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Abstract
The SARS-CoV-2 pandemic has challenged humankind’s ability to quickly determine the cascade of health effects caused by a novel infection. Even with the unprecedented speed at which vaccines were developed and introduced into society, identifying therapeutic interventions and drug targets for patients infected with the virus remains important as new strains of the virus evolve, or future coronaviruses may emerge that are resistant to current vaccines. The application of transcriptomic RNA sequencing of infected samples may shed new light on the pathways involved in viral mechanisms and host responses. We describe the application of the previously developed “dual RNA-seq” approach to investigate, for the first time, the co-regulation between the human and SARS-CoV-2 transcriptomes. Together with differential expression analysis, we describe the tissue specificity of SARS-CoV-2 expression, an inferred lipopolysaccharide response, and co-regulation of CXCL’s, SPRR’s, S100’s with SARS-CoV-2 expression. Lipopolysaccharide response pathways in particular offer promise for future therapeutic research and the prospect of subgrouping patients based on chemokine expression that may help explain the vastly different reactions patients have to infection. Taken together these findings highlight unappreciated SARS-CoV-2 expression signatures and emphasize new considerations and mechanisms for SARS-CoV-2 therapeutic intervention.
Highlights
The SARS-CoV-2 pandemic has challenged humankind’s ability to quickly determine the cascade of health effects caused by a novel infection
While differential expression of gene families has been thoroughly investigated in SARS-CoV-2 infection, there has been no attempt to date to correlate SARSCoV-2 genes with the human host gene expression program
In a more extreme manner, Bronchoalveolar lavage fluid (BALF) and PBMC samples showed 275 matched directional expression changes and 683 mismatched directional expression changes, demonstrating that the majority of gene expression changes are very significantly discordant (Chi-Square 173.7, p < 1e−38) with BALF samples (Fig. 2F). For both PBMC and lung samples there was a dominant discordance in gene expression changes compared to BALF. This is consistent with our observations above in which we found robust SARS-CoV-2 expression levels in BALF compared with undetectable levels in PBMC and lung
Summary
The SARS-CoV-2 pandemic has challenged humankind’s ability to quickly determine the cascade of health effects caused by a novel infection. Lipopolysaccharide response pathways in particular offer promise for future therapeutic research and the prospect of subgrouping patients based on chemokine expression that may help explain the vastly different reactions patients have to infection Taken together these findings highlight unappreciated SARS-CoV-2 expression signatures and emphasize new considerations and mechanisms for SARS-CoV-2 therapeutic intervention. A variety of model systems and tissue types have been used to study the transcriptional response to SARSCoV-2 infection in an effort to better understand the molecular basis of COVID-1911,12. These studies have revealed a cytokine, chemokine, and immune response to SARS-CoV-2 infection. Modern sequencing yields a high enough read depth to provide accurate quantification of the entire host and pathogen transcriptomes without the need for additional library enrichment steps
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