Biology subjects

Devaprasad, A.

Publications and source records attributed to Devaprasad, A..

5 recordsLinked to original sources

bioRxiv2024

A resource for extracellular vesicles from activated CD4 T cells that relay pro-inflammatory signals

CD4 T helper cells (TH cells) play a vital role in coordinating and amplifying the immune response to specific pathogens. They constitutively produce different kinds of extracellular vesicles (EVs), which mediate cell-to cell communication and play diverse roles in immune regulation and inflammatory processes. Here we provide a resource documenting the composition of activated TH cell EVs and demonstrating their ability to instigate pro-inflammatory response in antigen-presenting cells (APCs). EVs were characterized by lipidomics, proteomics, and NanoFCM. The activated TH cells derived EVs (act-EVs) were found to be enriched in TH cell-specific proteins, transmembrane and cytosolic EV marker proteins, and HLA proteins relative to resting CD4 T cells EVs (rest-EVs). The pro-inflammatory effect of act-EVs vs rest-EVs on donor matched APCs were characterized by chemokine and cytokine profiling and flow cytometry analysis. There was no discernible contrast in endotoxin levels between act-EVs and rest-EVs. Functional distinctions were seen to arise from variations in the content and composition of these EVs. Moreover, we validated our findings with an in-vivo investigation in mice, demonstrating the recruitment of monocytes, dendritic cells (DCs), neutrophils, and NK cells in the spleen, accompanied by the release of pro-inflammatory cytokines in the serum after administering act-EVs. In summary, this study sheds light on the role of TH cell released EVs in modulating the immune response during pro-inflammatory responses and this resource provides a foundation for development of novel therapeutics on EV based scaffolds.

immunology↗

bioRxiv2024

Zfp263 is a transcriptional checkpoint of neutrophil development

During development neutrophils undergo extensive changes in nuclear morphology, gene expression programmes, and acquire specific effector functions. However, molecular mechanisms controlling neutrophil development remain largely unknown. Here we systematically analysed changes in gene expression and chromatin landscape across stages of neutrophil differentiation, to construct a network of transcription factors, predicted to control neutrophil development and acquisition of functions. Zinc finger protein 263 (Zfp263) emerged at the apex of this network. Neutrophil maturation ex vivo and in vivo was blocked in cells lacking Zfp263 and accelerated if its levels were induced. Mechanistically, Zfp263 acts as a direct transcriptional repressor of the ERK1/2 pathway, that supports the proliferative capacity of neutrophil progenitors and limits their differentiation into mature cells. Blocking ERK1/2 signalling in the Zfp263 deficient cells using chemical inhibitors, rescues neutrophil differentiation. Other targets of Zfp263 include genes involved in neutrophil migration, cytokine and chemokine expression, reactive oxygen species and formation of neutrophil extracellular traps. Thus, our study outlines a framework for modulation of neutrophil development and / or function, aimed at neutrophil-mediated diseases.

genomics↗

bioRxiv2021

Enrichment of SARS-CoV-2 entry factors and interacting intracellular genes in peripheral immune cells

SARS-CoV-2 uses ACE2 and TMPRSS2 to gain entry into the cell. However, recent studies have shown that SARS-CoV-2 may use additional host factors that are required for the viral lifecycle. Here we used publicly available datasets, CoV associated genes and machine learning algorithms to explore the SARS-CoV-2 interaction landscape in different tissues. We find that in general a small fraction of cells expresses ACE2 in the different tissues including nasal, bronchi and lungs. We show that a small fraction of immune cells (including T-cells, macrophages, dendritic cells) found in tissues also express ACE2. We show that healthy circulating immune cells do not express ACE2 and TMPRSS2. However, a small fraction of circulating immune cells (including dendritic cells, monocytes, T-cells) in the PBMC of COVID-19 patients express ACE2 and TMPRSS2. Additionally, we found that a large spectrum of cells (in circulation and periphery) in both healthy and COVID-19 positive patients were significantly enriched for SARS-CoV-2 factors. Thus, we propose that further research is needed to explore if SARS-CoV-2 can directly infect peripheral immune cells to better understand the virus mechanism of action.

bioinformatics↗

bioRxiv2019

Integration of immunome with disease gene network reveals pleiotropy and novel drug repurposing targets

ObjectiveDevelopment and progression of immune-mediated inflammatory diseases (IMIDs) involve intricate dysregulation of the disease associated genes (DAGs) and their expressing immune cells. Due to the complex molecular mechanism, identifying the top disease associated cells (DACs) in IMIDs has been challenging. Here, we aim to identify the top DACs and DAGs to help understand the cellular mechanism involved in IMIDs and further explore therapeutic strategies. MethodUsing transcriptome profiles of 40 different immune cells, unsupervised machine learning, and disease-gene networks, we constructed the Disease-gene IMmune cell Expression (DIME) network, and identified top DACs and DAGs of 12 phenotypically different IMIDs. We compared the DIME networks of IMIDs to identify common pathways between them. We used the common pathways and publicly available drug-gene network to identify promising drug repurposing targets. ResultWe found CD4+Treg, CD4+Th1, and NK cells as top DACs in the inflammatory arthritis such as ankylosing spondylitis (AS), psoriatic arthritis, and rheumatoid arthritis (RA); neutrophils, granulocytes and BDCA1+CD14+ cells in systemic lupus erythematosus and systemic scleroderma; ILC2, CD4+Th1, CD4+Treg, and NK cells in the inflammatory bowel diseases (IBDs). We identified lymphoid cells (CD4+Th1, CD4+Treg, and NK) and their associated pathways to be important in HLA-B27 type diseases (psoriasis, AS, and IBDs) and in primary-joint-inflammation-based inflammatory arthritis (AS and RA). Based on the common cellular mechanisms, we identified lifitegrast as potential drug repurposing candidate for Crohns disease, and other IMIDs. ConclusionOur method identified top DACs, DAGs, common pathways, and proposed potential drug repurposing targets between IMIDs. To extend our method to other diseases, we built the DIME tool. Thus paving way for future (pre-)clinical research.

bioinformatics↗

bioRxiv2019

CXCL4 links inflammation and fibrosis through transcriptional and epigenetic reprogramming of monocyte-derived cells

Fibrosis is a condition shared by numerous inflammatory diseases. Our incomplete understanding of the molecular mechanisms underlying fibrosis has severely hampered effective drug development. CXCL4 is associated with the onset and extent of fibrosis development in systemic sclerosis, a prototypic inflammatory and fibrotic disease. Here, we integrated 65 paired longitudinal transcriptional and methylation profiles from monocyte-derived cells with/without CXCL4 exposure. Using data-driven gene regulatory network analyses, we demonstrate that CXCL4 dramatically alters the trajectory of monocyte differentiation, inducing a novel pro-inflammatory and pro-fibrotic phenotype mediated via key transcriptional regulators including CIITA. CXCL4 exposed monocyte-derived cells directly trigger a fibrotic cascade by producing ECM molecules and inducing myofibroblast differentiation. Inhibition of CIITA mimicked CXCL4 in inducing a pro-inflammatory and pro-fibrotic phenotype, validating the relevance of the gene regulatory network. Our study unveils CXCL4 as a key secreted factor driving innate immune training and forming the long-sought link between inflammation and fibrosis.

bioinformatics↗