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Principal Investigator: Behdad Afzali
Organization: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
Fiscal Year: 2024
Award: $2,757,763
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
In the past years we had shown that cell-autonomous Complement is produced both from immune and non-immune cells and delineated the major pathways of their induction, notably LFA-induced signals in T cells and type I interferons in respiratory epithelial cells. These findings were important because they indicated that inflamed tissues, which are unable to access plasma-circulating complement, actually represent a complement-rich environment, the complement here being derived from both immune and non-cells.
We thus hypothesized that studying transcriptomes of Complement-activated T cells would reveal the effects of Complement on T cells. We showed that Complement induces a self-contained autocrine/paracrine vitamin D (VitD) system in T cells that is required for appropriate inflammatory T cell shut-down, permitting tissue healing to take place. Briefly, we found that Complement induced a cell-intrinsic VitD system permitting T cells to both activate and respond to VitD. Sensing of active VitD caused genome-wide epigenetic changes that generated new and augmented existing super-enhancers, and recruited key TFs (principally VDR, c-JUN, STAT3 and BACH2) that shaped the VitD response in T cells. We found, as we had done before, that BACH2 was a central TF in these events. T cells of patients with COVID-19 showed Th1 hyper-activation and evidence of dysregulation of this VitD shut-down program, indicating either a lack of substrate (VitD deficiency) and/or abnormal regulation of this system. These data may explain the epidemiologic link between vitamin D insufficiency/deficiency and risk of both developing COVID-19 and suffering mortality after infection. They are also noteworthy because they establish cross-regulation between the two main interests of our lab, Complement and the TF BACH2. We found that this system was operational in psoriatic skin and dysregulated in cells from patients with Job and BRIDA syndromes. As part of a collaboration with colleagues in the UK we also showed that activated Vitamin D represses glycolytic programs in effector CD4+ T cells to repress inflammatory functions. This paper was published in Nature Immunology. Through a collaboration with the Portilla and Lionakis labs, respectively, we also demonstrated that the Complement C5 system is also key to activation of myeloid cells in the kidneys that drive tissue scarring following acute kidney injury (the folic acid model) and that C5 is essential for anti-fungal immunity. Thus, C5 antagonism in humans and mice predisposes to invasive fungal diseases. These findings were published in the American Journal of Physiology and Cell, respectively. In parallel, with the Lazarevic lab, we showed that the transcription factor EGR2 is essential for promoting pathogenic potential in Th17 cells, which then mediate autoimmune brain inflammation. These findings were published in Nature Immunology. These were supplemented with a collaboration with the Mathe group in NCATS, with whom we showed using data from the N3C dataset that patients with pre-existing autoimmunity and/or on immunosuppressive medication were significantly more at risk of developing severe COVID-19 after infection with SARS-CoV2. This was published in Clinical Infectious Diseases. We also collaborated with the Lionakis lab this year on a publication in the New England Journal of Medicine demonstrating the JAK inhibitors can be beneficial for patients with APECED syndrome. This was a direct follow-on from our prior collaboration detailing this pathway published in Science.
Our work on transcriptional regulators of T cells culminated in two review articles delineating the roles of non-coding RNAs in autoimmunity in T cells (published in the Journal of Autoimmunity) and the role of transcription factors in shaping regulatory T cell identify (published in Nature Reviews Immunology).
Finally, in addition to our work in complement biology, we developed the Benchmark platform and Pathway Ensemble Tool (PET)in collaboration with Dr Kazemian's group at Purdue. These tools integrate multiple computational methods to identify disease-relevant biological pathways from omics data, reducing researcher bias and providing unbiased insights. PET has successfully identified novel prognostic pathways, biomarkers, and therapeutic drugs across various cancers. Notably, it highlighted CCT068127, a CDK2/9 inhibitor, as highly effective against bladder cancer, outperforming current treatments in lab and animal models. This was published in Nature Communications. Both Benchmark and PET are available online, offering valuable resources for improving the understanding and treatment of complex diseases.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><APECED><Acceleration><Acute Renal Failure with Renal Papillary Necrosis><American><Animal Model><Animal Models and Related Studies><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Autocrine Systems><Autoimmune><Autoimmune Diseases><Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal-Dystrophy><Autoimmune Status><Autoimmune polyendocrine syndrome type 1><Autoimmune polyglandular syndrome type 1><Autoimmunity><Automobile Driving><BACH2><BACH2 gene><BTB and CNC Homology 2><Basal Transcription Factor><Basal transcription factor genes><Basic Leucine Zipper Transcription Factor 2><Behavior><Benchmarking><Best Practice Analysis><Biological><Biological Markers><Biology><Bladder Cancer><Blood Plasma><Body Tissues><Brain Inflammation><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CDK2><CDK2 gene><COVID infected patient><COVID patient><COVID positive patient><COVID-19><COVID-19 infected patient><COVID-19 patient><COVID-19 positive patient><COVID-19 virus><COVID19 patient><COVID19 positive patient><COVID19 virus><CV-19><Cancers><Cell Body><Cell Communication and Signaling><Cell Division Kinase 2><Cell Lineage><Cell Locomotion><Cell Migration><Cell Movement><Cell Signaling><Cells><Cellular Migration><Cellular Motility><Cicatrix><Clinical><CoV-2><CoV2><Collaborations><Communicable Diseases><Communication><Complement><Complement 5><Complement C5><Complement Component 5><Complement Proteins><Complement component C5><Complex><Computing Methodologies><Coronavirus Infectious Disease 2019><Cyclin-Dependent Kinase 2><Data><Data Set><Discipline><Disease><Disorder><Drugs><EGR2><EGR2 gene><Encephalitis><Enhancers><Environment><Epidemiology><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Epithelial Cells><Event><Failure><Folate><Folic Acid><Functional RNA><Functional impairment><Gene Action Regulation><Gene Expression><Gene Expression Regulation><Gene Regulation><Gene Regulation Process><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic Transcription><Human><Immune><Immune system><Immunes><Immunity><Immunology><Immunomodulation><Immunosuppressants><Immunosuppression><Immunosuppression Effect><Immunosuppressive Agents><Immunosuppressive Effect><Immunosuppressive drug><Immunosuppressive treatment><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Inflammation><Inflammatory><Injury><Interferon Type I><Intracellular Communication and Signaling><Investigators><JUN Family Gene><JUN Proto-oncogene Family><JUN gene><Jobs><Journals><KROX20><Kidney><Kidney Diseases><Kidney Urinary System><Knowledge><Life><Link><Lymphatic cell><Lymphocyte><Lymphocytic><Magazine><Malignant Bladder Neoplasm><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Bladder><Malignant neoplasm of urinary bladder><Mammalia><Mammals><Mediating><Mediator><Medical><Medication><Medicine><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Morbidity><Morbidity - disease rate><Murine><Mus><Myeloid Cell Activation><NCATS><National Center for Advancing Translational Sciences><Nature><Neoplastic Cell Transformation><Nephropathy><New England><Non-Coding><Non-Coding RNA><Non-translated RNA><Noncoding RNA><Nontranslated RNA><Northeastern United States><Occupations><Organ><Paper><Pathogenicity><Pathway interactions><Patients><Pharmaceutical Preparations><Physiology><Plasma><Plasma Serum><Polyglandular Autoimmune Syndrome Type I><Process><Professional Positions><Psoriasis><Pteroylglutamic Acid><Publications><Publishing><RNA Expression><Regulation><Regulatory T-Lymphocyte><Renal Disease><Renal function><Repression><Research><Research Personnel><Research Resources><Researchers><Resolution><Resources><Respiratory Epithelium><Reticuloendothelial System, Serum, Plasma><Risk><Role><SARS corona virus 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epithelium><Syndrome><System><T cell differentiation><T-Cell Activation><T-Cells><T-Lymphocyte><T4 Cells><T4 Lymphocytes><Therapeutic><Therapeutic Fungicides><Tissues><Transcription><Transcription Factor Proto-Oncogene><Transcription factor genes><Treg><Untranslated RNA><Urinary Bladder Cancer><Urinary Bladder Malignant Tumor><VIT D><Vitamin D><Vitamin D Deficiency><Vitamin M><Work><Wuhan coronavirus><activate T cells><acute kidney injury><after COVID-19 infection><after SARS-CoV-2 infection><after SARS-CoV2 infection><after infection by SARS-CoV-2><after severe acute respiratory distress syndrome CoV-2 infection><airway epithelium><antagonism><antagonist><anti-fungal><anti-fungal agents><anti-fungal drug><autocrine><autoimmune condition><autoimmune disorder><autoimmune polyendocrinopathy syndrome type 1><autoimmunity disease><benchmark><bio-markers><biologic><biologic marker><biological signal transduction><biomarker><c jun><c-jun Gene><cell motility><complementation><computational 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suppressive agent><immune suppressive function><immune suppressor><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunosuppressive activity><immunosuppressive function><immunosuppressive response><immunosuppressive substance><immunosuppressor><improved><inhibitor><injuries><injury and repair><insight><interest><kidney disorder><kidney function><life-threatening COVID><life-threatening COVID-19><life-threatening SARS-CoV-2><life-threatening coronavirus disease><life-threatening coronavirus disease 2019><life-threatening severe acute respiratory syndrome coronavirus 2><lymph cell><malignancy><model of animal><mortality><nCoV2><neoplasm/cancer><neoplastic transformation><noncoding><novel><paracrine><pathway><patient infected with COVID><patient infected with COVID-19><patient infected with SARS-CoV-2><patient infected with coronavirus disease><patient infected with coronavirus disease 2019><patient infected with severe acute respiratory syndrome coronavirus 2><patient with COVID><patient with COVID-19><patient with COVID19><patient with SARS-CoV-2><patient with coronavirus disease><patient with coronavirus disease 2019><patient with severe acute respiratory distress syndrome coronavirus 2><post SARS-CoV-2 infection><prevent><preventing><previous COVID-19 infection><previous SARS-CoV-2 infection><previous SARS-CoV2 infection><previous severe acute respiratory distress syndrome CoV-2 infection><prior COVID-19 infection><prior SARS-CoV-2 infection><prior SARS-CoV2 infection><prior severe acute respiratory distress syndrome CoV-2 infection><prognostic><programs><psoriasiform><psoriatic><recruit><regulatory T-cells><renal><renal disorder><resolutions><respiratory tract epithelium><response><serious COVID><serious COVID-19><serious SARS-CoV-2><serious coronavirus disease><serious coronavirus disease 2019><serious severe acute respiratory syndrome coronavirus 2><severe COVID><severe COVID-19><severe COVID19><severe SARS-CoV-2><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><severe coronavirus disease><severe coronavirus disease 19><severe coronavirus disease 2019><severe severe acute respiratory syndrome coronavirus 2><social role><thymus derived lymphocyte><tool><transcription factor><transcriptome><vitamin Bc>