ORCID Profile
0000-0001-9159-3021
Current Organisation
Walter and Eliza Hall Institute of Medical Research
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Publisher: Elsevier BV
Date: 11-2019
DOI: 10.1016/J.CELREP.2019.10.087
Abstract: Despite the key role that antibodies play in protection, the cellular processes mediating the acquisition of humoral immunity against malaria are not fully understood. Using an infection model of severe malaria, we find that germinal center (GC) B cells upregulate the transcription factor T-bet during infection. Molecular and cellular analyses reveal that T-bet in B cells is required not only for IgG
Publisher: Elsevier BV
Date: 08-2021
Publisher: Frontiers Media SA
Date: 20-05-2021
DOI: 10.3389/FIMMU.2021.641879
Abstract: Febrile neutropenia (FN) causes treatment disruption and unplanned hospitalization in children with cancer. Serum biomarkers are infrequently used to stratify these patients into high or low risk for serious infection. This study investigated plasma abundance of cytokines in children with FN and their ability to predict bacteraemia. Thirty-three plasma cytokines, C-reactive protein (CRP) and procalcitonin (PCT) were measured using ELISA assays in s les taken at FN presentation (n = 79) and within 8–24 h (Day 2 n = 31). Optimal thresholds for prediction of bacteraemia were identified and the predictive ability of biomarkers in addition to routinely available clinical variables was assessed. The median age of included FN episodes was 6.0 years and eight (10%) had a bacteraemia. On presentation, elevated PCT, IL-10 and Mip1-beta were significantly associated with bacteraemia, while CRP, IL-6 and IL-8 were not. The combination of PCT (≥0.425 ng/ml) and IL-10 (≥4.37 pg/ml) had a sensitivity of 100% (95% CI 68.8–100%) and specificity of 89% (95% CI 80.0–95.0%) for prediction of bacteraemia, correctly identifying all eight bacteraemia episodes and classifying 16 FN episodes as high-risk. There was limited additive benefit of incorporating clinical variables to this model. On Day 2, there was an 11-fold increase in PCT in episodes with a bacteraemia which was significantly higher than that observed in the non-bacteraemia episodes. Elevated PCT and IL-10 accurately identified all bacteraemia episodes in our FN cohort and may enhance the early risk stratification process in this population. Prospective validation and implementation is required to determine the impact on health service utilisation.
Publisher: Proceedings of the National Academy of Sciences
Date: 23-04-2021
Abstract: Neutralizing antibodies are important for immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and as therapeutics for the prevention and treatment of COVID-19. We identified high-affinity nanobodies against SARS-CoV-2 receptor-binding domain and found that nanobody cocktails consisting of two noncompeting nanobodies were able to block ACE2 engagement with RBD variants present in human populations and potently neutralize both wild-type SARS-CoV-2 and the N501Y D614G variant at low concentrations. Prophylactic administration of nanobody cocktails reduced viral loads in mice infected with the N501Y D614G SARS-CoV-2 virus, showing that nanobody cocktails are useful as prophylactic agents against SARS-CoV-2.
Publisher: Hindawi Limited
Date: 06-12-2016
DOI: 10.1111/CMI.12693
Abstract: Infectious diseases are a leading cause of death worldwide. Novel therapeutics are urgently required to treat multidrug-resistant organisms such as Mycobacterium tuberculosis and to mitigate morbidity and mortality caused by acute infections such as malaria and dengue fever virus as well as chronic infections such as human immunodeficiency virus-1 and hepatitis B virus. The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system, which has revolutionized biomedical research, holds great promise for the identification and validation of novel drug targets. Since its discovery as an adaptive immune system in prokaryotes, the CRISPR/Cas9 system has been developed into a multi-faceted genetic modification tool, which can now be used to induce gene deletions or specific gene insertions, such as conditional alleles or endogenous reporters in virtually any organism. The generation of CRISPR/Cas9 libraries that can be used to perform phenotypic whole genome screens provides an important new tool that will aid in the identification of critical host factors involved in the pathogenesis of infectious diseases. In this review, we will discuss the development and recent applications of the CRISPR/Cas9 system used to identify novel regulators, which might become important in the fight against infectious diseases.
Publisher: Springer Science and Business Media LLC
Date: 12-03-2015
Abstract: Subversion of host cell apoptosis is an important survival strategy for viruses to ensure their own proliferation and survival. Certain viruses express proteins homologous in sequence, structure and function to mammalian pro-survival B-cell lymphoma 2 (Bcl-2) proteins, which prevent rapid clearance of infected host cells. In vaccinia virus (VV), the virulence factor F1L was shown to be a potent inhibitor of apoptosis that functions primarily be engaging pro-apoptotic Bim. Variola virus (VAR), the causative agent of smallpox, harbors a homolog of F1L of unknown function. We show that VAR F1L is a potent inhibitor of apoptosis, and unlike all other characterized anti-apoptotic Bcl-2 family members lacks affinity for the Bim Bcl-2 homology 3 (BH3) domain. Instead, VAR F1L engages Bid BH3 as well as Bak and Bax BH3 domains. Unlike its VV homolog, variola F1L only protects against Bax-mediated apoptosis in cellular assays. Crystal structures of variola F1L bound to Bid and Bak BH3 domains reveal that variola F1L forms a domain-swapped Bcl-2 fold, which accommodates Bid and Bak BH3 in the canonical Bcl-2-binding groove, in a manner similar to VV F1L. Despite the observed conservation of structure and sequence, variola F1L inhibits apoptosis using a startlingly different mechanism compared with its VV counterpart. Our results suggest that unlike during VV infection, Bim neutralization may not be required during VAR infection. As molecular determinants for the human-specific tropism of VAR remain essentially unknown, identification of a different mechanism of action and utilization of host factors used by a VAR virulence factor compared with its VV homolog suggest that studying VAR directly may be essential to understand its unique tropism.
Publisher: Oxford University Press (OUP)
Date: 15-12-2018
Abstract: The ability of Mycobacterium tuberculosis to cause disease hinges upon successfully thwarting the innate defenses of the macrophage host cell. The pathogen's trump card is its armory of virulence factors that throw normal host cell signaling into disarray. This process of subverting the macrophage begins upon entry into the cell, when M. tuberculosis actively inhibits the fusion of the bacilli-laden phagosomes with lysosomes. The pathogen then modulates an array of host signal transduction pathways, which d ens the macrophage's host-protective cytokine response, while simultaneously adapting host cell metabolism to stimulate lipid body accumulation. Mycobacterium tuberculosis also renovates the surface of its innate host cells by altering the expression of key molecules required for full activation of the adaptive immune response. Finally, the pathogen coordinates its exit from the host cell by shifting the balance from the host-protective apoptotic cell death program toward a lytic form of host cell death. Thus, M. tuberculosis exploits its extensive repertoire of virulence factors in order to orchestrate the infection process to facilitate its growth, dissemination, and entry into latency. This review offers critical insights into the most recent advances in our knowledge of how M. tuberculosis manipulates host cell signaling. An appreciation of such interactions between the pathogen and host is critical for guiding novel therapies and understanding the factors that lead to the development of active disease in only a subset of exposed in iduals.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 13-05-2022
Abstract: Tumor necrosis factor (TNF) is a key component of the innate immune response. Upon binding to its receptor, TNFR1, it promotes production of other cytokines via a membrane-bound complex 1 or induces cell death via a cytosolic complex 2. To understand how TNF-induced cell death is regulated, we performed mass spectrometry of complex 2 and identified tankyrase-1 as a native component that, upon a death stimulus, mediates complex 2 poly–ADP-ribosylation (PARylation). PARylation promotes recruitment of the E3 ligase RNF146, resulting in proteasomal degradation of complex 2, thereby limiting cell death. Expression of the ADP-ribose–binding/hydrolyzing severe acute respiratory syndrome coronavirus 2 macrodomain sensitizes cells to TNF-induced death via abolishing complex 2 PARylation. This suggests that disruption of ADP-ribosylation during an infection can prime a cell to retaliate with an inflammatory cell death.
Publisher: Springer Science and Business Media LLC
Date: 14-04-2017
DOI: 10.1038/CDD.2017.53
Publisher: Proceedings of the National Academy of Sciences
Date: 31-07-2023
Abstract: The ersity of COVID-19 disease in otherwise healthy people, from seemingly asymptomatic infection to severe life-threatening disease, is not clearly understood. We passaged a naturally occurring near-ancestral SARS-CoV-2 variant, capable of infecting wild-type mice, and identified viral genomic mutations coinciding with the acquisition of severe disease in young adult mice and lethality in aged animals. Transcriptomic analysis of lung tissues from mice with severe disease elucidated a host antiviral response dominated mainly by interferon and IL-6 pathway activation in young mice, while in aged animals, a fatal outcome was dominated by TNF and TGF-β signaling. Congruent with our pathway analysis, we showed that young TNF-deficient mice had mild disease compared to controls and aged TNF-deficient animals were more likely to survive infection. Emerging clinical correlates of disease are consistent with our preclinical studies, and our model may provide value in defining aberrant host responses that are causative of severe COVID-19.
Publisher: Wiley
Date: 2021
DOI: 10.1002/CTI2.1235
Publisher: Springer Science and Business Media LLC
Date: 28-09-2023
Publisher: Elsevier BV
Date: 09-2023
Publisher: Elsevier BV
Date: 03-2022
Publisher: Elsevier BV
Date: 10-2019
DOI: 10.1016/J.COPH.2019.03.013
Abstract: Intracellular pathogens such as HIV, hepatitis B virus, and Mycobacterium tuberculosis are responsible for millions of deaths worldwide and represent major obstacles to global health. Current treatment options have improved patient outcomes and extended life-expectancy in many countries however, challenges such as latency, drug-resistance, and inflammatory pathology have necessitated advancements in curative strategies which go beyond the traditional antimicrobial focus. This review highlights recent advances in host-directed therapies to eradicate intracellular pathogens or augment the endogenous immune response by targeting host cell pathways. The 'kick and kill' strategy for HIV latency, adjunct immunomodulatory compounds for tuberculosis, and pro-apoptotic small-molecule inhibitors in the case of chronic Hepatitis B are promising ex les of host-directed therapies that signal a paradigm shift in treatment and management of chronic infectious disease.
Publisher: Elsevier BV
Date: 12-2022
DOI: 10.1053/J.GASTRO.2022.08.040
Abstract: Necroptosis is a highly inflammatory mode of cell death that has been implicated in causing hepatic injury including steatohepatitis/ nonalcoholic steatohepatitis (NASH) however, the evidence supporting these claims has been controversial. A comprehensive, fundamental understanding of cell death pathways involved in liver disease critically underpins rational strategies for therapeutic intervention. We sought to define the role and relevance of necroptosis in liver pathology. Several animal models of human liver pathology, including diet-induced steatohepatitis in male mice and erse infections in both male and female mice, were used to dissect the relevance of necroptosis in liver pathobiology. We applied necroptotic stimuli to primary mouse and human hepatocytes to measure their susceptibility to necroptosis. Paired liver biospecimens from patients with NASH, before and after intervention, were analyzed. DNA methylation sequencing was also performed to investigate the epigenetic regulation of RIPK3 expression in primary human and mouse hepatocytes. Identical infection kinetics and pathologic outcomes were observed in mice deficient in an essential necroptotic effector protein, MLKL, compared with control animals. Mice lacking MLKL were indistinguishable from wild-type mice when fed a high-fat diet to induce NASH. Under all conditions tested, we were unable to induce necroptosis in hepatocytes. We confirmed that a critical activator of necroptosis, RIPK3, was epigenetically silenced in mouse and human primary hepatocytes and rendered them unable to undergo necroptosis. We have provided compelling evidence that necroptosis is disabled in hepatocytes during homeostasis and in the pathologic conditions tested in this study.
Publisher: Cold Spring Harbor Laboratory
Date: 12-09-2022
DOI: 10.1101/2022.09.08.507056
Abstract: Across the globe, 2-3% of humans carry the p.Ser132Pro single nucleotide polymorphism in MLKL , the terminal effector protein of the inflammatory form of programmed cell death, necroptosis. We show that this substitution confers a gain in necroptotic function in human cells, with more rapid accumulation of activated MLKL S132P in biological membranes and MLKL S132P overriding pharmacological and endogenous inhibition of MLKL. In mouse cells, the equivalent Mlkl S131P mutation confers a gene dosage dependent reduction in sensitivity to TNF-induced necroptosis in both hematopoietic and non-hematopoietic cells, but enhanced sensitivity to IFN-β induced death in non-hematopoietic cells. In vivo , Mlkl S131P homozygosity reduces the capacity to clear Salmonella from major organs and retards recovery of hematopoietic stem cells. Thus, by dysregulating necroptosis, the S131P substitution impairs the return to homeostasis after systemic challenge. Present day carriers of the MLKL S132P polymorphism may be the key to understanding how MLKL and necroptosis modulate the progression of complex polygenic human disease.
Publisher: Frontiers Media SA
Date: 12-04-2022
DOI: 10.3389/FCHEM.2022.861209
Abstract: The COVID-19 pandemic continues unabated, emphasizing the need for additional antiviral treatment options to prevent hospitalization and death of patients infected with SARS-CoV-2. The papain-like protease (PLpro) domain is part of the SARS-CoV-2 non-structural protein (nsp)-3, and represents an essential protease and validated drug target for preventing viral replication. PLpro moonlights as a deubiquitinating (DUB) and deISGylating enzyme, enabling adaptation of a DUB high throughput (HTS) screen to identify PLpro inhibitors. Drug repurposing has been a major focus through the COVID-19 pandemic as it may provide a fast and efficient route for identifying clinic-ready, safe-in-human antivirals. We here report our effort to identify PLpro inhibitors by screening the ReFRAME library of 11,804 compounds, showing that none inhibit PLpro with any reasonable activity or specificity to justify further progression towards the clinic. We also report our latest efforts to improve piperidine-scaffold inhibitors, 5c and 3k , originally developed for SARS-CoV PLpro. We report molecular details of binding and selectivity, as well as in vitro absorption, distribution, metabolism and excretion (ADME) studies of this scaffold. A co-crystal structure of SARS-CoV-2 PLpro bound to inhibitor 3k guides medicinal chemistry efforts to improve binding and ADME characteristics. We arrive at compounds with improved and favorable solubility and stability characteristics that are tested for inhibiting viral replication. Whilst still requiring significant improvement, our optimized small molecule inhibitors of PLpro display decent antiviral activity in an in vitro SARS-CoV-2 infection model, justifying further optimization.
Publisher: Springer Science and Business Media LLC
Date: 05-10-2020
DOI: 10.1038/S41590-020-0789-Z
Abstract: Sepsis is a biphasic disease characterized by an acute inflammatory response, followed by a prolonged immunosuppressive phase. Therapies aimed at controlling inflammation help to reduce the time patients with sepsis spend in intensive care units, but they do not lead to a reduction in overall mortality. Recently, the focus has been on addressing the immunosuppressive phase, often caused by apoptosis of immune cells. However, molecular triggers of these events are not yet known. Using whole-genome CRISPR screening in mice, we identified a triggering receptor expressed on myeloid cells (TREM) family receptor, TREML4, as a key regulator of inflammation and immune cell death in sepsis. Genetic ablation of Treml4 in mice demonstrated that TREML4 regulates calcium homeostasis, the inflammatory cytokine response, myeloperoxidase activation, the endoplasmic reticulum stress response and apoptotic cell death in innate immune cells, leading to an overall increase in survival rate, both during the acute and chronic phases of polymicrobial sepsis.
Publisher: EMBO
Date: 26-08-2020
Publisher: Elsevier BV
Date: 06-2016
Publisher: Wiley
Date: 07-12-2021
DOI: 10.1111/TID.13531
Abstract: Cytomegalovirus (CMV) is a significant cause of morbidity and mortality in the immunocompromised host. Atypical presentations which include pseudotumors or “cancer mimics” have been described. The etiology of these lesions remains unclear. The authors describe two previously unpublished cases that have arisen in the context of newer immunomodulating therapy and review the existing non‐HIV‐associated CMV pseudotumors described in the literature.
Publisher: Springer Science and Business Media LLC
Date: 12-04-2013
DOI: 10.1038/CDD.2013.29
Publisher: Elsevier BV
Date: 03-2020
Publisher: EMBO
Date: 17-01-2023
Abstract: Genetic lesions in X‐linked inhibitor of apoptosis (XIAP) pre‐dispose humans to cell death–associated inflammatory diseases, although the underlying mechanisms remain unclear. Here, we report that two patients with XIAP deficiency–associated inflammatory bowel disease display increased inflammatory IL‐1β maturation as well as cell death–associated caspase‐8 and Gasdermin D (GSDMD) processing in diseased tissue, which is reduced upon patient treatment. Loss of XIAP leads to caspase‐8‐driven cell death and bioactive IL‐1β release that is only abrogated by combined deletion of the apoptotic and pyroptotic cell death machinery. Namely, extrinsic apoptotic caspase‐8 promotes pyroptotic GSDMD processing that kills macrophages lacking both inflammasome and apoptosis signalling components (caspase‐1, ‐3, ‐7, ‐11 and BID), while caspase‐8 can still cause cell death in the absence of both GSDMD and GSDME when caspase‐3 and caspase‐7 are present. Neither caspase‐3 and caspase‐7‐mediated activation of the pannexin‐1 channel, or GSDMD loss, prevented NLRP3 inflammasome assembly and consequent caspase‐1 and IL‐1β maturation downstream of XIAP inhibition and caspase‐8 activation, even though the pannexin‐1 channel was required for NLRP3 triggering upon mitochondrial apoptosis. These findings uncouple the mechanisms of cell death and NLRP3 activation resulting from extrinsic and intrinsic apoptosis signalling, reveal how XIAP loss can co‐opt dual cell death programs, and uncover strategies for targeting the cell death and inflammatory pathways that result from XIAP deficiency.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 25-03-2022
DOI: 10.1126/SCIIMMUNOL.ABN8041
Abstract: Targeting the potent immunosuppressive properties of FOXP3 + regulatory T cells (T regs ) has substantial therapeutic potential for treating autoimmune and inflammatory diseases. Yet, the molecular mechanisms controlling T reg homeostasis, particularly during inflammation, remain unclear. We report that caspase-8 is a central regulator of T reg homeostasis in a context-specific manner that is decisive during immune responses. In mouse genetic models, targeting caspase-8 in T regs led to accumulation of effector T regs resistant to apoptotic cell death. Conversely, inflammation induced the MLKL-dependent necroptosis of caspase-8–deficient lymphoid and tissue T regs , which enhanced immunity to a variety of chronic infections to promote clearance of viral or parasitic pathogens. However, improved immunity came at the risk of lethal inflammation in overwhelming infections. Caspase-8 inhibition using a clinical-stage compound revealed that human T regs have heightened sensitivity to necroptosis compared with conventional T cells. These findings reveal a fundamental mechanism in T regs that could be targeted to manipulate the balance between immune tolerance versus response for therapeutic benefit.
Publisher: Elsevier BV
Date: 07-2022
Publisher: Wiley
Date: 26-01-2015
DOI: 10.1111/FEBS.13190
Abstract: BH 3‐only proteins are the sentinels of cellular stress, and their activation commits cells to apoptosis. Since the discovery of the first BH 3‐only protein BAD almost 20 years ago, at least seven more BH 3‐only proteins have been identified in mammals. They are regulated by a variety of environmental stimuli or by developmental cues, and play a crucial role in cellular homeostasis. Some are considered to be tumor suppressors, and also play a significant role in other pathologies. Their non‐apoptotic functions are controversial, but there is broad consensus emerging regarding their role in apoptosis, which may help in designing better therapeutic agents for treating a variety of human diseases.
Publisher: Springer Science and Business Media LLC
Date: 03-10-2016
DOI: 10.1038/SREP34702
Abstract: Sepsis-induced lymphopenia is a major cause of morbidities in intensive care units and in populations with chronic conditions such as renal failure, diabetes, HIV and alcohol abuse. Currently, other than supportive care and antibiotics, there are no treatments for this condition. We developed an in vitro assay to understand the role of the ER-stress-mediated apoptosis process in lymphocyte death during polymicrobial sepsis, which was reproducible in in vivo mouse models. Modulating ER stress using chemical chaperones significantly reduced the induction of the pro-apoptotic protein Bim both i n vitro and in mice. Furthermore, in a ‘two-hit’ pneumonia model in mice, we have been able to demonstrate that administration of the chemical chaperone TUDCA helped to maintain lymphocyte homeostasis by significantly reducing lymphocyte apoptosis and this correlated with four-fold improvement in survival. Our results demonstrate a novel therapeutic opportunity for treating sepsis-induced lymphopenia in humans.
Publisher: Portland Press Ltd.
Date: 04-03-2022
DOI: 10.1042/BCJ20210602
Abstract: Two years after the emergence of SARS-CoV-2, our understanding of COVID-19 disease pathogenesis is still incomplete. Despite unprecedented global collaborative scientific efforts and rapid vaccine development, an uneven vaccine roll-out and the emergence of novel variants of concern such as omicron underscore the critical importance of identifying the mechanisms that contribute to this disease. Overt inflammation and cell death have been proposed to be central drivers of severe pathology in COVID-19 patients and their pathways and molecular components therefore present promising targets for host-directed therapeutics. In our review, we summarize the current knowledge on the role and impact of erse programmed cell death (PCD) pathways on COVID-19 disease. We dissect the complex connection of cell death and inflammatory signaling at the cellular and molecular level and identify a number of critical questions that remain to be addressed. We provide rationale for targeting of cell death as potential COVID-19 treatment and provide an overview of current therapeutics that could potentially enter clinical trials in the near future.
Publisher: Springer Science and Business Media LLC
Date: 20-10-2021
Publisher: Springer New York
Date: 2016
DOI: 10.1007/978-1-4939-3581-9_6
Abstract: Sepsis is amongst the world's biggest public health problems with more than 20 million cases worldwide and a high morbidity rate of up to 50 %. Despite advances in modern medicine in the past few decades, incidence is expected to further increase due to an aging population and accompanying comorbidities such as cancer and diabetes. Due to the complexity of the disease, available treatment options are limited. Growing evidence links apoptotic cell death of lymphocytes and concomitant immune suppression to overall patient survival. In order to establish novel therapeutic approaches targeting this life threatening immune paralysis, researchers rely heavily on animal models to decipher the molecular mechanisms underlying this high impact disease. Here we describe variations of in vivo mouse models that can be used to study inflammation, cellular apoptosis, and survival in mice subjected to experimental polymicrobial sepsis and to a secondary infection during the immune suppressive secondary stage.
Publisher: Springer Science and Business Media LLC
Date: 09-08-2012
Publisher: Elsevier BV
Date: 09-2020
Publisher: Wiley
Date: 17-09-2020
DOI: 10.1111/FEBS.15552
Publisher: Wiley
Date: 08-12-2020
DOI: 10.1111/IMCB.12426
Publisher: Springer Science and Business Media LLC
Date: 22-06-2017
Publisher: Cold Spring Harbor Laboratory
Date: 19-06-2020
DOI: 10.1101/2020.06.18.160614
Abstract: Coronaviruses, including SARS-CoV-2, encode multifunctional proteases that are essential for viral replication and evasion of host innate immune mechanisms. The papain-like protease PLpro cleaves the viral polyprotein, and reverses inflammatory ubiquitin and anti-viral ubiquitin-like ISG15 protein modifications 1,2 . Drugs that target SARS-CoV-2 PLpro (hereafter, SARS2 PLpro) may hence be effective as treatments or prophylaxis for COVID-19, reducing viral load and reinstating innate immune responses 3 . We here characterise SARS2 PLpro in molecular and biochemical detail. SARS2 PLpro cleaves Lys48-linked polyubiquitin and ISG15 modifications with high activity. Structures of PLpro bound to ubiquitin and ISG15 reveal that the S1 ubiquitin binding site is responsible for high ISG15 activity, while the S2 binding site provides Lys48 chain specificity and cleavage efficiency. We further exploit two strategies to target PLpro. A repurposing approach, screening 3727 unique approved drugs and clinical compounds against SARS2 PLpro, identified no compounds that inhibited PLpro consistently or that could be validated in counterscreens. More promisingly, non-covalent small molecule SARS PLpro inhibitors were able to inhibit SARS2 PLpro with high potency and excellent antiviral activity in SARS-CoV-2 infection models.
Publisher: Wiley
Date: 2022
DOI: 10.1002/CTI2.1383
Abstract: Febrile neutropenia (FN) is a major cause of treatment disruption and unplanned hospitalization in childhood cancer patients. This study investigated the transcriptome of peripheral blood mononuclear cells (PBMCs) in children with cancer and FN to identify potential predictors of serious infection. Whole‐genome transcriptional profiling was conducted on PBMCs collected during episodes of FN in children with cancer at presentation to the hospital (Day 1 n = 73) and within 8–24 h (Day 2 n = 28) after admission. Differentially expressed genes as well as gene pathways that correlated with clinical outcomes were defined for different infectious outcomes. Global differences in gene expression associated with specific immune responses in children with FN and documented infection, compared to episodes without documented infection, were identified at admission. These differences resolved over the subsequent 8–24 h. Distinct gene signatures specific for bacteraemia were identified both at admission and on Day 2. Differences in gene signatures between episodes with bacteraemia and episodes with bacterial infection, viral infection and clinically defined infection were also observed. Only subtle differences in gene expression profiles between non‐bloodstream bacterial and viral infections were identified. Blood transcriptome immune profiling analysis during FN episodes may inform monitoring and aid in defining adequate treatment for different infectious aetiologies in children with cancer.
Publisher: Public Library of Science (PLoS)
Date: 29-06-2023
DOI: 10.1371/JOURNAL.PNTD.0011394
Abstract: Critical knowledge gaps regarding infection with Mycobacterium ulcerans , the cause of Buruli ulcer (BU), have impeded development of new therapeutic approaches and vaccines for prevention of this neglected tropical disease. Here, we review the current understanding of host–pathogen interactions and correlates of immune protection to explore the case for establishing a controlled human infection model of M . ulcerans infection. We also summarise the overarching safety considerations and present a rationale for selecting a suitable challenge strain.
Publisher: Proceedings of the National Academy of Sciences
Date: 16-07-2019
Abstract: It is believed that the Bcl-2 family protein Bok has a redundant role similar to Bax and Bak in regulating apoptosis. We report that this protein interacts with the key enzyme involved in uridine biosynthesis, uridine monophosphate synthetase, and positively regulates uridine biosynthesis and chemoconversion of 5-fluorouracil (5-FU). Bok-deficient cell lines are resistant to 5-FU. Bok down-regulation is a key feature of cell lines and primary colorectal tumor tissues that are resistant to 5-FU. Our data also show that through its impact on nucleotide metabolism, Bok regulates p53 level and cellular proliferation. Our results have implications for developing Bok as a biomarker for 5-FU resistance and for the development of BOK mimetics for sensitizing 5-FU-resistant cancers.
Publisher: Springer Science and Business Media LLC
Date: 15-02-2023
DOI: 10.1038/S41419-023-05635-0
Abstract: Necroptosis is a lytic and inflammatory form of cell death that is highly constrained to mitigate detrimental collateral tissue damage and impaired immunity. These constraints make it difficult to define the relevance of necroptosis in diseases such as chronic and persistent viral infections and within in idual organ systems. The role of necroptotic signalling is further complicated because proteins essential to this pathway, such as receptor interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL), have been implicated in roles outside of necroptotic signalling. We sought to address this issue by in idually defining the role of RIPK3 and MLKL in chronic lymphocytic choriomeningitis virus (LCMV) infection. We investigated if necroptosis contributes to the death of LCMV-specific CD8 + T cells or virally infected target cells during infection. We provide evidence showing that necroptosis was redundant in the pathogenesis of acute forms of LCMV (Armstrong strain) and the early stages of chronic (Docile strain) LCMV infection in vivo. The number of immune cells, their specificity and reactivity towards viral antigens and viral loads are not altered in the absence of either MLKL or RIPK3 during acute and during the early stages of chronic LCMV infection. However, we identified that RIPK3 promotes immune dysfunction and prevents control of infection at later stages of chronic LCMV disease. This was not phenocopied by the loss of MLKL indicating that the phenotype was driven by a necroptosis-independent function of RIPK3. We provide evidence that RIPK3 signaling evoked a dysregulated type 1 interferone response which we linked to an impaired antiviral immune response and abrogated clearance of chronic LCMV infection.
Location: Australia
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Marcel Doerflinger.