A5061906689- Inflammasome and immune disorders
- SARS-CoV-2 and COVID-19 Research
- COVID-19 Clinical Research Studies
- interferon and immune responses
- Immune Cell Function and Interaction
- Long-Term Effects of COVID-19
- Immune Response and Inflammation
- Viral Infections and Outbreaks Research
- Adipokines, Inflammation, and Metabolic Diseases
- Zoonotic diseases and public health
- Animal Disease Management and Epidemiology
- Monoclonal and Polyclonal Antibodies Research
- Cytomegalovirus and herpesvirus research
- Cytokine Signaling Pathways and Interactions
- RNA Research and Splicing
- Respiratory viral infections research
- Intracranial Aneurysms: Treatment and Complications
- Kawasaki Disease and Coronary Complications
- Cholesterol and Lipid Metabolism
- Immune responses and vaccinations
- Immune cells in cancer
- Phagocytosis and Immune Regulation
- Atherosclerosis and Cardiovascular Diseases
- Epigenetics and DNA Methylation
- Histone Deacetylase Inhibitors Research
The University of Queensland
2010-2024
MRC Laboratory of Molecular Biology
2017-2019
Medical Research Council
2017-2019
University of Bonn
2012-2017
University Hospital Bonn
2012-2017
Institute of Science and Ethics
2014
Highlights•Macrophages react with specific transcriptional programming upon distinct signals•Activation by TNF, PGE2, and P3C activates a STAT4-associated program•NFKB1, JUNB, CREB1 are central transcription factors of macrophage activation•Inflammatory signatures lost in alveolar macrophages from COPD patientsSummaryMacrophage activation is associated profound reprogramming. Although much progress has been made the understanding activation, polarization, function, programs regulating these...
Methods for the targeted disruption of protein function have revolutionized science and greatly expedited systematic characterization genes. Two main approaches are currently used to disrupt function: DNA knockout RNA interference, which act at genome mRNA level, respectively. A method that directly alters endogenous levels is not available. Here, we present Trim-Away, a technique degrade proteins acutely in mammalian cells without prior modification or mRNA. Trim-Away harnesses cellular...
The cyclic oligosaccharide 2-hydroxypropyl-β-cyclodextrin facilitates atheroprotective mechanisms through oxysterol-mediated reprogramming of macrophages.
Evolutionary change in gene expression is generally considered to be a major driver of phenotypic differences between species. We investigated innate immune diversification by analyzing interspecies the transcriptional responses primary human and mouse macrophages Toll-like receptor (TLR)–4 agonist lipopolysaccharide (LPS). By using custom platform permitting cross-species interrogation coupled with deep sequencing mRNA 5′ ends, we identified extensive divergence LPS-regulated orthologous...
Thrombotic and microvascular complications are frequently seen in deceased COVID-19 patients. However, whether this is caused by direct viral infection of the endothelium or inflammation-induced endothelial activation remains highly contentious.Here, we use patient autopsy samples, primary human cells an vitro model pulmonary epithelial-endothelial cell barrier.We show that express very low levels SARS-CoV-2 receptor ACE2 protease TMPRSS2, which blocks their capacity for productive...
Abstract Selective inhibitor studies in macrophages implicate class II HDAC enzymes TLR-mediated inflammatory pathways and I HDACs as negative regulators. Broad-spectrum inhibitors of are therapeutic many disease models but exacerbated a mouse model atherosclerosis. have anti- proinflammatory effects on vitro. We report here that several broad-spectrum inhibitors, including TSA SAHA, suppressed the LPS-induced mRNA expression mediators Edn-1, Ccl-7/MCP-3, Il-12p40 amplified proatherogenic...
Cytokines and IFNs downstream of innate immune pathways are critical for mounting an appropriate response to microbial infection. However, the expression these inflammatory mediators is tightly regulated, as uncontrolled production can result in tissue damage lead chronic conditions autoimmune diseases. Activating transcription factor 3 (ATF3) important transcriptional modulator that limits by controlling a number cytokines chemokines. its role modulating IFN responses remains poorly...
Macrophages are key cellular contributors to the pathogenesis of COVID-19, disease caused by virus SARS-CoV-2. The SARS-CoV-2 entry receptor ACE2 is present only on a subset macrophages at sites infection in humans. Here, we investigated whether can enter macrophages, replicate, and release new viral progeny; need sense replicating drive cytokine release; and, if so, involved these mechanisms. We found that could enter, but did not replicate within, ACE2-deficient human primary induce...
Broad-spectrum inhibitors of histone deacetylases (HDACs) constrain Toll-like receptor (TLR)-inducible production key proinflammatory mediators. Here we investigated HDAC-dependent inflammatory responses in mouse macrophages. Of the classical Hdacs, Hdac7 was expressed at elevated levels macrophages (thioglycollate-elicited peritoneal macrophages) as compared with bone marrow-derived and RAW264 cell line. Overexpression a specific, alternatively spliced isoform lacking N-terminal 22 amino...
The noncanonical inflammasome is a signalling complex critical for cell defence against cytosolic Gram-negative bacteria. A key step in the human pathway involves unleashing proteolytic activity of caspase-4 within this complex. Caspase-4 induces inflammatory responses by cleaving gasdermin-D (GSDMD) to initiate pyroptosis; however, molecular mechanisms that activate and govern its capacity cleave substrates remain poorly defined. Caspase-11, murine counterpart caspase-4, acquires protease...
Children typically experience more mild symptoms of Coronavirus Disease 2019 (COVID-19) when compared to adults. There is a strong body evidence that children are also less susceptible Severe Acute Respiratory Syndrome 2 (SARS-CoV-2) infection with the ancestral viral isolate. However, emergence SARS-CoV-2 variants concern (VOCs) has been associated an increased number pediatric infections. Whether this result widespread adult vaccination or fundamental changes in biology remain be...
Inflammasomes are potent innate immune signalling complexes that couple cytokine release with pro-inflammatory cell death. However, pathogens have evolved strategies to evade this autonomous system. Here, we show how antibodies combine sensors in primary human macrophages detect viral infection and activate the inflammasome. Our data demonstrate antibody opsonisation of virions can multiple ways. In first, binding adenovirus causes lysosomal damage, activating NLRP3 drive inflammasome...
Sensing of nucleic acids by TLRs is crucial in the host defense against viruses and bacteria. Unc-93 homolog B1 (UNC93B1) regulates trafficking acid-sensing from endoplasmic reticulum to endolysosomes, where encounter their respective ligands become activated. In this article, we show that a carboxyl-terminal tyrosine-based sorting motif (YxxΦ) UNC93B1 differentially human receptor- ligand-specific manner. Destruction YxxΦ abolished TLR7, TLR8, TLR9 activity toward B cells monocytes, whereas...
Genome-wide assessment of protein–DNA interaction by chromatin immunoprecipitation followed massive parallel sequencing (ChIP-seq) is a key technology for studying transcription factor (TF) localization and regulation gene expression. Signal-to-noise-ratio signal specificity in ChIP-seq studies depend on many variables, including antibody affinity specificity. Thus far, efforts to improve reagents experiments have focused mainly generating higher quality antibodies. Here we introduce KOIN...
ABSTRACT Globally, over 65 million individuals are estimated to suffer from post-acute sequelae of COVID-19 (PASC). A large number living with PASC experience cardiovascular symptoms (i.e. chest pain and heart palpitations) (PASC-CVS). The role chronic inflammation in these symptoms, particular persisting for >1 year after SARS-CoV-2 infection, remains be clearly defined. In this cross-sectional study, blood samples were obtained three different sites Australia i) a resolved infection...
The hematopoietic prostaglandin D2 synthase has a proinflammatory effect in range of diseases, including allergic asthma, where its product (PGD2) role regulating many the hallmark disease characteristics. Here we describe development and characterization novel series inhibitors with potency similar to that known inhibitors. Compounds N-benzhydryl-5-(3-hydroxyphenyl)thiophene-2-carboxamide (compound 8) N-(1-amino-1-oxo-3-phenylpropan-2-yl)-6-(thiophen-2-yl)nicotinamide 34) demonstrated low...