A5044293923- Autophagy in Disease and Therapy
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Immune Response and Inflammation
- Immune cells in cancer
- Viral gastroenteritis research and epidemiology
- Redox biology and oxidative stress
- Virus-based gene therapy research
- Immunotherapy and Immune Responses
- Toxoplasma gondii Research Studies
- Adenosine and Purinergic Signaling
- Viral Infections and Immunology Research
- CRISPR and Genetic Engineering
- Cytomegalovirus and herpesvirus research
- T-cell and B-cell Immunology
- Influenza Virus Research Studies
- CAR-T cell therapy research
- Respiratory viral infections research
- Advanced Glycation End Products research
- Inflammasome and immune disorders
- Immune Cell Function and Interaction
- Cell Adhesion Molecules Research
- Sulfur Compounds in Biology
- Extracellular vesicles in disease
- Heme Oxygenase-1 and Carbon Monoxide
- Skin and Cellular Biology Research
VIR Biotechnology (United States)
2020-2024
University of Calgary
2011-2023
Washington University in St. Louis
2018-2023
Matrix Research (United States)
2014
University of Veterinary Medicine
2010
BC Cancer Agency
2009
Aiding and abetting norovirus disease Norovirus is highly infectious usually causes transient, acute disease. In some individuals, persists associated with inflammatory bowel disorders. While investigating the cell tropism for murine norovirus, Wilen et al. discovered that a rare type, tuft cells, carrying CD300lf receptor were virus's specific target. Tuft cells proliferate in response to type 2 cytokines interleukin-4 interleukin-25, which thereby amplify infection. Moreover, infected are...
Rapidly evolving influenza A viruses (IAVs) and B (IBVs) are major causes of recurrent lower respiratory tract infections. Current vaccines elicit antibodies predominantly to the highly variable head region haemagglutinin their effectiveness is limited by viral drift1 suboptimal immune responses2. Here we describe a neuraminidase-targeting monoclonal antibody, FNI9, that potently inhibits enzymatic activity all group 1 2 IAVs, as well Victoria/2/87-like, Yamagata/16/88-like ancestral IBVs....
Epithelial permeability is often increased in inflammatory bowel diseases. We hypothesized that perturbed mitochondrial function would cause barrier dysfunction and hence epithelial mitochondria could be targeted to treat intestinal inflammation. Mitochondrial was induced human colon-derived cell lines or colonic biopsy specimens using dinitrophenol, assessed by transepithelial flux of Escherichia coli with without mitochondria-targeted antioxidant (MTA) cotreatment. The impact antioxidants...
The phagosomal lumen in macrophages is the site of numerous interacting chemistries that mediate microbial killing, macromolecular degradation, and antigen processing. Using a non-hypothesis-based screen to explore interconnectivity functions, we found NADPH oxidase (NOX2) negatively regulates levels proteolysis within maturing phagosome macrophages. Unlike NOX2 mechanism proteolytic control reported dendritic cells, this phenomenon independent changes lumenal pH also hydrolase delivery...
The chemistries within phagosomes of APCs mediate microbial destruction as well generate peptides for presentation on MHC class II. antimicrobial effector NADPH oxidase (NOX2), which generates superoxide maturing phagosomes, has also been shown to regulate activities cysteine cathepsins through modulation the lumenal redox potential. Using real-time analyses microenvironmental parameters, in conjunction with hydrolysis pattern assessment phagocytosed proteins, we demonstrated that NOX2...
Although it is known that lysosomal cysteine cathepsins require a reducing environment for optimal activity, not firmly established how these enzymes are maintained in their reduced-active state the acidic and occasionally oxidative within phagosomes lysosomes. γ-Interferon-inducible thiol reductase (GILT) has been only enzyme described endosomes, lysosomes, with potential to catalyze reduction of cathepsins. Our goal current study was assess effect GILT on major phagosomal functions an...
Second mitochondrial activator of caspase (Smac)-mimetic compounds and oncolytic viruses were developed to kill cancer cells directly. However, Smac-mimetic compound virus therapies also modulate host immune responses in ways we hypothesized would complement one another promoting anticancer T-cell immunity. We show that synergize driving CD8
Hypomethylation of the cathepsin Z locus has been proposed as an epigenetic risk factor for multiple sclerosis (MS). Cathepsin is a unique lysosomal cysteine expressed primarily by antigen presenting cells. While expression associated with neuroinflammatory disorders, role in mediating neuroinflammation not previously established. Experimental autoimmune encephalomyelitis (EAE) was induced both wildtype mice and deficient Z. The effects Z-deficiency on processing presentation autoantigen...
Noroviruses (NoVs) are a leading cause of gastroenteritis worldwide, yet host factors that restrict NoV replication not well understood. Here, we use CRISPR activation genome-wide screening to identify genes can inhibit murine norovirus (MNoV) in human cells. Our screens identified with high confidence 49 MNoV infection when overexpressed. A significant number these interferon and immune regulation signaling networks, but surprisingly, the majority neither associated innate or adaptive...
Macrophages activated with interferon-γ (IFN-γ) in combination other proinflammatory stimuli, such as lipopolysaccharide or tumor necrosis factor-α (TNF-α), respond transcriptional and cellular changes that enhance clearance of intracellular pathogens at the risk damaging tissues. IFN-γ effects must therefore be carefully balanced inhibitory mechanisms to prevent immunopathology. We performed a genome-wide CRISPR knockout screen macrophage cell line identify negative regulators responses....
Recognition of pathogen-or-damage-associated molecular patterns is critical to inflammation. However, most exist within intact microbes/cells and are typically part non-diffusible, stable macromolecules that not optimally immunostimulatory or available for immune detection. Partial digestion following phagocytosis potentially generates new diffusible patterns, however, our current understanding phagosomal biology would have these molecules sequestered destroyed phagolysosomes. Here, we show...
Significance Sepsis is a multifactorial syndrome with increasing incidence and significant mortality. While previous work implicated tumor necrosis factor (TNF)-induced cell death in sepsis, role for interferon-gamma (IFNγ), which synergizes TNF to activate macrophages, incompletely understood. We demonstrate using genome-wide CRISPR/Cas9 screening that genes regulating the cytosolic degradative pathway of autophagy protect against IFNγ-induced death. This requires its receptor depends on...
Transcription factor EB (TFEB) activates lysosomal biogenesis genes in response to environmental cues. Given implications of impaired TFEB signaling and dysfunction metabolic, neurological, infectious diseases, we aim systematically identify TFEB-directed circuits by examining transcriptional responses subcellular localization stimulation. We reveal that steady-state nuclear is sufficient activate transcription lysosomal, autophagy, innate immunity genes, whereas other targets require higher...
Interferon-γ (IFNγ) is a critical mediator of cell-intrinsic immunity to intracellular pathogens. Understanding the complex cellular mechanisms supporting robust interferon-γ-induced host defenses could aid in developing new therapeutics treat infections. Here, we examined impact autophagy genes response. We demonstrate that within pathway including
NK cells have two main functions, namely cell-mediated cytotoxicity and production of cytokines. Multiple inhibitory receptors that regulate NK-cell been characterized whereas little is known about regulating cytokine production. Here we report CD72, which considered to be an important co-receptor B-cell activation, also expressed on mouse cells. expressing high levels upon stimulation with IL-12 IL-18 or target cells, produce significantly less IFN-gamma than those low both subsets are...
Porcine reproductive and respiratory syndrome virus (PRRSV), a positive-sense, ssRNA of the genus Arterivirus, is devastating disease swine worldwide. Key early targets PRRSV infection in pigs include professional phagocytes lung, such as alveolar interstitial macrophages dendritic cells, dysfunction which believed to be responsible for much associated mortality. In order study effect on phagocyte function, development robust, reproducible model would advantageous. Given limitations current...
In the aftermath of COVID-19 pandemic, opportunities to modulate biological pathways common lifecycles viruses need be carefully considered.
Proteolysis and the reduction of disulfides, both major components protein degradation, are profoundly influenced by phagosomal redox conditions in macrophages. We evaluated activation phagocytic receptors that known to influence phagocyte NADPH oxidase (NOX2), its effect on degradation. Population-based single phagosome analyses chemistries murine macrophages revealed NOX2 via Fcγ receptor (FcγR) during phagocytosis decreased rates proteolysis disulfide reduction. Immunoglobulin G...
Abstract Although endosomes, lysosomes, and phagosomes require a reductive environment for the optimal activity of disulfide reductases other thiol-dependent enzymes, how these environments are established maintained remain unknown. Our goal in this study was to begin elucidate redox control systems responsible maintaining redox-sensitive enzymatic activities phagolysosome murine macrophages. Through use specific inhibitors genetic knockdown known we identified pathways that influence...