Comparative analysis of cell-cell communication at single-cell resolution

Inference of cell-cell communication (CCC) from single-cell RNA-sequencing data is a powerful technique to uncover putative axes of multicellular coordination, yet existing methods perform this analysis at the level of the cell type or cluster, discarding single-cell level information. Here we present Scriabin - a flexible and scalable framework for comparative analysis of CCC at single-cell resolution. We leverage multiple published datasets to show that Scriabin recovers expected CCC edges and use spatial transcriptomic data, genetic perturbation screens, and direct experimental manipulation of receptor-ligand interactions to validate that the recovered edges are biologically meaningful. We then apply Scriabin to uncover co-expressed programs of CCC from atlas-scale datasets, validating known communication pathways required for maintaining the intestinal stem cell niche and revealing species-specific communication pathways. Finally, we utilize single-cell communication networks calculated using Scriabin to follow communication pathways that operate between timepoints in longitudinal datasets, highlighting bystander cells as important initiators of inflammatory reactions in acute SARS-CoV-2 infection. Our approach represents a broadly applicable strategy to leverage single-cell resolution data maximally toward uncovering CCC circuitry and rich niche-phenotype relationships in health and disease.

Cytokine profile in plasma of severe COVID-19 does not differ from ARDS and sepsis

RationaleElevated levels of inflammatory cytokines have been associated with poor outcomes among COVID-19 patients. It is unknown, however, how these levels compare to those observed in critically ill patients with ARDS or sepsis due to other causes. ObjectivesTo directly compare plasma levels of inflammatory cytokines, with a focus on 6 cytokines associated with cytokine storm (IL-1b, IL-1RA, IL-6, IL-8, IL-18, and TNF), between hospitalized COVID-19 patients and banked plasma samples from ARDS and sepsis patients from prior to the COVID-19 pandemic. Findings15 hospitalized COVID-19 patients, 9 of whom were critically ill, were compared to 28 critically ill patients with ARDS or sepsis. There were no statistically significant differences in baseline levels of IL-1b, IL-1RA, IL-6, IL-8, IL-18, and TNF between patients with severe COVID-19 and critically ill controls with ARDS or sepsis. ConclusionsLevels of inflammatory cytokines IL-1b, IL-1RA, IL-6, IL-8, IL-18, and TNF were not higher in critically ill COVID-19 patients than in critically ill patients admitted with ARDS or sepsis due to other causes in this small cohort. Broad use of immunosuppressive therapies in ARDS has failed in numerous Phase 3 studies; use of these therapies in unselected patients with COVID-19 is likely unwarranted.