Biochemistry and Pharmacology - Research Publications
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ItemSystemic inflammatory response syndrome triggered by blood-borne pathogens induces prolonged dendritic cell paralysis and immunosuppression(CELL PRESS, 2024-02-27)Blood-borne pathogens can cause systemic inflammatory response syndrome (SIRS) followed by protracted, potentially lethal immunosuppression. The mechanisms responsible for impaired immunity post-SIRS remain unclear. We show that SIRS triggered by pathogen mimics or malaria infection leads to functional paralysis of conventional dendritic cells (cDCs). Paralysis affects several generations of cDCs and impairs immunity for 3-4 weeks. Paralyzed cDCs display distinct transcriptomic and phenotypic signatures and show impaired capacity to capture and present antigens in vivo. They also display altered cytokine production patterns upon stimulation. The paralysis program is not initiated in the bone marrow but during final cDC differentiation in peripheral tissues under the influence of local secondary signals that persist after resolution of SIRS. Vaccination with monoclonal antibodies that target cDC receptors or blockade of transforming growth factor β partially overcomes paralysis and immunosuppression. This work provides insights into the mechanisms of paralysis and describes strategies to restore immunocompetence post-SIRS.
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ItemNo Preview AvailableMulti-targeted loss of the antigen presentation molecule MR1 during HSV-1 and HSV-2 infection.(Elsevier BV, 2024-02-16)The major histocompatibility complex (MHC), Class-I-related (MR1) molecule presents microbiome-synthesized metabolites to Mucosal-associated invariant T (MAIT) cells, present at sites of herpes simplex virus (HSV) infection. During HSV type 1 (HSV-1) infection there is a profound and rapid loss of MR1, in part due to expression of unique short 3 protein. Here we show that virion host shutoff RNase protein downregulates MR1 protein, through loss of MR1 transcripts. Furthermore, a third viral protein, infected cell protein 22, also downregulates MR1, but not classical MHC-I molecules. This occurs early in the MR1 trafficking pathway through proteasomal degradation. Finally, HSV-2 infection results in the loss of MR1 transcripts, and intracellular and surface MR1 protein, comparable to that seen during HSV-1 infection. Thus HSV coordinates a multifaceted attack on the MR1 antigen presentation pathway, potentially protecting infected cells from MAIT cell T cell receptor-mediated detection at sites of primary infection and reactivation.
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ItemMR1 antigen presentation to MAIT cells and other MR1-restricted T cells(NATURE PORTFOLIO, 2024-03)MHC antigen presentation plays a fundamental role in adaptive and semi-invariant T cell immunity. Distinct MHC molecules bind antigens that differ in chemical structure, origin and location and present them to specialized T cells. MHC class I-related protein 1 (MR1) presents a range of small molecule antigens to MR1-restricted T (MR1T) lymphocytes. The best studied MR1 ligands are derived from microbial metabolism and are recognized by a major class of MR1T cells known as mucosal-associated invariant T (MAIT) cells. Here, we describe the MR1 antigen presentation pathway: the known types of antigens presented by MR1, the location where MR1-antigen complexes form, the route followed by the complexes to the cell surface, the mechanisms involved in termination of MR1 antigen presentation and the accessory cellular proteins that comprise the MR1 antigen presentation machinery. The current road map of the MR1 antigen presentation pathway reveals potential strategies for therapeutic manipulation of MR1T cell function and provides a foundation for further studies that will lead to a deeper understanding of MR1-mediated immunity.
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ItemNo Preview AvailableMonocyte Signature Associated with Herpes Simplex Virus Reactivation and Neurological Recovery after Brain Injury(AMER THORACIC SOC, 2022-08-01)Rationale: Brain injury induces systemic immunosuppression, increasing the risk of viral reactivations and altering neurological recovery. Objectives: To determine if systemic immune alterations and lung replication of herpesviridae are associated and can help predict outcomes after brain injury. Methods: We collected peripheral blood mononuclear cells in patients with severe brain injury requiring invasive mechanical ventilation. We systematically searched for respiratory herpes simplex virus (HSV) replications in tracheal aspirates. We also performed chromatin immunoprecipitation sequencing, RNA-sequencing, and in vitro functional assays of monocytes and CD4 T cells collected on Day 1 to characterize the immune response to severe acute brain injury. The primary outcome was the Glasgow Outcome Scale Extended at 6 months. Measurements and Main Results: In 344 patients with severe brain injury, lung HSV reactivations were observed in 39% of the 232 patients seropositive for HSV and independently associated with poor neurological recovery at 6 months (hazard ratio, 1.90; 95% confidence interval, 1.08-3.57). Weighted gene coexpression network analyses of the transcriptomic response of monocytes to brain injury defined a module of 721 genes, including PD-L1 and CD80, enriched for the binding DNA motif of the transcriptional factor Zeb2 and whose ontogenic analyses revealed decreased IFN-γ-mediated and antiviral response signaling pathways. This monocyte signature was preserved in a validation cohort and predicted the neurological outcome at 6 months with good accuracy (area under the curve, 0.786; 95% confidence interval, 0.593-0.978). Conclusions: A specific monocyte signature is associated with HSV reactivation and predicts poor recovery after brain injury. The alterations of the immune control of herpesviridae replication are understudied and represent a novel therapeutic target.
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ItemNo Preview AvailableSpatiotemporal Adaptations of Macrophage and Dendritic Cell Development and Function(ANNUAL REVIEWS, 2022)Macrophages and conventional dendritic cells (cDCs) are distributed throughout the body, maintaining tissue homeostasis and tolerance to self and orchestrating innate and adaptive immunity against infection and cancer. As they complement each other, it is important to understand how they cooperate and the mechanisms that integrate their functions. Both are exposed to commensal microbes, pathogens, and other environmental challenges that differ widely among anatomical locations and over time. To adjust to these varying conditions, macrophages and cDCs acquire spatiotemporal adaptations (STAs) at different stages of their life cycle that determine how they respond to infection. The STAs acquired in response to previous infections can result in increased responsiveness to infection, termed training, or in reduced responses, termed paralysis, which in extreme cases can cause immunosuppression. Understanding the developmental stage and location where macrophages and cDCs acquire their STAs, and the molecular and cellular players involved in their induction, may afford opportunities to harness their beneficial outcomes and avoid or reverse their deleterious effects. Here we review our current understanding of macrophage and cDC development, life cycle, function, and STA acquisition before, during, and after infection.We propose a unified framework to explain how these two cell types adjust their activities to changing conditions over space and time to coordinate their immunosurveillance functions.
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ItemMarginal zone B cells acquire dendritic cell functions by trogocytosis(AMER ASSOC ADVANCEMENT SCIENCE, 2022-02-11)Marginal zone (MZ) B cells produce broad-spectrum antibodies that protect against infection early in life. In some instances, antibody production requires MZ B cells to display pathogen antigens bound to major histocompatibility complex class II (MHC II) molecules to T cells. We describe the trogocytic acquisition of these molecules from conventional dendritic cells (cDCs). Complement component 3 (C3) binds to murine and human MHC II on cDCs. MZ B cells recognize C3 with complement receptor 2 (CR2) and trogocytose the MHC II-C3 complexes, which become exposed on their cell surface. The ubiquitin ligase MARCH1 limits the number of MHC II-C3 complexes displayed on cDCs to prevent their elimination through excessive trogocytosis. Capture of C3 by MHC II thus enables the transfer of cDC-like properties to MZ B cells.
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ItemNo Preview AvailableVaricella Zoster Virus Impairs Expression of the Nonclassical Major Histocompatibility Complex Class I-Related Gene Protein (MR1)(OXFORD UNIV PRESS INC, 2023-02-01)The antigen presentation molecule MR1 (major histocompatibility complex, class I-related) presents ligands derived from the riboflavin (vitamin B) synthesis pathway, which is not present in mammalian species or viruses, to mucosal-associated invariant T (MAIT) cells. In this study, we demonstrate that varicella zoster virus (VZV) profoundly suppresses MR1 expression. We show that VZV targets the intracellular reservoir of immature MR1 for degradation, while preexisting, ligand-bound cell surface MR1 is protected from such targeting, thereby highlighting an intricate temporal relationship between infection and ligand availability. We also identify VZV open reading frame (ORF) 66 as functioning to suppress MR1 expression when this viral protein is expressed during transient transfection, but this is not apparent during infection with a VZV mutant virus lacking ORF66 expression. This indicates that VZV is likely to encode multiple viral genes that target MR1. Overall, we identify an immunomodulatory function of VZV whereby infection suppresses the MR1 biosynthesis pathway.
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ItemNo Preview AvailableIntestinal microbe-derived metabolites instruct macrophages in the lungs(NATURE PORTFOLIO, 2022-12)
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ItemNo Preview AvailableTrogocytosis and cross-dressing in antigen presentation(CURRENT BIOLOGY LTD, 2023-08)Antigen (Ag)-presenting cells capture or synthesize Ags that are processed into peptides bound and displayed on the plasma membrane by major histocompatibility complex (MHC) molecules. Here, we review a mechanism that enables cells to present Ag-loaded MHC molecules that they have not produced themselves, namely trogocytosis. During trogocytosis, a cell acquires fragments from another living cell without, in most cases, affecting the viability of the donor cell. The trogocytic cell can incorporate into its own plasma membrane (becoming cross-dressed) proteins acquired from the donor cell, including intact Ag and MHC molecules. Trogocytosis and cross-dressing expand the immunological functions that immune and nonimmune cells are able to carry out, with both beneficial and deleterious consequences.