Integrative computational approach identifies drug targets in CD4+ T-cell-mediated immune disorders
Open Access
- 22 January 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in npj Systems Biology and Applications
- Vol. 7 (1), 1-18
- https://doi.org/10.1038/s41540-020-00165-3
Abstract
CD4+ T cells provide adaptive immunity against pathogens and abnormal cells, and they are also associated with various immune-related diseases. CD4+ T cells’ metabolism is dysregulated in these pathologies and represents an opportunity for drug discovery and development. Genome-scale metabolic modeling offers an opportunity to accelerate drug discovery by providing high-quality information about possible target space in the context of a modeled disease. Here, we develop genome-scale models of naïve, Th1, Th2, and Th17 CD4+ T-cell subtypes to map metabolic perturbations in rheumatoid arthritis, multiple sclerosis, and primary biliary cholangitis. We subjected these models to in silico simulations for drug response analysis of existing FDA-approved drugs and compounds. Integration of disease-specific differentially expressed genes with altered reactions in response to metabolic perturbations identified 68 drug targets for the three autoimmune diseases. In vitro experimental validation, together with literature-based evidence, showed that modulation of fifty percent of identified drug targets suppressed CD4+ T cells, further increasing their potential impact as therapeutic interventions. Our approach can be generalized in the context of other diseases, and the metabolic models can be further used to dissect CD4+ T-cell metabolism.Keywords
Funding Information
- U.S. Department of Health & Human Services | National Institutes of Health (1R35GM119770-04, 1R35GM119770-04, 1R35GM119770-04, 1R35GM119770-04, 1R35GM119770-04, 1R35GM119770-04)
- U.S. Department of Health & Human Services | National Institutes of Health
- U.S. Department of Health & Human Services | National Institutes of Health
- U.S. Department of Health & Human Services | National Institutes of Health
- U.S. Department of Health & Human Services | National Institutes of Health
- U.S. Department of Health & Human Services | National Institutes of Health
- University of Surrey (Systems Biology Grant)
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