Notch1-CD22-Dependent Immune Dysregulation in the SARS-CoV2-Associated Multisystem Inflammatory Syndrome in Children (preprint)

Multisystem inflammatory syndrome in children (MIS-C) evolves in some pediatric patients following acute infection with SARS-CoV-2 by hitherto unknown mechanisms. Whereas acute-COVID-19 severity and outcome were previously correlated with Notch4 expression on regulatory T (Treg) cells, here we show that the Treg cells in MIS-C are destabilized in association with increased Notch1 expression. Genetic analysis revealed that MIS-C patients were enriched in rare deleterious variant impacting inflammation and autoimmunity pathways, including dominant negative mutations in the Notch1 regulators NUMB and NUMBL. Notch1 signaling in Treg cells induced CD22, leading to their destabilization in an mTORC1 dependent manner and to the promotion of systemic inflammation. These results establish a Notch1-CD22 signaling axis that disrupts Treg cell function in MIS-C and point to distinct immune checkpoints controlled by individual Treg cell Notch receptors that shape the inflammatory outcome in SARS-CoV-2 infection.

Mutations in SARS-CoV-2 spike protein and RNA polymerase complex are associated with COVID-19 mortality risk (preprint)

SARS-CoV-2 mortality has been extensively studied in relationship to a patient's predisposition to the disease. However, how sequence variations in the SARS-CoV-2 genome affect mortality is not understood. To address this issue, we used a whole-genome sequencing (WGS) association study to directly link death of SARS-CoV-2 patients with sequence variation in the viral genome. Specifically, we analyzed 3,626 single stranded RNA-genomes of SARS-CoV-2 patients in the GISAID database (Elbe and Buckland-Merrett, 2017; Shu and McCauley, 2017) with reported patient’s health status from COVID-19, i.e. deceased versus non-deceased. In total, evaluating 28,492 loci of the viral genome for association with patient/host mortality, two loci, 12,053bp and 25,088bp, achieved genome-wide significance (p-values of 1.24e-12, and 1.24e-26, respectively). Mutations at 25,088bp occur in the S2 subunit of the SARS-CoV-2 spike protein, which plays a key role in viral entry of target host cells. Additionally, mutations at 12,053bp are within the ORF1ab gene, in a region encoding for the protein nsp7, which is necessary to form the RNA polymerase complex responsible for viral replication and transcription. Both mutations altered amino acid coding sequences, potentially imposing structural changes that could enhance viral infectivity and symptom severity, and may be important to consider as targets for therapeutic development.