Project 1: pediatric COVID-19
Our objective was to assess the Immune perturbations induced by SARS-CoV2 in two-month-old infants with mild and severe disease. We also compared our findings to children and adult cohorts.
Our study is currently under revision and is available as a preprint here: link.
Summary:
Differences in immune profiles of children and adults with COVID-19 have been previously described. However, no systematic studies have been reported from infants hospitalized with severe disease. We applied a multidimensional approach to decipher the immune responses of SARS-CoV-2 infected infants (n=26; 10 subacute, 11 moderate and 5 severe; median age=~1.6 months) and matched controls (n=14; median age=~2 months). Single cell (scRNA-seq) profiling of PBMCs revealed substantial alterations in cell composition in SARS-CoV-2 infected infants; with most cell-types switching to an interferon-stimulated gene (ISGhi) state including: (i) CD14+ monocytes co-expressing ISGs and inflammasome-related molecules, (ii) ISGhi naïve CD4+ T cells, (iii) ISGhi proliferating cytotoxic CD8+ T cells, and (iv) ISGhi naïve and transitional B cells. Concurrently, we observed increased serum concentrations of both interferons and inflammatory cytokines in infected infants. Antibody responses to SARS-CoV-2 were also consistently detected in the absence of anti-IFN autoantibodies. Compared with infected adults, infants displayed a similar ISG signature in monocytes but a markedly enhanced ISG signature in T and B cells. These findings provide new insights into the distinct immune responses to SARS-CoV-2 in the first year of life and underscore the importance of further defining the unique features of early life immunity.
Project 2: adult COVID-19 - Epigenetic memory
Epigenetic Memory of COVID-19 in Innate Immune Cells and Their Progenitors.
Collboration with Josefowicz (Weill Cornell Medicine) and Ucar (The Jackson laboratory) labs
This project was published in Cell in 2023 and can be found here:
Highlights:
1- Severe COVID-19 programs durable epigenetic changes and hyper-activation in monocytes
2- Circulating HSPC capture post-COVID-19 changes in hematopoiesis and stem cell programs
3- Post-COVID-19 HSPC convey epigenetic and transcriptional memory to mature progeny cells
4- IL-6 contributes to epigenetic reprogramming of mouse and human HSPC and myeloid cells
Summary:
Inflammation can trigger lasting phenotypes in immune and non-immune cells. Whether and how human infections and associated inflammation can form innate immune memory in hematopoietic stem and progenitor cells (HSPC) has remained unclear. We found that circulating HSPC, enriched from peripheral blood, captured the diversity of bone marrow HSPC, enabling investigation of their epigenomic reprogramming following coronavirus disease 2019 (COVID-19). Alterations in innate immune phenotypes and epigenetic programs of HSPC persisted for months to 1 year following severe COVID-19 and were associated with distinct transcription factor (TF) activities, altered regulation of inflammatory programs, and durable increases in myelopoiesis. HSPC epigenomic alterations were conveyed, through differentiation, to progeny innate immune cells. Early activity of IL-6 contributed to these persistent phenotypes in human COVID-19 and a mouse coronavirus infection model. Epigenetic reprogramming of HSPC may underlie altered immune function following infection and be broadly relevant, especially for millions of COVID-19 survivors.