Impaired activation of Transposable Elements in SARS-CoV-2 infection

Abstract

Transposable elements (TEs) are induced in response to viral infections. TEs induction triggers a robust and durable interferon (IFN) response, providing a host defense mechanism. Still, the connection between SARS-CoV-2 IFN response and TEs remained unexplored. Here, we analyzed TE expression changes in response to SARS-CoV-2 infection in different human cellular models. We find that compared to other viruses, which cause global upregulation of TEs, SARS-CoV-2 infection results in a significantly milder TE response in both primary lung epithelial cells and in iPSC-derived lung alveolar type 2 cells. In general, we observe that TE activation correlates with, and precedes, the induction of IFN-related genes, suggesting that the failure to activate TEs may be the reason for the weak IFN response. Moreover, we identify two variables which explain most of the observed diverseness in immune responses: basal expression levels of TEs in the pre-infected cell, and the viral load. Since basal TE levels increase with age, we propose that "TE desensitization" leads to age-related death from COVID19. This work provides a potential mechanistic explanation for SARS-CoV-2s success in its fight against the host immune system, and suggests that TEs could be used as sensors or serve as potential drug targets for COVID-19.

Transcriptome and DNA methylome analysis of peripheral blood samples reveals incomplete restoration and transposable element activation after 3-months recovery of COVID-19

“…Another important supporting evidence is that our analysis of RNA-seq data of acute patients showed activation of the cGAS-STING pathway (see Figure 1B for cGAS upregulation in acute patients) which can be triggered by upregulation of retrotransposon-derived cytoplasmic DNA ( Decout et al, 2021 ). Interestingly, a recent preprint manuscript showed that viral load of SARS-CoV-2 was positively correlated with TE upregulation ( Sorek et al, 2021 ), and this is in agreement with our result that TE activation was positively correlated with COVID-19 severity at the recovery stage. However, the study also showed that TE activation was relatively mild during SARS-CoV-2 infection, and this may be partially explained by the cGAS-STING pathway which can be activated upon SARS-CoV-2 infection and may be responsible for the degradation of cytoplasmic retrotransposon-derived DNA to inactivate retrotransposons.…”

Induction of transposable element expression is central to innate sensing

“…For example, various RNA viruses, including influenza, activate TLR4 (21), and although they do not contain DNA, they can, unexpectedly, activate and/or express inhibitors for the cGAS/STING pathway (62,63). IAV infection has previously been shown to induce LINE1 expression (64,65). We therefore tested the effect of manipulating the mechanism of innate immune amplification, that we have described, on IAV infection.…”

“…also trigger cGAS/STING sensing, and SARS-CoV2 at least has been demonstrated to induce LINE1 expression(65,83). Concordantly, RNA viruses influenza (84), SARS-CoV(85,86), SARS-CoV2 (87), Porcine epidemic diarrhea virus (88), Dengue virus (89), Yellow fever virus (90), Zika virus(91), and Hepatitis C virus (92) all inhibit the cGAS/STING DNA sensing pathway.…”

Human endogenous retroviruses in viral disease and therapy

“…The study revealed that expression of HERV‐W in COVID‐19 patients correlated with disease outcome suggesting utilizing of HERVs as biomarkers for viral infection. Moreover, HERVs were up‐regulated in a human cell line after SARS‐CoV‐2 infection and bronchoalveolar lavage fluid of COVID‐19 patients 40,41 …”

“…Moreover, HERVs were up-regulated in a human cell line after SARS-CoV-2 infection and bronchoalveolar lavage fluid of COVID-19 patients. 40,41…”