Biology subjects

Chowdhary, K.

Publications and source records attributed to Chowdhary, K..

3 recordsLinked to original sources

bioRxiv2021

FoxP3 associates with enhancer-promoter loopsto regulate Treg-specific gene expression

Gene expression programs are specified by higher-order chromatin structure and enhancer-promoter loops (EPL). T regulatory cells (Treg) identity is dominantly specified by the transcription factor FoxP3, whose mechanism of action is unclear. We applied proximity-ligation with chromatin immunoprecipitation (HiChIP) in Treg and closely related conventional CD4+ T cells (Tconv). EPL identified by H3K27Ac HiChIP showed a range of connection intensity, with some super-connected genes. TF-specific HiChIP showed that FoxP3 interacts with EPLs at a large number of genes, including some not differentially expressed in Treg vs Tconv, but enriched at the core Treg signature loci that it upregulates. FoxP3 association correlates with heightened H3H27Ac looping, as ascertained by analysis of FoxP3-deficient Treg-like cells. There was marked asymmetry in the loci where FoxP3 associated at the enhancer- or the promoter-side of EPLs, with enrichment for different transcriptional cofactors. FoxP3 EPL intensity distinguished gene clusters identified by single-cell ATAC-seq as co-varying between individual Tregs, supporting a direct transactivation model for FoxP3 in determining Treg identity. One Sentence SummaryFoxP3 is associated with enhancer-promoter loops in Treg cells, and correlates with heightened enhancer-promoter cross-talk

immunology↗

bioRxiv2021

A virus-specific monocyte inflammatory phenotype is induced by SARS-CoV2 at the immune-epithelial interface

Infection by SARS-CoV2 provokes a potentially fatal pneumonia with multiorgan failure, and high systemic inflammation. To gain mechanistic insight and ferret out the root of this immune dysregulation, we modeled by in vitro co-culture the interactions between infected epithelial cells and immunocytes. A strong response was induced in monocytes and B cells, with a SARS-CoV2-specific inflammatory gene cluster distinct from that seen in influenza-A or Ebola virus-infected co-cultures, and which reproduced deviations reported in blood or lung myeloid cells from COVID-19 patients. A substantial fraction of the effect could be reproduced after individual transfection of several SARS-CoV2 proteins (Spike and some non-structural proteins), mediated by soluble factors, but not via transcriptional induction. This response was greatly muted in monocytes from healthy children, perhaps a clue to the age-dependency of COVID-19. These results suggest that the inflammatory malfunction in COVID-19 is rooted in the earliest perturbations that SARS-CoV2 induces in epithelia.

immunology↗

bioRxiv2020

Profound Treg perturbations correlate with COVID-19 severity

The hallmark of severe COVID-19 disease has been an uncontrolled inflammatory response, resulting from poorly understood immunological dysfunction. We explored the hypothesis that perturbations in FoxP3+ T regulatory cells (Treg), key enforcers of immune homeostasis, contribute to COVID-19 pathology. Cytometric and transcriptomic profiling revealed a distinct Treg phenotype in severe COVID-19 patients, with an increase in both Treg proportions and intracellular levels of the lineage-defining transcription factor FoxP3, which correlated with poor outcomes. Accordingly, these Tregs over-expressed a range of suppressive effectors, but also pro-inflammatory molecules like IL32. Most strikingly, they acquired similarity to tumor-infiltrating Tregs, known to suppress local anti-tumor responses. These traits were most marked in acute patients with severe disease, but persisted somewhat in convalescent patients. These results suggest that Tregs may play nefarious roles in COVID-19, via suppressing anti-viral T cell responses during the severe phase of the disease, and/or via a direct pro-inflammatory role.

immunology↗