Tu211 - Comparative Single Cell Analysis Reveals Distinct Transcriptional and Epigenetic Immune Signatures of sars-cov-2 and Respiratory Syncytial Virus Infections in Infants

Asunción Mejías – Department of Infectious Diseases – St. Jude Children’s Research Hospital, Memphis, TN; Djamel Nehar-Belaid – The Jackson Laboratory for Genomic Medicine, Farmington, CT; Radu Marches – The Jackson Laboratory for Genomic Medicine, Farmington, CT; Jacques Banchereau – Immunai, New York, NY; Virginia Pascual – Drukier Institute for Children’s Health and Department of Pediatrics – Weill Cornell Medicine, New York, NY; Duygu Ucar – The Jackson Laboratory for Genomic Medicine, Farmington, CT; Octavio Ramilo – Department of Infectious Diseases – St. Jude Children’s Research Hospital, Memphis, TN

Abstract Text: Both SARS-CoV-2 and respiratory syncytial virus (RSV) can cause severe disease in infants, leading to hospitalization or even death. However, how these viruses affect the immune systems of infants at the molecular and cellular level remains unknown. To fill this gap, we profiled peripheral blood mononuclear cells (PBMCs) from 68 infants: 31 SARS-CoV-2 infected (10 convalescent, 12 moderate, 9 severe), 19 RSV infected (5 mild, 7 moderate, 7 severe), and 18 healthy controls, using single cell RNA-sequencing (scRNA-seq) and single nucleus assay for transposase-accessible chromatin with sequencing (snATAC-seq). scRNA-seq data revealed common infectious disease signatures including virus-induced interferon-stimulated transcriptional (ISGhi) states observed across T, B, and Myeloid lineages and depletion of dendritic cells. In contrast, we observed i) a SARS-CoV-2 infection specific depletion of γδ T cells, ii) RSV infection specific expansion of cytotoxic (GZMKhi) memory CD4+ T cells, iii) RSV specific depletion of CD56bright NK cells, and iv) depletion of CD16+ NK cells in severe RSV infection. Epigenetic analyses revealed that binding activity for NK maturation transcription factors T-BET (TBX21) and EOMES was lower specifically in CD56bright NK cells from RSV-infected infants. Moreover, in CD14+ Monocytes, the binding activity for interferon regulatory factors IRF7 and IRF9 and interferon mediator STAT1:STAT2 heterodimer was increased upon RSV-infections yet decreased upon severe SARS-CoV-2 infection. Altogether, we uncovered shared and distinct immune responses to SARS-CoV-2 and RSV infections in infants, highlighting RSV specific changes in circulating NK cells, and transcriptionally shared interferon signatures that are epigenetically distinct between SARS-CoV-2 and RSV infections.