Impaired activation of transposable elements in SARS‐CoV‐2 infection

Abstract

Emerging evidence shows that transposable elements (TEs) are induced in response to viral infections. This TE induction is suggested to trigger a robust and durable interferon response, providing a host defense mechanism. Here, we analyze TE expression changes in response to SARS‐CoV‐2 infection in different human cellular models. Unlike other viruses, SARS‐CoV‐2 infection does not lead to global upregulation of TEs in primary cells. We report a correlation between TEs activation and induction of interferon‐related genes, suggesting that failure to activate TEs may account for the weak interferon response. Moreover, we identify two variables that explain most of the observed diverseness in immune responses: basal expression levels of TEs in the pre‐infected cells and the viral load. Finally, analyzing the SARS‐CoV‐2 interactome and the epigenetic landscape around the TEs activated following infection, we identify SARS‐CoV‐2 interacting proteins, which may regulate chromatin structure and TE transcription. This work provides a possible functional explanation for SARS‐CoV‐2 success in its fight against the host immune system and suggests that TEs could serve as potential drug targets for COVID‐19. image Unlike other viruses, SARS‐CoV‐2 fails to globally upregulate TEs, and this failure may contribute to the weak IFN response induced by SARS‐CoV‐2. SARS‐CoV‐2 interacts with several chromatin modifiers that regulate histone marks around TEs, providing a potential explanation for the weak IFN response. Unlike other viruses, SARS‐CoV‐2 invokes a weak and inefficient transposable element (TE) response. TE induction precedes and predicts IFN response. SARS‐CoV‐2 induces distinct chromatin and enhancer binding profile on TEs.