A5032789364- Inflammasome and immune disorders
- Tuberculosis Research and Epidemiology
- Biomedical Research and Pathophysiology
- Immune Response and Inflammation
- Streptococcal Infections and Treatments
- interferon and immune responses
- Autoimmune and Inflammatory Disorders Research
- ATP Synthase and ATPases Research
- Kawasaki Disease and Coronary Complications
- Cell death mechanisms and regulation
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Cancer therapeutics and mechanisms
- IL-33, ST2, and ILC Pathways
- Bone Tumor Diagnosis and Treatments
- Heme Oxygenase-1 and Carbon Monoxide
- Hepatitis Viruses Studies and Epidemiology
- vaccines and immunoinformatics approaches
- Salmonella and Campylobacter epidemiology
- Liver Disease and Transplantation
- Sphingolipid Metabolism and Signaling
- Biochemical and Molecular Research
- Oral and Maxillofacial Pathology
- Antibiotic Resistance in Bacteria
- Mycobacterium research and diagnosis
- Neonatal and Maternal Infections
The University of Queensland
2015-2024
Centenary Institute
2019
Cornell University
2007-2013
The University of Sydney
2013
Neutrophils form gasdermin D pores and expel antimicrobial neutrophil extracellular traps to defend against cytosolic bacteria.
Host-protective caspase-1 activity must be tightly regulated to prevent pathology, but mechanisms controlling the duration of cellular are unknown. Caspase-1 is activated on inflammasomes, signaling platforms that facilitate dimerization and autoprocessing. Previous studies with recombinant protein identified a tetramer composed two p20 p10 subunits (p20/p10) as an active species. In this study, we report in cell, dominant species dimers elicited by inflammasomes fact full-length p46...
Humans encode two inflammatory caspases that detect cytoplasmic LPS, caspase‐4 and caspase‐5. When activated, these trigger pyroptotic cell death caspase‐1‐dependent IL‐1β production; however the mechanism underlying this process is not yet confirmed. We now show a specific NLRP3 inhibitor, MCC950, prevents caspase‐4/5‐dependent production elicited by transfected LPS. Given both caspase‐5 can it possible proteins exhibit some degree of redundancy. Therefore, we generated human monocytic...
IL-1β requires processing by caspase-1 to generate the active, pro-inflammatory cytokine. Acute secretion from inflammasome-activated macrophages caspase-1-dependent GSDMD cleavage, which also induces pyroptosis. Mechanisms of pyroptotic and non-pyroptotic cells, precise functions therein, are unresolved. Here, we show that, while efficient early endogenous primary myeloid cells in vitro GSDMD, later release vivo proceeds independently GSDMD. maturation is sufficient for slow,...
Significance Chronic bacterial infections, such as those caused by Mycobacterium tuberculosis ( Mtb ), continue to claim the lives of millions people. New antibiotics are needed treat these but their development is hindered a lack targets whose inhibition quickly eradicates pathogens and prevents survival drug-tolerant persisters. We describe unique dual-control (DUC) switch that combines repression transcription controlled proteolysis silence gene activities in . By conditionally...
Summary Bacterial nutrition is an essential aspect of host–pathogen interaction. For the intracellular pathogen Mycobacterium tuberculosis (Mtb), causative agent in humans, fatty acids derived from lipid droplets are considered major carbon source. However, many other soluble nutrients available inside host cells and may be used as alternative sources. Lactate pyruvate abundant human fluids, particularly during inflammation. In this work, we study Mtb metabolism lactate combining classic...
Many processes that are essential for mycobacterial growth poorly understood. To facilitate genetic analyses of such in mycobacteria, we and others have developed regulated expression systems repressed by a tetracycline repressor (TetR) induced with tetracyclines, permitting the construction conditional mutants genes. A disadvantage these is tetracyclines function as transcriptional inducers to be removed initiate gene silencing. Recently, reverse TetR were identified require co-repressors....
We aimed to characterize antimicrobial zinc trafficking within macrophages and determine whether the professional intramacrophage pathogen Salmonella enterica serovar Typhimurium (S. Typhimurium) subverts this pathway. Using both Escherichia coli S. Typhimurium, we show that TLR signaling promotes accumulation of vesicular primary human macrophages. Vesicular is delivered E. promote microbial clearance, whereas evades response via pathogenicity island (SPI)-1. Even in absence SPI-1 exporter...
Vincristine is an important component of many regimens used for pediatric and adult malignancies, but it causes a dose-limiting sensorimotor neuropathy which there no effective treatment. This study aimed to delineate the neuro-inflammatory mechanisms contributing development mechanical allodynia gait disturbances in murine model vincristine-induced neuropathy, as well identify novel treatment approaches. Here, we show that peripheral driven by activation NLRP3 inflammasome subsequent...
Abstract Inflammasomes are signaling hubs that activate inflammatory caspases to drive cytokine maturation and cell lysis. Inflammasome activation by Salmonella Typhimurium infection or Salmonella-derived molecules is extensively studied in murine myeloid cells. Salmonella-induced inflammasome human innate immune cells, however, poorly characterized. Here, we show mutation inactivate the pathogenicity island-2 type III secretion system (SPI2 T3SS) potentiates S. Typhimurium-induced responses...
Abstract While apoptosis dismantles the cell to enforce immunological silence, pyroptotic death provokes inflammation. Little is known of structural architecture cells undergoing pyroptosis, and whether corpses are immunogenic. Here we report that inflammasomes trigger Gasdermin-D- calcium-dependent eruption filopodia from plasma membrane minutes before rupture, crown resultant corpse with filopodia. As a rich store F-actin, recognized by dendritic through F-actin receptor, CLEC9A (DNGR1)....
The globally significant human pathogen group A <i>Streptococcus</i> (GAS) sequesters the host protease plasmin to cell surface during invasive disease initiation. Recent evidence has shown that localized activity prevents opsonization of several bacterial species by key components innate immune system in vitro. Here we demonstrate at GAS resulted degradation complement factor C3b, and plasminogen acquisition is associated with a decrease C3b neutrophil-mediated killing...
Group A Streptococcus (GAS) is a Gram-positive bacterial pathogen that causes an array of infectious diseases in humans. Accumulating clinical evidence suggests proinflammatory interleukin (IL)-1β signaling plays important role GAS disease progression. The host regulates the production and secretion IL-1β via cytosolic inflammasome pathway. Activation NLR family pyrin domain-containing 3 (NLRP3) complex requires two signals: priming signal stimulates increased transcription genes encoding...
Caspase-1 location in cells has been studied with fluorochrome-labeled inhibitors of caspase-1 (FLICA reagents). We report that FLICA reagents have limited cell-membrane permeability. This impacts experimental design as intact membranes, including knockout cells, are not appropriate controls for inflammasome-induced gasdermin D membrane pores. is an inflammatory initiator caspase responsible the maturation pro-inflammatory cytokines IL-1β and IL-18 pyroptotic cell death. Inhibitors important...
Abstract In Gram-negative bacterial sepsis, excessive caspase 4/11 activation in response to circulating lipid LPS (endotoxemia) can cause organ damage and mortality. Current inhibitors of also block 1 activity are therefore not appealing clinical candidates for treating sepsis. Here, we identify double-unsaturated 18:2 cardiolipin as a selective inhibitor 4/11-dependent inflammatory cytokine secretion pyroptosis, without affecting caspase-1 responses. Cardiolipin targets the CARD domain...