ORCID Profile
0000-0003-2691-0283
Current Organisation
Monash University
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Research Topics
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Top 5 Research Topics
ANZSRC Field of Research (FoR)
Biochemistry and Cell Biology | Biochemistry and Cell Biology not elsewhere classified | Cell Development, Proliferation and Death | Infectious Agents | Protein Trafficking | Plant Cell and Molecular Biology | Plant Biology | Structural Biology (incl. Macromolecular Modelling) | Microbiology not elsewhere classified
ANZSRC Socio-Economic Objective (SEO)
Infectious Diseases | Expanding Knowledge in the Biological Sciences | Reproductive System and Disorders | Cancer and Related Disorders | Production of Biofuels (Biomass) | Immune System and Allergy |
Related Links
Publications
SecretEPDB: a comprehensive web-based resource for secreted effector proteins of the bacterial types III, IV and VI secretion systems
Publisher: Springer Science and Business Media LLC
Date: 23-01-2017
DOI: 10.1038/SREP41031
Abstract: Bacteria translocate effector molecules to host cells through highly evolved secretion systems. By definition, the function of these effector proteins is to manipulate host cell biology and the sequence, structural and functional annotations of these effector proteins will provide a better understanding of how bacterial secretion systems promote bacterial survival and virulence. Here we developed a knowledgebase, termed SecretEPDB (Bacterial Secret ed E ffector P rotein D ata B ase), for effector proteins of type III secretion system (T3SS), type IV secretion system (T4SS) and type VI secretion system (T6SS). SecretEPDB provides enriched annotations of the aforementioned three classes of effector proteins by manually extracting and integrating structural and functional information from currently available databases and the literature. The database is conservative and strictly curated to ensure that every effector protein entry is supported by experimental evidence that demonstrates it is secreted by a T3SS, T4SS or T6SS. The annotations of effector proteins documented in SecretEPDB are provided in terms of protein characteristics, protein function, protein secondary structure, Pfam domains, metabolic pathway and evolutionary details. It is our hope that this integrated knowledgebase will serve as a useful resource for biological investigation and the generation of new hypotheses for research efforts aimed at bacterial secretion systems.
Targeting NLRP3 and Staphylococcal pore-forming toxin receptors in human-induced pluripotent stem cell-derived macrophages
Publisher: Oxford University Press (OUP)
Date: 12-06-2020
Abstract: Staphylococcus aureus causes necrotizing pneumonia by secreting toxins such as leukocidins that target front-line immune cells. The mechanism by which leukocidins kill innate immune cells and trigger inflammation during S. aureus lung infection, however, remains unresolved. Here, we explored human-induced pluripotent stem cell-derived macrophages (hiPSC-dMs) to study the interaction of the leukocidins Panton–Valentine leukocidin (PVL) and LukAB with lung macrophages, which are the initial leukocidin targets during S. aureus lung invasion. hiPSC-dMs were susceptible to the leukocidins PVL and LukAB and both leukocidins triggered NLPR3 inflammasome activation resulting in IL-1β secretion. hiPSC-dM cell death after LukAB exposure, however, was only temporarily dependent of NLRP3, although NLRP3 triggered marked cell death after PVL treatment. CRISPR/Cas9-mediated deletion of the PVL receptor, C5aR1, protected hiPSC-dMs from PVL cytotoxicity, despite the expression of other leukocidin receptors, such as CD45. PVL-deficient S. aureus had reduced ability to induce lung IL-1β levels in human C5aR1 knock-in mice. Unexpectedly, inhibiting NLRP3 activity resulted in increased wild-type S. aureus lung burdens. Our findings suggest that NLRP3 induces macrophage death and IL-1β secretion after PVL exposure and controls S. aureus lung burdens.
FBXO11 governs macrophage cell death and inflammation in response to bacterial toxins
Publisher: Life Science Alliance, LLC
Date: 28-03-2023
Abstract: Staphylococcus aureus causes severe infections such as pneumonia and sepsis depending on the pore-forming toxin Panton–Valentine leukocidin (PVL). PVL kills and induces inflammation in macrophages and other myeloid cells by interacting with the human cell surface receptor, complement 5a receptor 1 (C5aR1). C5aR1 expression is tighly regulated and may thus modulate PVL activity, although the mechanisms involved remain incompletely understood. Here, we used a genome-wide CRISPR/Cas9 screen and identified F-box protein 11 (FBXO11), an E3 ubiquitin ligase complex member, to promote PVL toxicity. Genetic deletion of FBXO11 reduced the expression of C5aR1 at the mRNA level, whereas ectopic expression of C5aR1 in FBXO11 −/− macrophages, or priming with LPS, restored C5aR1 expression and thereby PVL toxicity. In addition to promoting PVL-mediated killing, FBXO11 d ens secretion of IL-1β after NLRP3 activation in response to bacterial toxins by reducing mRNA levels in a BCL-6–dependent and BCL-6–independent manner. Overall, these findings highlight that FBXO11 regulates C5aR1 and IL-1β expression and controls macrophage cell death and inflammation following PVL exposure.
Metabolic competition between host and pathogen dictates inflammasome responses to fungal infection
Publisher: Public Library of Science (PLoS)
Date: 04-08-2020
Metabolic Pathways Required for the Intracellular Survival of Leishmania
Publisher: Annual Reviews
Date: 13-10-2011
DOI: 10.1146/ANNUREV-MICRO-090110-102913
Abstract: Leishmania spp. are sandfly-transmitted parasitic protozoa that cause a spectrum of important diseases and lifelong chronic infections in humans. In the mammalian host, these parasites proliferate within acidified vacuoles in several phagocytic host cells, including macrophages, dendritic cells, and neutrophils. In this review, we discuss recent progress that has been made in defining the nutrient composition of the Leishmania parasitophorous vacuole, as well as metabolic pathways required by these parasites for virulence. Analysis of the virulence phenotype of Leishmania mutants has been particularly useful in defining carbon sources and nutrient salvage pathways that are essential for parasite persistence and/or induction of pathology. We also review data suggesting that intracellular parasite stages modulate metabolic processes in their host cells in order to generate a more permissive niche.
Programmed cell death in Legionella infection
Publisher: Future Medicine Ltd
Date: 2014
DOI: 10.2217/FMB.13.139
Abstract: ABSTRACT: The causative agent of Legionnaires’ disease, Legionella pneumophila, resides within alveolar macrophages by exporting 295 bacterial virulence proteins (effectors) to modulate host cell processes. This leads to the formation of a unique vacuolar niche and the suppression of macrophage cell death pathways, which, in turn, promote bacterial survival and allow sufficient time for replication. However, once nutrients within the vacuole are depleted, Legionella must act to induce host cell death in order to facilitate bacterial egress and reinfect new cells. Intracellular Legionella also evade detection by the host cell’s innate immune system, which seeks to destroy invading pathogens by activating inflammasome complexes, thereby promoting proinflammatory cytokine activation and pyroptotic cell death. Understanding how different forms of programmed cell death contribute to Legionella infectivity and are manipulated by Legionella effector proteins will be important for identifying novel antibacterial therapeutic targets.
Eliminating Legionella by inhibiting BCL-XL to induce macrophage apoptosis
Publisher: Springer Science and Business Media LLC
Date: 24-02-2016
DOI: 10.1038/NMICROBIOL.2015.34
Abstract: Human pathogenic Legionella replicate in alveolar macrophages and cause a potentially lethal form of pneumonia known as Legionnaires' disease(1). Here, we have identified a host-directed therapeutic approach to eliminate intracellular Legionella infections. We demonstrate that the genetic deletion, or pharmacological inhibition, of the host cell pro-survival protein BCL-XL induces intrinsic apoptosis of macrophages infected with virulent Legionella strains, thereby abrogating Legionella replication. BCL-XL is essential for the survival of Legionella-infected macrophages due to bacterial inhibition of host-cell protein synthesis, resulting in reduced levels of the short-lived, related BCL-2 pro-survival family member, MCL-1. Consequently, a single dose of a BCL-XL-targeted BH3-mimetic therapy, or myeloid cell-restricted deletion of BCL-XL, limits Legionella replication and prevents lethal lung infections in mice. These results indicate that repurposing BH3-mimetic compounds, originally developed to induce cancer cell apoptosis, may have efficacy in treating Legionnaires' and other diseases caused by intracellular microbes.
Intracellular growth and pathogenesis of Leishmania parasites
Publisher: Portland Press Ltd.
Date: 24-10-2011
DOI: 10.1042/BSE0510081
Abstract: Parasitic protozoa belonging to the genus Leishmania are the cause of a spectrum of diseases in humans, as well as chronic long-term infections. These parasites exhibit a remarkable capacity to survive and proliferate within the phagolysosome compartment of host macrophages. Studies with defined Leishmania mutants in mouse models of infection have highlighted processes that are required for parasite survival in macrophages. Parasite mutants have been identified that (i) are poorly virulent when the insect (promastigote) stage is used to initiate infection, but retain wild-type virulence following transformation to the obligate intracellular amastigote stage, (ii) are highly attenuated when either promastigotes or amastigotes are used, and (iii) are unable to induce characteristic lesion granulomas, but can persist within macrophages in other tissues. From these analyses it can be concluded that promastigote stages of some species require the surface expression of lipophosphoglycan, but not other surface components. Survival and subsequent proliferation of Leishmania in macrophages requires the activation of heat-shock responses (involving the up-regulation and/or phosphorylation of heat-shock proteins), the presence of oxidative and nitrosative defence mechanisms, and uptake and catabolism of carbon sources (glycoproteins, hexoses and amino acids) and essential nutrients (purines, amino acids and vitamins). Parasite mutants with defects in specific kinase hosphatase-dependent signalling pathways are also severely attenuated in amastigote virulence, highlighting the potential importance of post-translational regulatory mechanisms in parasite adaptation to this host niche.
Macrophage cell death in microbial infections
Publisher: Hindawi Limited
Date: 22-02-2016
DOI: 10.1111/CMI.12573
Abstract: Macrophages can respond to microbial infections with programmed cell death. The major cell death pathways of apoptosis, pyroptosis and necroptosis are tightly regulated to ensure adequate immune reactions to virulent and persistent invaders. Macrophage death eliminates the replicative niche of intracellular pathogens and induces immune attack. Not surprisingly, successful pathogens have evolved strategies to modulate macrophage cell death pathways to enable microbial survival and replication. Uncontrolled macrophage death can also lead to tissue damage, which may augment bacterial dissemination and pathology. In this review, we highlight how pathogens hijack macrophage cell death signals to promote microbial survival and immune evasion.
Golgi-Located NTPDase1 of Leishmania major Is Required for Lipophosphoglycan Elongation and Normal Lesion Development whereas Secreted NTPDase2 Is Dispensable for Virulence
Publisher: Public Library of Science (PLoS)
Date: 18-12-2014
Leishmania major Methionine Sulfoxide Reductase A Is Required for Resistance to Oxidative Stress and Efficient Replication in Macrophages
Publisher: Public Library of Science (PLoS)
Date: 20-02-2013
Targeting of RNA Polymerase II by a nuclearLegionella pneumophilaDot/Icm effector SnpL
Publisher: Hindawi Limited
Date: 18-05-2018
DOI: 10.1111/CMI.12852
Abstract: The intracellular pathogen Legionella pneumophila influences numerous eukaryotic cellular processes through the Dot/Icm-dependent translocation of more than 300 effector proteins into the host cell. Although many translocated effectors localise to the Legionella replicative vacuole, other effectors can affect remote intracellular sites. Following infection, a subset of effector proteins localises to the nucleus where they subvert host cell transcriptional responses to infection. Here, we identified Lpw27461 (Lpp2587), Lpg2519 as a new nuclear-localised effector that we have termed SnpL. Upon ectopic expression or during L. pneumophila infection, SnpL showed strong nuclear localisation by immunofluorescence microscopy but was excluded from nucleoli. Using immunoprecipitation and mass spectrometry, we determined the host-binding partner of SnpL as the eukaryotic transcription elongation factor, Suppressor of Ty5 (SUPT5H)/Spt5. SUPT5H is an evolutionarily conserved component of the DRB sensitivity-inducing factor complex that regulates RNA Polymerase II dependent mRNA processing and transcription elongation. Protein interaction studies showed that SnpL bound to the central Kyprides, Ouzounis, Woese motif region of SUPT5H. Ectopic expression of SnpL led to massive upregulation of host gene expression and macrophage cell death. The activity of SnpL further highlights the ability of L. pneumophila to control fundamental eukaryotic processes such as transcription that, in the case of SnpL, leads to global upregulation of host gene expression.
Calcineurin is required for Leishmania major stress response pathways and for virulence in the mammalian host
Publisher: Wiley
Date: 08-03-2011
DOI: 10.1111/J.1365-2958.2011.07584.X
Abstract: Leishmania parasites must adapt to elevated temperatures and other environmental stresses during infection of their mammalian hosts. How these environmental cues are sensed is poorly understood. In this study we show that calcium uptake is required for parasite thermotolerance at 34-37°C. To identify potential downstream targets of calcium influx, a Leishmania major mutant lacking the essential regulatory subunit (CnB) of the Ca(2+) /calmodulin-dependent serine/threonine-specific phosphatase, calcineurin, was generated. The Δcnb mutant grew as well as wild-type parasites at 27°C and differentiated normally to infective metacyclic promastigotes. However, Δcnb parasites lost viability when exposed to increased temperature (34°C) and were hypersensitive to endoplasmic reticulum and membrane stress, induced by tunicamycin and inhibitors of sterol and sphingolipid biosynthesis respectively. Δcnb promastigotes were internalized by macrophages, but their differentiation to the heat adapted amastigote stage was delayed and the resulting parasites failed to proliferate. Strikingly, the Δcnb parasites were completely cleared by susceptible BALB/c mice. Complementation of Δcnb parasites with CnB restored thermotolerance and infectivity in both macrophages and animal models. Our results suggest that Ca(2+) influx and calcineurin signalling are required for both early and long-term adaptive parasite responses to environmental stresses encountered in the mammalian host.
Legionella pneumophila Secretes a Mitochondrial Carrier Protein during Infection
Publisher: Public Library of Science (PLoS)
Date: 05-01-2012
Evidence That Intracellular Stages of Leishmania major Utilize Amino Sugars as a Major Carbon Source
Publisher: Public Library of Science (PLoS)
Date: 23-12-2010
Conserved Motifs Reveal Details of Ancestry and Structure in the Small TIM Chaperones of the Mitochondrial Intermembrane Space
Publisher: Oxford University Press (OUP)
Date: 13-02-2007
Abstract: The mitochondrial inner and outer membranes are composed of a variety of integral membrane proteins, assembled into the membranes posttranslationally. The small translocase of the inner mitochondrial membranes (TIMs) are a group of approximately 10 kDa proteins that function as chaperones to ferry the imported proteins across the mitochondrial intermembrane space to the outer and inner membranes. In yeast, there are 5 small TIM proteins: Tim8, Tim9, Tim10, Tim12, and Tim13, with equivalent proteins reported in humans. Using hidden Markov models, we find that many eukaryotes have proteins equivalent to the Tim8 and Tim13 and the Tim9 and Tim10 subunits. Some eukaryotes provide "snapshots" of evolution, with a single protein showing the features of both Tim8 and Tim13, suggesting that a single progenitor gene has given rise to each of the small TIMs through duplication and modification. We show that no "Tim12" family of proteins exist, but rather that variant forms of the cognate small TIMs have been recently duplicated and modified to provide new functions: the yeast Tim12 is a modified form of Tim10, whereas in humans and some protists variant forms of Tim9, Tim8, and Tim13 are found instead. Sequence motif analysis reveals acidic residues conserved in the Tim10 substrate-binding tentacles, whereas more hydrophobic residues are found in the equivalent substrate-binding region of Tim13. The substrate-binding region of Tim10 and Tim13 represent structurally independent domains: when the acidic domain from Tim10 is attached to Tim13, the Tim8-Tim13(10) complex becomes essential and the Tim9-Tim10 complex becomes dispensable. The conserved features in the Tim10 and Tim13 subunits provide distinct binding surfaces to accommodate the broad range of substrate proteins delivered to the mitochondrial inner and outer membranes.
Virulence of Leishmania major in macrophages and mice requires the gluconeogenic enzyme fructose-1,6-bisphosphatase
Publisher: Proceedings of the National Academy of Sciences
Date: 04-04-2006
Abstract: Leishmania are protozoan parasites that replicate within mature phagolysosomes of mammalian macrophages. To define the biochemical composition of the phagosome and carbon source requirements of intracellular stages of L. major , we investigated the role and requirement for the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP). L. major FBP was constitutively expressed in both extracellular and intracellular stages and was primarily targeted to glycosomes, modified peroxisomes that also contain glycolytic enzymes. A L. major FBP -null mutant was unable to grow in the absence of hexose, and suspension in glycerol-containing medium resulted in rapid depletion of internal carbohydrate reserves. L. major Δ fbp promastigotes were internalized by macrophages and differentiated into amastigotes but were unable to replicate in the macrophage phagolysosome. Similarly, the mutant persisted in mice but failed to generate normal lesions. The data suggest that Leishmania amastigotes reside in a glucose-poor phagosome and depend heavily on nonglucose carbon sources. Feeding experiments with [ 13 C]fatty acids showed that fatty acids are poor gluconeogenic substrates, indicating that amino acids are the major carbon source in vivo . The need for amino acids may have forced Leishmania spp. to adapt to life in the mature phagolysosome.
The pathogen Candida albicans hijacks pyroptosis for escape from macrophages
Publisher: American Society for Microbiology
Date: 05-2014
Abstract: The fungal pathogen Candida albicans causes macrophage death and escapes, but the molecular mechanisms remained unknown. Here we used live-cell imaging to monitor the interaction of C. albicans with macrophages and show that C. albicans kills macrophages in two temporally and mechanistically distinct phases. Early upon phagocytosis, C. albicans triggers pyroptosis, a proinflammatory macrophage death. Pyroptosis is controlled by the developmental yeast-to-hypha transition of Candida . When pyroptosis is inactivated, wild-type C. albicans hyphae cause significantly less macrophage killing for up to 8 h postphagocytosis. After the first 8 h, a second macrophage-killing phase is initiated. This second phase depends on robust hyphal formation but is mechanistically distinct from pyroptosis. The transcriptional regulator Mediator is necessary for morphogenesis of C. albicans in macrophages and the establishment of the wild-type surface architecture of hyphae that together mediate activation of macrophage cell death. Our data suggest that the defects of the Mediator mutants in causing macrophage death are caused, at least in part, by reduced activation of pyroptosis. A Mediator mutant that forms hyphae of apparently wild-type morphology but is defective in triggering early macrophage death shows a breakdown of cell surface architecture and reduced exposed 1,3 β-glucan in hyphae. Our report shows how Candida uses host and pathogen pathways for macrophage killing. The current model of mechanical piercing of macrophages by C. albicans hyphae should be revised to include activation of pyroptosis by hyphae as an important mechanism mediating macrophage cell death upon C. albicans infection. IMPORTANCE Upon phagocytosis by macrophages, Candida albicans can transition to the hyphal form, which causes macrophage death and enables fungal escape. The current model is that the highly polarized growth of hyphae results in macrophage piercing. This model is challenged by recent reports of C. albicans mutants that form hyphae of wild-type morphology but are defective in killing macrophages. We show that C. albicans causes macrophage cell death by at least two mechanisms. Phase 1 killing (first 6 to 8 h) depends on the activation of the pyroptotic programmed host cell death by fungal hyphae. Phase 2 (up to 24 h) is rapid and depends on robust hyphal formation but is independent of pyroptosis. Our data provide a new model for how the interplay between fungal morphogenesis and activation of a host cell death pathway mediates macrophage killing by C. albicans hyphae.
The WD40 Protein BamB Mediates Coupling of BAM Complexes into Assembly Precincts in the Bacterial Outer Membrane
Publisher: Elsevier BV
Date: 05-2018
DOI: 10.1016/J.CELREP.2018.04.093
Abstract: The β-barrel assembly machinery (BAM) complex is essential for localization of surface proteins on bacterial cells, but the mechanism by which it functions is unclear. We developed a direct stochastic optical reconstruction microscopy (dSTORM) methodology to view the BAM complex in situ. Single-cell analysis showed that discrete membrane precincts housing several BAM complexes are distributed across the E. coli surface, with a nearest neighbor distance of ∼200 nm. The auxiliary lipoprotein subunit BamB was crucial for this spatial distribution, and in situ crosslinking shows that BamB makes intimate contacts with BamA and BamB in neighboring BAM complexes within the precinct. The BAM complex precincts swell when outer membrane protein synthesis is maximal, visual proof that the precincts are active in protein assembly. This nanoscale interrogation of the BAM complex in situ suggests a model whereby bacterial outer membranes contain highly organized assembly precincts to drive integral protein assembly.
Role of hexosamine biosynthesis in Leishmania growth and virulence
Publisher: Wiley
Date: 23-07-2008
DOI: 10.1111/J.1365-2958.2008.06314.X
Abstract: Leishmania parasites incorporate N-acetylglucosamine (GlcNAc) into surface-expressed glycosylphosphatidylinositol (GPI) glycolipids and N-linked glycans. To investigate whether these glycoconjugates are required for infectivity of promastigote and intracellular amastigote stages, we generated a Leishmania major mutant lacking the gene encoding glutamine : fructose-6-phosphate amidotransferase (GFAT). The L. majorDeltagfat mutant is unable to synthesize GlcN-6-phosphate de novo and is auxotrophic for GlcN or GlcNAc. GlcN starvation leads to the rapid depletion of dolichol-linked oligosaccharides and GPI precursors, hypersensitivity to elevated temperatures encountered in the mammalian host and eventual parasite death. Short-term tunicamycin treatment induces a similar hypersensitivity to temperature, indicating that N-linked glycans are required for thermotolerance and viability. L. majorDeltagfat promastigotes are unable to proliferate in ex vivo infected macrophages, demonstrating that GlcN(Ac) levels in the phagolysosome are low. In contrast, Deltagfat amastigotes grow as well as wild-type amastigotes in macrophages and induce lesions in susceptible mice. These stages still require GlcN(Ac) for viability but can apparently scavenge all of their glucosamine requirements from the macrophage phagolysosome. These results highlight significant differences in the nutrient requirements of promastigote and amastigote stages and suggest that enzymes involved in UDP-GlcNAc biosynthesis are essential for pathogenesis in the mammalian host.
Towards re-purposing BH3-mimetics in Legionella and viral infections
Publisher: Informa UK Limited
Date: 29-11-2017
Evidence That Intracellular β1-2 Mannan Is a Virulence Factor in Leishmania Parasites
Publisher: Elsevier BV
Date: 10-2003
Glycosylated compounds of parasitic protozoa
Publisher: Elsevier
Date: 2010
Central metabolic interactions of immune cells and microbes: prospects for defeating infections
Publisher: EMBO
Date: 21-06-2019
Surface Determinants of Leishmania Parasites and their Role in Infectivity in the Mammalian Host
Publisher: Bentham Science Publishers Ltd.
Date: 09-2004
Abstract: Leishmania are intracellular protozoan parasites that reside primarily in host mononuclear phagocytes. Infection of host macrophages is initiated by infective promastigote stages and perpetuated by an obligate intracellular amastigote stage. Studies undertaken over the last decade have shown that the composition of the complex surface glycocalyx of these stages (comprising lipophosphoglycan, GPI-anchored glycoproteins, proteophosphoglycans and free GPI glycolipids) changes dramatically as promastigotes differentiate into amastigotes. Marked stage-specific changes also occur in the expression of other plasma membrane components, including type-1, polytopic and peripheral membrane proteins, reflecting the distinct microbicidal responses and nutritional environments encountered by these stages. More recently, a number of Leishmania mutants lacking single or multiple surface components have been generated. While some of these mutants are less virulent than wild type parasites, many of these mutants exhibit only mild or no loss of virulence. These studies suggest that, 1) the major surface glycocalyx components of the promastigote stage (i.e. LPG, GPI-anchored proteins) only have a transient or minor role in macrophage invasion, 2) that there is considerable functional redundancy in the surface glycocalyx and/or loss of some components can be compensated for by the acquisition of equivalent host glycolipids, 3) the expression of specific nutrient transporters is essential for life in the macrophage and 4) the role(s) of some surface components differ markedly in different Leishmania species. These mutants will be useful for identifying other surface or intracellular components that are required for virulence in macrophages.
Living in a phagolysosome; metabolism of Leishmania amastigotes
Publisher: Elsevier BV
Date: 08-2007
Abstract: Leishmania amastigotes primarily proliferate within macrophages in the mammalian host. Genome-based metabolic reconstructions, combined with biochemical, reverse genetic and mRNA or protein profiling studies are providing new insights into the metabolism of this intracellular stage. We propose that the complex nutritional requirements of amastigotes have contributed to the tropism of these parasites for the amino acid-rich phagolysosome of macrophages. Amastigote metabolism in this compartment is robust because many metabolic mutants are capable of either growing normally or persisting long term in susceptible animals. New approaches for measuring amastigote metabolism in vivo are discussed.
Legionella pneumophila Strain 130b Evades Macrophage Cell Death Independent of the Effector SidF in the Absence of Flagellin
Publisher: Frontiers Media SA
Date: 16-02-2017
The Leishmania-macrophage interaction: a metabolic perspective
Publisher: Hindawi Limited
Date: 09-12-2007
DOI: 10.1111/J.1462-5822.2007.01096.X
Abstract: Protozoan parasites belonging to the genus Leishmania exhibit a pronounced tropism for macrophages although they have the capacity to infect a variety of other phagocytic and non-phagocytic mammalian cells. Unlike most other intramacrophage pathogens, the major proliferative stage of Leishmania resides in the mature phagolysosomes of these host cells. In this review we highlight some of the strategies utilized by the intracellular amastigote stage of Leishmania to survive in this compartment. Remarkably, and in contrast to many other intracellular pathogens, Leishmania amastigotes have a minimalist surface glycocalyx which may facilitate uptake of essential lipids and promote exposure of phospholipids required for phagocytosis via macrophage apoptotic cell receptors. Leishmania amastigotes also differ from many other intracellular pathogens in having complex nutritional requirements which must be scavenged from the host cell. Amino acids and polyamines appear to be important carbon sources and growth-limiting nutrients, respectively, and their availability to intracellular amastigotes may be regulated by the activation state of host macrophages. Metabolic processes in both the parasite and host cell may thus be crucial determinants of disease outcome.
Central carbon metabolism ofLeishmaniaparasites
Publisher: Cambridge University Press (CUP)
Date: 17-02-2010
DOI: 10.1017/S0031182010000077
Abstract: Leishmania spp. are sandfly-transmitted protozoa parasites that cause a spectrum of diseases in humans. Many enzymes involved in Leishmania central carbon metabolism differ from their equivalents in the mammalian host and are potential drug targets. In this review we summarize recent advances in our understanding of Leishmania central carbon metabolism, focusing on pathways of carbon utilization that are required for growth and pathogenesis in the mammalian host. While Leishmania central carbon metabolism shares many features in common with other pathogenic trypanosomatids, significant differences are also apparent. Leishmania parasites are also unusual in constitutively expressing most core metabolic pathways throughout their life cycle, a feature that may allow these parasites to exploit a range of different carbon sources (primarily sugars and amino acids) rapidly in both the insect vector and vertebrate host. Indeed, recent gene deletion studies suggest that mammal-infective stages are dependent on multiple carbon sources in vivo . The application of metabolomic approaches, outlined here, are likely to be important in defining aspects of central carbon metabolism that are essential at different stages of mammalian host infection.
A1 is induced by pathogen ligands to limit myeloid cell death and NLRP3 inflammasome activation
Publisher: EMBO
Date: 17-10-2023
Isotopomer Profiling of Leishmania mexicana Promastigotes Reveals Important Roles for Succinate Fermentation and Aspartate Uptake in Tricarboxylic Acid Cycle (TCA) Anaplerosis, Glutamate Synthesis, and Growth
Publisher: Elsevier BV
Date: 08-2011
Neisseria gonorrhoeae-derived outer membrane vesicles package β-lactamases to promote antibiotic resistance
Publisher: Oxford University Press (OUP)
Date: 2022
Abstract: Neisseria gonorrhoeae causes the sexually transmitted disease gonorrhoea. The treatment of gonorrhoea is becoming increasingly challenging, as N. gonorrhoeae has developed resistance to antimicrobial agents routinely used in the clinic. Resistance to penicillin is wide-spread partly due to the acquisition of β-lactamase genes. How N. gonorrhoeae survives an initial exposure to β-lactams before acquiring resistance genes remains to be understood. Here, using a panel of clinical isolates of N. gonorrhoeae we show that the β-lactamase enzyme is packaged into outer membrane vesicles (OMVs) by strains expressing blaTEM-1B or blaTEM-106, which protects otherwise susceptible clinical isolates from the β-lactam drug amoxycillin. We characterized the phenotypes of these clinical isolates of N. gonorrhoeae and the time courses over which the cross-protection of the strains is effective. Imaging and biochemical assays suggest that OMVs promote the transfer of proteins and lipids between bacteria. Thus, N. gonorrhoeae strains secret antibiotic degrading enzymes via OMVs enabling survival of otherwise susceptible bacteria.
LeishCyc: A Guide to Building a Metabolic Pathway Database and Visualization of Metabolomic Data
Publisher: Humana Press
Date: 2012
DOI: 10.1007/978-1-61779-827-6_17
Abstract: The complexity of the metabolic networks in even the simplest organisms has raised new challenges in organizing metabolic information. To address this, specialized computer frameworks have been developed to capture, manage, and visualize metabolic knowledge. The leading databases of metabolic information are those organized under the umbrella of the BioCyc project, which consists of the reference database MetaCyc, and a number of pathway/genome databases (PGDBs) each focussed on a specific organism. A number of PGDBs have been developed for bacterial, fungal, and protozoan pathogens, greatly facilitating dissection of the metabolic potential of these organisms and the identification of new drug targets. Leishmania are protozoan parasites belonging to the family Trypanosomatidae that cause a broad spectrum of diseases in humans. In this work we use the LeishCyc database, the BioCyc database for Leishmania major, to describe how to build a BioCyc database from genomic sequences and associated annotations. By using metabolomic data generated in our group, we show how such databases can be utilized to elucidate specific changes in parasite metabolism.
Glucose Homeostasis Is Important for Immune Cell Viability during Candida Challenge and Host Survival of Systemic Fungal Infection
Publisher: Elsevier BV
Date: 05-2018
Microbial Egress: A Hitchhiker's Guide to Freedom
Publisher: Public Library of Science (PLoS)
Date: 24-07-2014
Mitochondrial dysfunction caused by outer membrane vesicles from Gram-negative bacteria activates intrinsic apoptosis and inflammation
Publisher: Springer Science and Business Media LLC
Date: 17-08-2020
A bioinformatic strategy for the detection, classification and analysis of bacterial autotransporters
Publisher: Public Library of Science (PLoS)
Date: 14-08-2012
Intracellular Survival of Leishmania major Depends on Uptake and Degradation of Extracellular Matrix Glycosaminoglycans by Macrophages
Publisher: Public Library of Science (PLoS)
Date: 03-09-2015
Outer membrane vesicles from Neisseria gonorrhoeae target PorB to mitochondria and induce apoptosis
Publisher: Public Library of Science (PLoS)
Date: 30-03-2018
The short chain fatty acid butyrate prevents intracellular replication of Legionella by regulating cysteine levels in macrophages
Publisher: Research Square Platform LLC
Date: 31-08-2021
DOI: 10.21203/RS.3.RS-829027/V1
Abstract: Macrophages can prevent infections from intracellular pathogens by restricting access to essential nutrients, termed nutritional immunity. With the exception of tryptophan depletion, it is unclear if other amino acids are similarly regulated in infected macrophages. Here, we show that the expression of nutrient transporters in Legionella-infected macrophages is modulated by the short chain fatty acid butyrate. Butyrate prevented the upregulation of the cystine/glutamate exchanger, Slc7a11, in macrophages infected with L. pneumophila, which decreased cellular cysteine levels. Butyrate and the Slc7a11 inhibitor erastin impaired intracellular Legionella replication in macrophages in vitro, with these being restored by exogenous supplementation with cysteine. Butyrate caused increased histone acetylation in infected macrophages, and pan- and class II HDAC inhibitors also restricted intracellular Legionella growth in a cysteine-dependent manner. Intranasal administration of butyrate reduced L. pneumophila lung burdens in mice. Our data suggest that butyrate alters the metabolism of macrophages to promote nutritional immunity by decreasing cysteine levels and that this can be harnessed to treat bacterial lung infections.
Characterization of a Leishmania mexicana mutant defective in synthesis of free and protein-linked GPI glycolipids
Publisher: Elsevier BV
Date: 11-2002
DOI: 10.1016/S0166-6851(02)00236-0
Abstract: The cell surface of the promastigote stage of the protozoan parasite, Leishmania mexicana is coated by a number of glycosylphosphatidylinositol (GPI)-anchored proteins, a GPI-anchored lipophosphoglycan (LPG) and an abundant class of free GPIs, termed glycoinositolphospholipids (GIPLs). We have developed a new screen for isolating L. mexicana mutants that are defective in GPI biosynthesis, involving concanavalin A selection of a parental strain with a modified surface coat. One mutant was isolated that lacked the major GIPL species and mature GPI-protein anchor precursors, but synthesized normal levels of LPG anchor precursors. Based on analysis of apolar GIPLs that accumulate in this mutant and in vivo and in vitro synthesized GPIs, this mutant was found to have a defect in the addition of an alpha1-6 linked mannose to the common precursor, Man(1)GlcN-PI. The apolar GIPLs were transported to the cell surface with the same kinetics as mature GIPLs. However, non-anchored isoforms of the major GPI-anchored protein, gp63, were either slowly secreted (with a t(1/2) of 2 h) or retained within the endoplasmic reticulum, respectively. These findings suggest that common enzymes are involved in the synthesis of GIPLs and protein anchors and have implications for understanding how the biosynthesis of the major surface components of these parasites is regulated.
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