Background
Long COVID-19 has now been shown to have a lasting impact on people’s lives [
1,
2]. As new variants of COVID-19 and other viruses emerge, COVID-19 vaccine breakthroughs urgently require researchers to fully explore the pathogenic mechanisms of COVID-19 infection [
3]. At present, alternative splicing (AS), as one of the most important mechanisms to regulate gene expression and produce proteome diversity in the host, has attracted increasing attention in COVID-19 studies [
4‐
8].
Previous studies have suggested that the immune response in COVID-19 patients is similar to that of many infectious diseases, including SARS-CoV, human immunodeficiency virus (HIV), influenza A virus (IAV), human cytomegalovirus (HCMV), herpes simplex virus (HSV), dengue virus 2, bacterial infections and viremia [
9‐
12]. Recent studies have demonstrated that hundreds of host genes show alternative mRNA splicing in COVID-19 and other infectious diseases [
4,
11,
13,
14]. Being relevant to host gene regulation, AS is a key aspect of virus-host interaction and plays an essential role in the host immune response to microbial infection [
15]. For instance, the accessibility of hnRNP K transcripts is altered by IAV, triggering alterations in host cell splicing that promote IAV replication [
16]. RNA splicing in host cells is also inhibited by the Vpr protein of HIV-1 and the NS5 protein of dengue virus [
17]. Guttman et al. found that global mRNA splicing was altered due to the interaction between SARS-CoV-2 proteins and host mRNA, which consequently suppressed host defenses [
4]. It was also reported that the extent of splicing deregulation in the host was associated with the severity of COVID-19 and affected drug-protein interactions [
7]. In addition, it is widely accepted that viral infection-induced AS of host RNAs can alter the translation of proteins in the host cell [
7,
12].
There are several databases focused on AS in various cancers and during cell development in different species [
18,
19]. A database focused on interpreting the profiles of RNA expression, proteins, metabolites and lipid levels in COVID-19 promotes research on AS mechanisms related to COVID-19 [
20]. However, even though AS plays a very essential role in COVID-19 infection as reported, there is a lack of resources focusing on AS profiles under different conditions of COVID-19 infection which could otherwise facilitate AS-related research in COVID-19.
To address this issue, we present CASA, a comprehensive database featuring the COVID-19 Alternative Splicing Atlas. In CASA, thousands of samples with RNA-seq data and related clinical/phenotype information were manually collected, integrated and reanalyzed. CASA comprises data on AS events for 12 microbes (e.g., Alpha, Delta, and Omicron variants of SARS-CoV-2, SARS-CoV, HIV, influenza A virus, HCMV, HSV-1, dengue virus 2, bacteria, and viremia), each sampled from different tissues, organoids or cell lines, and presents information regarding conditions affecting AS such as disease severity (e.g., mild, moderate or severe COVID-19), cell types and infection time [
21]. To explore the potential function of microbe-induced AS, a series of tools are embedded in CASA, such as functional annotation for AS, drug-target interactions, identification of RNA-binding proteins (RBPs) and the distribution of AS on chromosomes. CASA is structured around condition-specific aspects of AS and is freely available at
http://www.splicedb.net/casa/ with an interface that allows users to search by microbe name, tissue, region and feature (e.g., project ID, symbol, AS type). The database provides details on AS events of interest and can be visualized at the inclusion level under specific conditions.
Discussion and conclusions
A broad program of AS of host genes tends to be induced when human cells are infected with microbes, including SARS-COV-2, SARS-CoV, HIV, influenza A virus, HCMV, HSV-1, and dengue virus 2 [
9]. There is an urgent need to investigate the role of AS in the mechanism of these infectious diseases. Several cancer- and development-related AS databases have been developed and are widely used by researchers [
12,
13,
23,
24], contributing to our knowledge of AS mechanisms in cancer and developmental biology. Herein, we developed CASA, the first comprehensive AS database for COVID-19 and COVID-19-related infectious diseases, to provide comprehensive AS information regarding different tissues in COVID-19 and nine other infectious diseases. In addition, potential RBP-regulated AS as well as corresponding functions enriched in AS are also displayed.
In the future, we promise that CASA will be kept up to date as follows: (i) Additional online tools will be provided in CASA based on user feedback, and (ii) we promise to integrate more samples and more infectious diseases into CASA and will continue to update the database every six months. New datasets released after May 2022 will be integrated and reanalyzed to ensure their value as user-friendly COVID-19-related AS databases. We believe that CASA will motivate research on the functions of virus-induced splicing alterations in host cells in terms of cell biology, as well as mechanisms involving AS in infectious diseases.
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