Exogenous Coronavirus Interacts With Endogenous Retrotransposon in Human Cells

Abstract

There is an increased global outbreak of diseases caused by coronaviruses affecting respiratory tracts of birds and mammals. Recent dangerous coronaviruses are MERS-CoV, SARS-CoV, and SARS-CoV-2, causing respiratory illness and even failure of several organs. However, profound impact of coronavirus on host cells remains elusive. In this study, we analyzed transcriptome of MERS-CoV, SARS-CoV, and SARS-CoV-2 infected human lung-derived cells, and observed that infection of these coronaviruses all induced increase of retrotransposon expression with upregulation of TET genes. Upregulation of retrotransposon was also observed in SARS-CoV-2 infected human intestinal organoids. Retrotransposon upregulation may lead to increased genome instability and enhanced expression of genes with readthrough from retrotransposons. Therefore, people with higher basal level of retrotransposon such as cancer patients and aged people may have increased risk of symptomatic infection. Additionally, we show evidence supporting long-term epigenetic inheritance of retrotransposon upregulation. We also observed chimeric transcripts of retrotransposon and SARS-CoV-2 RNA for potential human genome invasion of viral fragments, with the front and the rear part of SARS-CoV-2 genome being easier to form chimeric RNA. Thus, we suggest that primers and probes for nucleic acid detection should be designed in the middle of virus genome to identify live virus with higher probability. In summary, we propose our hypothesis that coronavirus invades human cells and interacts with retrotransposon, eliciting more severe symptoms in patients with underlying diseases. In the treatment of patients with coronavirus infection, it may be necessary to pay more attention to the potential harm contributed by retrotransposon dysregulation.

Reverse-transcribed SARS-CoV-2 RNA can integrate into the genome of cultured human cells and can be expressed in patient-derived tissues

“…In some cases, the resulting chimeric cDNAs were integrated without the generation of a target site duplication ( 29 ). A recent study has also suggested that the interaction between coronavirus sequences and endogenous retrotransposon could be a potential viral integration mechanism ( 40 ).…”

“…Endogenous LINE1 elements have been shown to be expressed in aged human tissues ( 35 ) and LINE1-mediated somatic retrotransposition is common in cancer patients ( 36 , 37 ). Moreover, expression of endogenous LINE1 and other retrotransposons in host cells is commonly up-regulated upon viral infection, including SARS-CoV-2 infection ( 38 – 40 ).…”

SARS-CoV-2-Host Chimeric RNA-Sequencing Reads Do Not Necessarily Arise From Virus Integration Into the Host DNA

“…Human-SARS-CoV-2 Chimeric Reads in RNA-seq Libraries of SARS-CoV-2 Infected Cell Lines Chimeric reads between human and SARS-CoV-2 RNA have been identified in RNA-seq data from infected cells in two recent studies (Zhang et al, 2020;Ying et al, 2021), presumed to be transcribed from reversed transcribed SARS-CoV-2 RNA integrated into the host DNA. To confirm these findings and exclude alternative origins of virus-host chimeric reads, we analyzed public RNA-seq datasets of cells infected with unrelated RNA viruses or SARS-CoV-2, and lung samples from a coronavirus disease 2019 (COVID-19) patient and a healthy control, using a standard pipeline, also used in the previous studies (Zhang et al, 2020;Ying et al, 2021).…”

“…Since detection of such chimeric reads in RNA-seq data would require transcription of the somatic integration, it would likely underestimate the total number of integrations. The high frequency of expressed somatic SARS-CoV-2 integrations reported (Zhang et al, 2020;Ying et al, 2021) was, therefore, unexpected. However, the majority of chimeric human-SARS-CoV-2 RNA reads may have a different origin.…”

“…Moreover, the substantially higher contribution of exonic than intronic or intergenic host sequences to human-SARS-CoV-2 chimeric reads is consistent with formation during RNA-seq library preparation, where exonic sequences are overrepresented relative to intronic or intergenic sequences. Detection of chimeric reads between SARS-CoV-2 RNA and human RNA is one of several distinct methods previously employed to estimate somatic SARS-CoV-2 integration (Zhang et al, 2020;Ying et al, 2021). Given its dependency on transcription of integrated SARS-CoV-2 cDNA, in addition to the integration step itself, it is likely to be the least sensitive.…”