SARS-CoV-2 infection severity and mortality is modulated by repeat-mediated regulation of alternative splicing
ABSTRACT Like single-stranded RNA viruses, SARS-CoV-2 hijacks the host transcriptional machinery for its own replication. Numerous traditional differential gene expression-based investigations have examined the diverse clinical symptoms caused by SARS-CoV-2 infection. The virus, on the other hand, a...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2023-10-01
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| Series: | Microbiology Spectrum |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/spectrum.01351-23 |
| _version_ | 1797658242207186944 |
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| author | Priyanka Mehta Partha Chattopadhyay Varsha Ravi Bansidhar Tarai Sandeep Budhiraja Rajesh Pandey |
| author_facet | Priyanka Mehta Partha Chattopadhyay Varsha Ravi Bansidhar Tarai Sandeep Budhiraja Rajesh Pandey |
| author_sort | Priyanka Mehta |
| collection | DOAJ |
| description | ABSTRACT Like single-stranded RNA viruses, SARS-CoV-2 hijacks the host transcriptional machinery for its own replication. Numerous traditional differential gene expression-based investigations have examined the diverse clinical symptoms caused by SARS-CoV-2 infection. The virus, on the other hand, also affects the host splicing machinery, causing host transcriptional dysregulation, which can lead to diverse clinical outcomes. Hence, in this study, we performed host transcriptome sequencing of 125 hospital-admitted COVID-19 patients to understand the transcriptomic differences between the severity sub-phenotypes of mild, moderate, severe, and mortality. We performed transcript-level differential expression analysis, investigated differential isoform usage, looked at the splicing patterns within the differentially expressed transcripts (DET), and elucidated the possible genome regulatory features. Our DTE analysis showed evidence of diminished transcript length and diversity as well as altered promoter site usage in the differentially expressed protein-coding transcripts in the COVID-19 mortality patients. We also investigated the potential mechanisms driving the alternate splicing and discovered a compelling differential enrichment of repeats in the promoter region and a specific enrichment of SINE (Alu) near the splicing sites of differentially expressed transcripts. These findings suggested a repeat-mediated plausible regulation of alternative splicing as a potential modulator of COVID-19 disease severity. In this work, we emphasize the role of scarcely elucidated functional role of alternative splicing in influencing COVID-19 disease severity sub-phenotypes, clinical outcomes, and its putative mechanism. IMPORTANCE The wide range of clinical symptoms reported during the COVID-19 pandemic inherently highlights the numerous factors that influence the progression and prognosis of SARS-CoV-2 infection. While several studies have investigated the host response and discovered immunological dysregulation during severe infection, most of them have the common theme of focusing only up to the gene level. Viruses, especially RNA viruses, are renowned for hijacking the host splicing machinery for their own proliferation, which inadvertently puts pressure on the host transcriptome, exposing another side of the host response to the pathogen challenge. Therefore, in this study, we examine host response at the transcript-level to discover a transcriptional difference that culminates in differential gene-level expression. Importantly, this study highlights diminished transcript diversity and possible regulation of transcription by differentially abundant repeat elements near the promoter region and splicing sites in COVID-19 mortality patients, which together with differentially expressed isoforms hold the potential to elaborate disease severity and outcome. |
| first_indexed | 2024-03-11T17:56:26Z |
| format | Article |
| id | doaj.art-b2152634c7184ab8b446b303ab1b8fe9 |
| institution | Directory Open Access Journal |
| issn | 2165-0497 |
| language | English |
| last_indexed | 2024-03-11T17:56:26Z |
| publishDate | 2023-10-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | Microbiology Spectrum |
| spelling | doaj.art-b2152634c7184ab8b446b303ab1b8fe92023-10-17T13:04:35ZengAmerican Society for MicrobiologyMicrobiology Spectrum2165-04972023-10-0111510.1128/spectrum.01351-23SARS-CoV-2 infection severity and mortality is modulated by repeat-mediated regulation of alternative splicingPriyanka Mehta0Partha Chattopadhyay1Varsha Ravi2Bansidhar Tarai3Sandeep Budhiraja4Rajesh Pandey5Division of Immunology and Infectious Disease Biology, INtegrative GENomics of HOst-PathogEn (INGEN-HOPE) Laboratory, CSIR-Institute of Genomics and Integrative Biology (CSIR-IGIB) , Delhi, IndiaDivision of Immunology and Infectious Disease Biology, INtegrative GENomics of HOst-PathogEn (INGEN-HOPE) Laboratory, CSIR-Institute of Genomics and Integrative Biology (CSIR-IGIB) , Delhi, IndiaDivision of Immunology and Infectious Disease Biology, INtegrative GENomics of HOst-PathogEn (INGEN-HOPE) Laboratory, CSIR-Institute of Genomics and Integrative Biology (CSIR-IGIB) , Delhi, IndiaMax Super Speciality Hospital (A Unit of Devki Devi Foundation), Max Healthcare , Delhi, IndiaMax Super Speciality Hospital (A Unit of Devki Devi Foundation), Max Healthcare , Delhi, IndiaDivision of Immunology and Infectious Disease Biology, INtegrative GENomics of HOst-PathogEn (INGEN-HOPE) Laboratory, CSIR-Institute of Genomics and Integrative Biology (CSIR-IGIB) , Delhi, IndiaABSTRACT Like single-stranded RNA viruses, SARS-CoV-2 hijacks the host transcriptional machinery for its own replication. Numerous traditional differential gene expression-based investigations have examined the diverse clinical symptoms caused by SARS-CoV-2 infection. The virus, on the other hand, also affects the host splicing machinery, causing host transcriptional dysregulation, which can lead to diverse clinical outcomes. Hence, in this study, we performed host transcriptome sequencing of 125 hospital-admitted COVID-19 patients to understand the transcriptomic differences between the severity sub-phenotypes of mild, moderate, severe, and mortality. We performed transcript-level differential expression analysis, investigated differential isoform usage, looked at the splicing patterns within the differentially expressed transcripts (DET), and elucidated the possible genome regulatory features. Our DTE analysis showed evidence of diminished transcript length and diversity as well as altered promoter site usage in the differentially expressed protein-coding transcripts in the COVID-19 mortality patients. We also investigated the potential mechanisms driving the alternate splicing and discovered a compelling differential enrichment of repeats in the promoter region and a specific enrichment of SINE (Alu) near the splicing sites of differentially expressed transcripts. These findings suggested a repeat-mediated plausible regulation of alternative splicing as a potential modulator of COVID-19 disease severity. In this work, we emphasize the role of scarcely elucidated functional role of alternative splicing in influencing COVID-19 disease severity sub-phenotypes, clinical outcomes, and its putative mechanism. IMPORTANCE The wide range of clinical symptoms reported during the COVID-19 pandemic inherently highlights the numerous factors that influence the progression and prognosis of SARS-CoV-2 infection. While several studies have investigated the host response and discovered immunological dysregulation during severe infection, most of them have the common theme of focusing only up to the gene level. Viruses, especially RNA viruses, are renowned for hijacking the host splicing machinery for their own proliferation, which inadvertently puts pressure on the host transcriptome, exposing another side of the host response to the pathogen challenge. Therefore, in this study, we examine host response at the transcript-level to discover a transcriptional difference that culminates in differential gene-level expression. Importantly, this study highlights diminished transcript diversity and possible regulation of transcription by differentially abundant repeat elements near the promoter region and splicing sites in COVID-19 mortality patients, which together with differentially expressed isoforms hold the potential to elaborate disease severity and outcome.https://journals.asm.org/doi/10.1128/spectrum.01351-23COVID-19differential transcript expressionalternative splicingalternate promoter usagerepeat elements |
| spellingShingle | Priyanka Mehta Partha Chattopadhyay Varsha Ravi Bansidhar Tarai Sandeep Budhiraja Rajesh Pandey SARS-CoV-2 infection severity and mortality is modulated by repeat-mediated regulation of alternative splicing Microbiology Spectrum COVID-19 differential transcript expression alternative splicing alternate promoter usage repeat elements |
| title | SARS-CoV-2 infection severity and mortality is modulated by repeat-mediated regulation of alternative splicing |
| title_full | SARS-CoV-2 infection severity and mortality is modulated by repeat-mediated regulation of alternative splicing |
| title_fullStr | SARS-CoV-2 infection severity and mortality is modulated by repeat-mediated regulation of alternative splicing |
| title_full_unstemmed | SARS-CoV-2 infection severity and mortality is modulated by repeat-mediated regulation of alternative splicing |
| title_short | SARS-CoV-2 infection severity and mortality is modulated by repeat-mediated regulation of alternative splicing |
| title_sort | sars cov 2 infection severity and mortality is modulated by repeat mediated regulation of alternative splicing |
| topic | COVID-19 differential transcript expression alternative splicing alternate promoter usage repeat elements |
| url | https://journals.asm.org/doi/10.1128/spectrum.01351-23 |
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