A5101982633- interferon and immune responses
- Sphingolipid Metabolism and Signaling
- T-cell and B-cell Immunology
- Immune Response and Inflammation
- Click Chemistry and Applications
- Immune Cell Function and Interaction
- Peptidase Inhibition and Analysis
- Cytokine Signaling Pathways and Interactions
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Immunotherapy and Immune Responses
- Ion Transport and Channel Regulation
- Lipid Membrane Structure and Behavior
- Adenosine and Purinergic Signaling
- Inflammasome and immune disorders
- IL-33, ST2, and ILC Pathways
- Galectins and Cancer Biology
- Ion Channels and Receptors
- Cancer Immunotherapy and Biomarkers
- Biochemical and Molecular Research
- Pediatric health and respiratory diseases
- Phagocytosis and Immune Regulation
- Glycosylation and Glycoproteins Research
- Pneumocystis jirovecii pneumonia detection and treatment
- Viral Infections and Vectors
- Systemic Lupus Erythematosus Research
Scripps Research Institute
2012-2024
Massachusetts General Hospital
2024
Harvard University
2024
Center for Experimental and Clinical Infection Research
2023
Medizinische Hochschule Hannover
2023
Centre for Individualised Infection Medicine
2023
Helmholtz Centre for Infection Research
2023
Scripps (United States)
2021
Scripps Institution of Oceanography
2021
University of California, San Diego
2015
Targeting STING for cancer therapy Activation of the (stimulator interferon genes) protein by cyclic dinucleotide metabolites plays a critical role in antitumor immunity. The development synthetic agonists is therefore being pursued as strategy therapy, but inherent instability dinucleotides has limited current efforts. Pan et al. and Chin identified stable that act “closed” conformation similar to natural ligand, guanosine monophosphate–adenosine monophosphate (see Perspective Gajewski...
Significance The sphingosine 1-phosphate receptor (S1PR1) is known to act by multiple mechanisms: limiting lymphocyte egress from secondary lymphoid organs, suppressing proinflammatory endothelial cell function, and acting directly on neurons astrocytes. Here, we report that (S1P)-S1PR1 signaling in plasmacytoid dendritic cells (pDCs) inhibits IFN-α autoamplification induced degradation of the interferon alpha 1 (IFNAR1) suppression signal transducer activator transcription (STAT1)...
The molecular pharmacology of the G protein–coupled receptors for sphingosine 1-phosphate (S1P) provides important insight into established and new therapeutic targets. A new, potent bitopic S1P<sub>3</sub> antagonist, SPM-354, with in vivo activity, has been used, together S1P<sub>3</sub>-knockin S1P<sub>3</sub>-knockout mice to define spatial functional properties regulating cardiac conduction. We show that is a key direct regulator rhythm both isolated perfused hearts....
Chronic infection and cancer are associated with suppressed T cell responses in the presence of cognate antigen. Recent work identified memory-like CXCR5+ TCF1+ CD8+ cells that sustain during persistent proliferate upon anti-PD1 treatment. Approaches to expand these sought. We show blockade interferon type 1 (IFN-I) receptor leads expansion an IL-27– STAT1-dependent manner. IFNAR1 promoted accelerated division retention TCF1 virus-specific cells. found cell–intrinsic IL-27 signaling...
Stimulation of the T cell antigen receptor (TCR) activates a set non-receptor protein tyrosine kinases that assist in delivering signals to interior. Among presumed substrates for these kinases, adaptor proteins, which juxtapose effector enzyme systems with complex, figure prominently. Previous studies suggested Lnk, 38-kDa consisting single SH2 domain and region containing potential phosphorylation sites, might serve join Grb2, phospholipase C-γ1, phosphatidylinositol 3-kinase TCR. To...
Sphingosine 1-phosphate receptor 1 (S1P<sub>1</sub>) is a G protein–coupled that critical for proper lymphocyte development and recirculation. Agonists to S1P<sub>1</sub> are currently in use clinically the treatment of multiple sclerosis, these drugs may act on both expressed lymphocytes within central nervous system. deficiency cause sequestration lymph nodes. In present study, we show antagonism induces nodes similar observed with agonists while upregulating endothelial cells....
Understanding vascular growth and maturation in developing tumors has important implications for tumor progression, spread, ultimately host survival. Modulating the signaling of endothelial G protein-coupled receptors (GPCRs) blood lymphatic vessels can enhance or limit progression. Sphingosine 1-phosphate receptor 1 (S1PR ) is a GPCR circulating lysophospholipid S1P that highly expressed vessels. Using S1PR - enhanced green fluorescent protein (eGFP) mouse model combination with intravital...
USP18 acts as a key effector molecule downstream of IFN-I signaling to promote primary and secondary bacterial infections.
Adult stem cells play a crucial role in tissue homeostasis and repair through multiple mechanisms. In addition to being able replace aged or damaged cells, provide signals that contribute the maintenance function of neighboring cells. lung, airway basal also produce cytokines chemokines response inhaled irritants, allergens, pathogens, which affect specific immune cell populations shape nature response. However, direct cell-to-cell signaling contact between has not been demonstrated....
The tyrosine kinase Jak3 plays a key role in transducing signals from the IL-2, -4, -7, -9, and -15 receptors. Mice lacking exhibit profound, early block both B T cell development. To examine mechanisms whereby influences function, we have reconstituted thymic development Jak3-/- animals by introducing transgene which expression was driven lck proximal promoter. Thymic reconstitution required activity, as catalytically inactive did not restore Furthermore, thymus-restricted pattern of...
GTP affinity probes are important tools for the study of GTP-binding proteins, and proteomic profiling is a powerful methodology well suited such diverse class proteins. Here, we synthesize characterize photoreactive probe that covalently photocross-links to protein targets has an alkyne handle click chemistry conjugation reporter tags. The GTP-BP-yne facilitated identification variety proteins by mass spectrometry, as small GTPases members GTP1/OBG family. Several ATP-binding were also...
An important checkpoint in early thymocyte development ensures that only thymocytes with an in-frame T cell receptor for antigen β (TCR-β) gene rearrangement will continue to mature. Proper assembly of the TCR-β chain into pre-TCR complex delivers signals through src-family protein tyrosine kinase p56lck stimulate proliferation and differentiation CD4+CD8+ stage. However, biochemical mechanisms governing activation remain poorly understood. In more mature thymocytes, is associated...
BACKGROUND/AIMS: During an immune response, type I interferon (IFN-I) signaling induces a wide range of changes, including those which are required to overcome viral infection and suppress cytotoxic T cells avoid immunopathology. certain bacterial infections, IFN-I exerts largely detrimental effects. Although the family proteins all share one common receptor, biologic responses vary depending on subtype. Here, we asked if subtype dominates pro-bacterial effect found that control Listeria...
Abstract The TAM family of receptor tyrosine kinases (MERTK, AXL, and TYRO3) are expressed on DCs macrophages, they serve a critical role in efferocytosis, by which apoptotic bodies cleared engulfment. Their activation drives phagocytic activity concomitant to promoting an immuno-suppressive, tolerogenic state the M2 polarization macrophages. This dual signaling mechanism allows for clearance cells undergoing non-pathologic turnover without inappropriately breaking self-tolerance driving...
Abstract ISG15, an IFN-stimulated gene, plays a crucial role in modulating immune responses during viral infections. Its upregulation is part of the host’s defense mechanism against viruses, contributing to antiviral state cells. However, altered ISG15 expression can also lead dysregulation and pathological outcomes, particularly persistent Understanding balance promoting immunity while avoiding immune-mediated pathology essential for developing targeted therapeutic interventions diseases....
Abstract Cytokine storm during respiratory viral infection is an indicator of disease severity and poor prognosis. Type 1 interferon (IFN-I) production signaling has been reported to be causal in cytokine storm-associated pathology several infections, however, the mechanisms by which IFN-I promotes pathogenesis remain poorly understood. Here, using Usp18- deficient, USP18 enzymatic-inactive Isg15 -deficient mouse models, we report that lack deISGylation persistent leads severe immune...
SUMMARY Vaccination-induced protection against influenza is greatly diminished and increasingly heterogeneous with age. We investigated longitudinally (up to five timepoints) a cohort of 234 elderly vaccinees across two independent seasons including up six modalities (multi-omics immunological parameters). System-level analyses revealed responders exhibited time-dependent changes attributed productive vaccine response all omics layers whereas non-responders did not follow such dynamics,...
Electrophilic compounds originating from nature or chemical synthesis have profound effects on immune cells. These are thought to act by cysteine modification alter the functions of immune-relevant proteins; however, our understanding electrophile-sensitive cysteines in human proteome remains limited. Here, we present a global map primary T cells that susceptible covalent electrophilic small molecules. More than 3000 covalently liganded were found functionally and structurally diverse...
Abstract Electrophilic compounds originating from nature or chemical synthesis have profound effects on immune cells. These are thought to act by cysteine modification alter the functions of immune-relevant proteins; however, our understanding electrophile-sensitive cysteines in human proteome remains limited. Here, we present a global map primary T cells that susceptible covalent electrophilic small molecules. More than 3000 covalently liganded were found functionally and structurally...
Type 1 interferon provides potent antiviral defense but unchecked IFN-I signaling can lead to pathology or immune suppression. The mechanisms by which contributes disease pathogenesis remain poorly understood. Here, using Usp18-deficient, USP18 enzymatic-inactive and Isg15-deficient mouse models, we report that lack of enzymatic function during persistent viral infection leads severe characterized hematological disruptions, pulmonary cytokine amplification, lung vascular leakage death. Lack...