequences known as transposable elements (TEs) play an essential role in the host response to viral infection and the development of disease. For instance, some TEs are capable of regulating the expression of antiviral factors and other host proteins through their activity as enhancers or promoters [1,2].
Furthermore, TE-derived nucleic acids may be sensed by cellular pattern recognition receptors and thereby amplify innate sensing cascades and the induction of Interferon-mediated immune responses . In line with a potential role in the outcome of viral infections, viruses such as the Human Immunodeficiency Virus (HIV), Human Cytomegalovirus (HCMV) or Influenza A Virus (IAV) trigger the activation of transposable elements that are otherwise silenced [2,4–6].
Here, we leverage publicly available transcriptome and chromatin datasets of infected cell lines and patient-derived samples to decipher the impact of SARS-CoV-2 on the TE expression profiles of virus-infected or -exposed cells. Several studies have reported an induction of HERV-K [7–9], HERV-W [10,11] or HERV-L [12–16] upon SARS-CoV-2 infection.
In line with this, we found that SARS-CoV-2 infection induces the activation of a particular subset of endogenous retroviruses (ERVs), so-called LTR69 repeats. These long terminal repeats (LTRs) represent solo-LTRs of the HERV-L family of endogenous retroviruses. In contrast to previous studies, we also performed mechanistic analyses and identified a SARS-CoV-2-responsive LTR69 repeat that acts as an enhancer and is activated by IRF3 and p65/RelA, two transcription factors that are activated upon sensing of viral RNA.
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Transposable elements (TEs) are DNA sequences that have the ability to move or “transpose” from one location in the genome to another. They make up a significant proportion of the human genome, with some estimates suggesting that they comprise up to 50% of the total DNA content.
While TEs were originally thought to be “junk” DNA with no functional significance, research over the past few decades has revealed that they play a critical role in a variety of biological processes, including gene regulation, chromatin structure, and genome evolution.
Recent studies have also shown that TEs can play an important role in the host response to viral infection and the development of disease. For example, TEs have been shown to:
- Trigger innate immune responses: Certain TEs, such as endogenous retroviruses (ERVs), can activate the innate immune system by inducing the production of type I interferons and other cytokines. This response can help to limit viral replication and spread.
- Modulate gene expression: TEs can insert into or near genes, leading to changes in gene expression. This can result in the upregulation or downregulation of genes involved in the immune response, inflammation, and other processes related to viral infection and disease.
- Provide a source of genetic diversity: TEs can create genetic diversity by inserting into new locations in the genome. This can lead to the generation of new protein-coding genes, the modification of existing genes, and the formation of new regulatory elements.
- Contribute to the development of cancer: TEs can disrupt the normal functioning of genes involved in cell growth and division, leading to the development of cancer. For example, the activation of certain TEs, such as LINE-1, has been linked to the development of several types of cancer.
Overall, these findings highlight the importance of TEs in the host response to viral infection and the development of disease. Further research is needed to fully understand the mechanisms underlying these processes and to explore the potential for targeting TEs as a therapeutic strategy for viral infections and related diseases.