Transcriptional profiling of leukocytes in critically ill COVID19 patients: implications for interferon response and coagulation

Abstract

Background COVID19 is caused by the SARS-CoV-2 virus and has been associated with severe inflammation leading to organ dysfunction and mortality. Our aim was to profile the transcriptome in leukocytes from critically ill patients positive for COVID19 compared to those negative for COVID19 to better understand the COVID19-associated host response. For these studies, all patients admitted to our tertiary care intensive care unit (ICU) suspected of being infected with SARS-CoV-2, using standardized hospital screening methodologies, had blood samples collected at the time of admission to the ICU. Transcriptome profiling of leukocytes via ribonucleic acid sequencing (RNAseq) was then performed and differentially expressed genes as well as significantly enriched gene sets were identified. Results We enrolled seven COVID19 + (PCR positive, 2 SARS-CoV-2 genes) and seven age- and sex-matched COVID19- (PCR negative) control ICU patients. Cohorts were well-balanced with the exception that COVID19− patients had significantly higher total white blood cell counts and circulating neutrophils and COVID19 + patients were more likely to suffer bilateral pneumonia. The mortality rate for this cohort of COVID19 + ICU patients was 29%. As indicated by both single-gene based and gene set (GSEA) approaches, the major disease-specific transcriptional responses of leukocytes in critically ill COVID19 + ICU patients were: (i) a robust overrepresentation of interferon-related gene expression; (ii) a marked decrease in the transcriptional level of genes contributing to general protein synthesis and bioenergy metabolism; and (iii) the dysregulated expression of genes associated with coagulation, platelet function, complement activation, and tumour necrosis factor/interleukin 6 signalling. Conclusions Our findings demonstrate that critically ill COVID19 + patients on day 1 of admission to the ICU display a unique leukocyte transcriptional profile that distinguishes them from COVID19− patients, providing guidance for future targeted studies exploring novel prognostic and therapeutic aspects of COVID19.

Detection and Profiling of Human Coronavirus Immunoglobulins in Critically Ill Coronavirus Disease 2019 Patients

“…A trend toward lower leukocyte counts was observed in COVID-19+ ICU patients, as opposed to COVID-19–. Previous functional enrichment analysis demonstrated a shift in the circulating leukocyte population in COVID-19+ ICU patients with a transcriptional enrichment for CD14+ monocytes and CD33+ myeloid cells ( 6 ), accentuating the relative lymphopenia in these COVID-19+ patients. Previous work by our study group, investigating many of these same patient samples, determined a unique inflammatory profile characterized by elevated TNF and serine proteases ( 5 ) and a thrombotic profile associated with endothelial activation and glycocalyx degradation ( 7 ).…”

“…Patients with severe COVID-19 are admitted to the ICU for increased monitoring and potential life-saving interventions, where the mortality rate can be high ( 2 ). COVID-19 induces an innate immune response ( 3 ) that includes increased interferons, tumor necrosis factor (TNF), bradykinin, and serine proteases ( 4 – 6 ). COVID-19 mortality has been attributed in part to microvascular disease ( 7 ), which is associated with the formation of pulmonary microthrombi ( 8 ).…”

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

“…To investigate the possibility that SARS-CoV-2 sequences integrated into the genome can be expressed, we analyzed published RNA-seq data from SARS-CoV-2–infected cells for evidence of chimeric transcripts ( 49 ). Examination of these datasets ( 50 – 55 ) ( SI Appendix , Fig. S5 ) revealed a number of human–viral chimeric reads ( SI Appendix , Fig.…”

Abnormal apelin-ACE2 and SGLT2 signaling contribute to adverse cardiorenal injury in patients with COVID-19

“…The normalized counts data for RNA-seq of isolated monocytes from peripheral blood of 6 COVID-19 patients and 3 healthy controls were available with accession number GSE160351 [ 15 ]. The normalized reads counts data for RNA-seq of buffy coat samples from COVID19+ and COVID19− critically ill patients were accessed from GSE154998 [ 16 ]. In addition, GEO Datasets SOFT files were available from https://www.ncbi.nlm.nih.gov/gds .…”