Gordon D Brown

University of Aberdeen, Aberdeen, Scotland, United Kingdom

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Publications (150)1265.06 Total impact

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    ABSTRACT: Neutrophils are critical for antifungal defense, but the mechanisms that clear hyphae and other pathogens that are too large to be phagocytosed remain unknown. We found that neutrophils sensed microbe size and selectively released neutrophil extracellular traps (NETs) in response to large pathogens, such as Candida albicans hyphae and extracellular aggregates of Mycobacterium bovis, but not in response to small yeast or single bacteria. NETs were fundamental in countering large pathogens in vivo. Phagocytosis via dectin-1 acted as a sensor of microbe size and prevented NET release by downregulating the translocation of neutrophil elastase (NE) to the nucleus. Dectin-1 deficiency led to aberrant NET release and NET-mediated tissue damage during infection. Size-tailored neutrophil responses cleared large microbes and minimized pathology when microbes were small enough to be phagocytosed.
    Nature immunology. 09/2014;
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    ABSTRACT: Chitin is an essential structural polysaccharide of fungal pathogens and parasites, but its role in human immune responses remains largely unknown. It is the second most abundant polysaccharide in nature after cellulose and its derivatives today are widely used for medical and industrial purposes. We analysed the immunological properties of purified chitin particles derived from the opportunistic human fungal pathogen Candida albicans, which led to the selective secretion of the anti-inflammatory cytokine IL-10. We identified NOD2, TLR9 and the mannose receptor as essential fungal chitin-recognition receptors for the induction of this response. Chitin reduced LPS-induced inflammation in vivo and may therefore contribute to the resolution of the immune response once the pathogen has been defeated. Fungal chitin also induced eosinophilia in vivo, underpinning its ability to induce asthma. Polymorphisms in the identified chitin receptors, NOD2 and TLR9, predispose individuals to inflammatory conditions and dysregulated expression of chitinases and chitinase-like binding proteins, whose activity is essential to generate IL-10-inducing fungal chitin particles in vitro, have also been linked to inflammatory conditions and asthma. Chitin recognition is therefore critical for immune homeostasis and is likely to have a significant role in infectious and allergic disease. Citation: Wagener J, Malireddi RKS, Lenardon MD, Kö berle M, Vautier S, et al. (2014) Fungal Chitin Dampens Inflammation through IL-10 Induction Mediated by NOD2 and TLR9 Activation. PLoS Pathog 10(4): e1004050. doi:10.1371/journal.ppat.1004050, AI101935) and the American Lebanese Syrian Associated Charities (ALSAC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist.
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    ABSTRACT: Chitin is an essential structural polysaccharide of fungal pathogens and parasites, but its role in human immune responses remains largely unknown. It is the second most abundant polysaccharide in nature after cellulose and its derivatives today are widely used for medical and industrial purposes. We analysed the immunological properties of purified chitin particles derived from the opportunistic human fungal pathogen Candida albicans, which led to the selective secretion of the anti-inflammatory cytokine IL-10. We identified NOD2, TLR9 and the mannose receptor as essential fungal chitin-recognition receptors for the induction of this response. Chitin reduced LPS-induced inflammation in vivo and may therefore contribute to the resolution of the immune response once the pathogen has been defeated. Fungal chitin also induced eosinophilia in vivo, underpinning its ability to induce asthma. Polymorphisms in the identified chitin receptors, NOD2 and TLR9, predispose individuals to inflammatory conditions and dysregulated expression of chitinases and chitinase-like binding proteins, whose activity is essential to generate IL-10-inducing fungal chitin particles in vitro, have also been linked to inflammatory conditions and asthma. Chitin recognition is therefore critical for immune homeostasis and is likely to have a significant role in infectious and allergic disease.
    PLoS Pathogens 04/2014; 10(4):e1004050. · 8.14 Impact Factor
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    ABSTRACT: Chitin is the second most abundant polysaccharide in nature after cellulose and an essential component of the cell wall of all fungal pathogens. The discovery of human chitinases and chitinase-like binding proteins indicates that fungal chitin is recognised by cells of the human immune system, shaping the immune response towards the invading pathogen. We show that three immune cell receptors- the mannose receptor, NOD2 and TLR9 recognise chitin and act together to mediate an anti-inflammatory response via secretion of the cytokine IL-10. This mechanism may prevent inflammation-based damage during fungal infection and restore immune balance after an infection has been cleared. By increasing the chitin content in the cell wall pathogenic fungi may influence the immune system in their favour, by down-regulating protective inflammatory immune responses. Furthermore, gene mutations and dysregulated enzyme activity in the described chitin recognition pathway are implicated in inflammatory conditions such as Crohn's Disease and asthma, highlighting the importance of the discovered mechanism in human health.
    PLoS Pathogens 04/2014; 10(4):e1004050. · 8.14 Impact Factor
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    ABSTRACT: Chromoblastomycosis is a subcutaneous mycosis that remains a therapeutic challenge with no standard treatment and high rates of relapse. Based on our recent discoveries in mouse models, we tested the efficacy of using topical applications of imiquimod to treat patients afflicted with this chronic fungal infection. We report here on the first four patients, who all displayed a marked improvement of their lesions, both with and without concurrent oral antifungal therapy.
    Clinical Infectious Diseases 03/2014; · 9.37 Impact Factor
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    ABSTRACT: Invasive fungal infections (IFIs) are a major cause of HIV-related mortality globally. Despite widespread rollout of combined antiretroviral therapy, there are still up to 1 million deaths annually from IFIs, accounting for 50% of all AIDS-related death. A historic failure to focus efforts on the IFIs that kill so many HIV patients has led to fundamental flaws in the management of advanced HIV infection. This review, based on the EMBO AIDS-Related Mycoses Workshop in Cape Town in July 2013, summarizes the current state of the-art in AIDS-related mycoses, and the key action points required to improve outcomes from these devastating infections.
    Trends in Microbiology 02/2014; · 8.43 Impact Factor
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    ABSTRACT: Metabolism is integral to the pathogenicity of Candida albicans, a major fungal pathogen of humans. As well as providing the platform for nutrient assimilation and growth in diverse host niches, metabolic adaptation affects the susceptibility of C. albicans to host-imposed stresses and antifungal drugs, the expression of key virulence factors, and fungal vulnerability to innate immune defences. These effects, which are driven by complex regulatory networks linking metabolism, morphogenesis, stress adaptation, and cell wall remodelling, influence commensalism and infection. Therefore, current concepts of Candida–host interactions must be extended to include the impact of metabolic adaptation upon pathogenicity and immunogenicity.
    Trends in microbiology. 01/2014;
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    ABSTRACT: The contribution of fungal infections to the morbidity and mortality of HIV-infected individuals is largely unrecognized. A recent meeting highlighted several priorities that need to be urgently addressed, including improved epidemiological surveillance, increased availability of existing diagnostics and drugs, more training in the field of medical mycology, and better funding for research and provision of treatment, particularly in developing countries.
    Trends in Microbiology 01/2014; 22(3):107–109. · 8.43 Impact Factor
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    ABSTRACT: Although Candida glabrata is an important pathogenic Candida species, relatively little is known about its innate immune recognition. Here we explore the potential role of Dectin-2 for host defense against C. glabrata. Dectin-2-deficient (Dectin-2(-/-)) mice were found to be more susceptible to C. glabrata infections, showing a defective fungal clearance in kidneys, but not in the liver. The increased susceptibility to infection was accompanied by lower production of T helper 1 (Th1) and Th17-derived cytokines by splenocytes of Dectin-2(-/-) mice, while macrophage-derived cytokines were less affected. These defects were associated with a moderate, yet significant, decreased phagocytosis of the fungus by the Dectin-2(-/-) macrophages and neutrophils. Neutrophils of Dectin-2(-/-) mice also displayed a lower production of reactive oxygen species (ROS) upon challenge with opsonized C. glabrata or C. albicans. This study suggests that Dectin-2 is important in host defense against C. glabrata and provides new insights in the host defense mechanisms against this important fungal pathogen.
    Infection and immunity 12/2013; · 4.21 Impact Factor
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    ABSTRACT: Signaling C-type lectin receptors (CLRs) are crucial in shaping the immune response to fungal pathogens, but comparably little is known about the role of these receptors in bacterial, viral and parasitic infections. CLRs have many diverse functions depending on the signaling motifs in their cytoplasmic domains, and can induce endocytic, phagocytic, antimicrobial, pro-inflammatory or anti-inflammatory responses which are either protective or not during an infection. Understanding the role of CLRs in shaping anti-microbial immunity offers great potential for the future development of therapeutics for disease intervention. In this review we will focus on the recognition of bacterial, viral and parasitic pathogens by CLRs, and how these receptors influence the outcome of infection. We will also provide a brief update on the role of CLRs in antifungal immunity.
    Cellular Microbiology 12/2013; · 4.81 Impact Factor
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    ABSTRACT: Intestinal microfold (M) cells possess a high transcytosis capacity and are able to transport a broad range of materials including particulate antigens, soluble macromolecules, and pathogens from the intestinal lumen to inductive sites of the mucosal immune system. M cells are also the primary pathway for delivery of secretory IgA (SIgA) to the gut-associated lymphoid tissue. However, although the consequences of SIgA uptake by M cells are now well known and described, the mechanisms whereby SIgA is selectively bound and taken up remain poorly understood. Here we first demonstrate that both the Cα1 region and glycosylation, more particularly sialic acid residues, are involved in M cell–mediated reverse transcytosis. Second, we found that SIgA is taken up by M cells via the Dectin-1 receptor, with the possible involvement of Siglec-5 acting as a co-receptor. Third, we establish that transcytosed SIgA is taken up by mucosal CX3CR1+ dendritic cells (DCs) via the DC-SIGN receptor. Fourth, we show that mucosal and systemic antibody responses against the HIV p24-SIgA complexes administered orally is strictly dependent on the expression of Dectin-1. Having deciphered the mechanisms leading to specific targeting of SIgA-based Ag complexes paves the way to the use of such a vehicle for mucosal vaccination against various infectious diseases.
    PLoS Biology 09/2013; 11(9). · 12.69 Impact Factor
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    ABSTRACT: Intestinal microfold (M) cells possess a high transcytosis capacity and are able to transport a broad range of materials including particulate antigens, soluble macromolecules, and pathogens from the intestinal lumen to inductive sites of the mucosal immune system. M cells are also the primary pathway for delivery of secretory IgA (SIgA) to the gut-associated lymphoid tissue. However, although the consequences of SIgA uptake by M cells are now well known and described, the mechanisms whereby SIgA is selectively bound and taken up remain poorly understood. Here we first demonstrate that both the Cα1 region and glycosylation, more particularly sialic acid residues, are involved in M cell-mediated reverse transcytosis. Second, we found that SIgA is taken up by M cells via the Dectin-1 receptor, with the possible involvement of Siglec-5 acting as a co-receptor. Third, we establish that transcytosed SIgA is taken up by mucosal CX3CR1(+) dendritic cells (DCs) via the DC-SIGN receptor. Fourth, we show that mucosal and systemic antibody responses against the HIV p24-SIgA complexes administered orally is strictly dependent on the expression of Dectin-1. Having deciphered the mechanisms leading to specific targeting of SIgA-based Ag complexes paves the way to the use of such a vehicle for mucosal vaccination against various infectious diseases.
    PLoS Biology 09/2013; 11(9):e1001658. · 12.69 Impact Factor
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    ABSTRACT: The contribution of fungal infections to the morbidity and mortality of HIV-infected individuals is largely unrec-ognized. A recent meeting highlighted several priorities that need to be urgently addressed, including improved epidemiological surveillance, increased availability of existing diagnostics and drugs, more training in the field of medical mycology, and better funding for research and provision of treatment, particularly in developing countries. Fungal infections in HIV patients Fungi are often harmless in the context of normal host responses, but immune deficiencies, particularly in HIV-positive patients, result in significantly increased suscept-ibility to many fungal infections. The global defects in immune function resulting from HIV infection, in particu-lar, cause susceptibility to several mucosal and life-threatening fungal diseases with pathogens such as Candida, Cryptococcus, and Pneumocystis. For example, it has been estimated that HIV/AIDS results in nearly 10 million cases of oral thrush and 2 million cases of esophageal fungal infections annually [1,2]. Of even greater concern is the high mortality associated with invasive fungal infec-tions, which often exceeds 50%, despite the availability of antifungal drugs [2]. For example, the US Centers for Dis-ease Control and Prevention (CDC) have estimated that there are approximately one million cases of cryptococcal meningitis globally every year in patients with HIV/AIDS with over 500 000 related deaths in sub-Saharan Africa in 2008 [3]. Although the accuracy of mortality estimates may be questionable, it is likely that fungal infections collectively kill about one and a half million people every year [1,2]. Thus, it is possible that at least as many people die from fungal diseases as tuberculosis (see
    EMBO Conference on AIDS related Mycoses; 07/2013
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    Rebecca A Drummond, Gordon D Brown
    PLoS Pathogens 07/2013; 9(7):e1003417. · 8.14 Impact Factor
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    ABSTRACT: It is now recognised that innate immunity to intestinal microflora plays a significant role in mediating immune health, and modulation of microbial sensing may underpin the impact of plant natural products in the diet or when used as nutraceuticals. In this context, we have examined five classes of plant-derived flavonoids (flavonols, flavones, flavanones, catechins and cyanidin) for their ability to regulate cytokine release induced by the Toll-like receptor 2 (TLR2) agonist Pam3CSK4. We found that the flavonols selectively co-stimulated IL-1β secretion but had no impact on the secretion of IL-6. Importantly, this costimulation of TLR2-induced cytokine secretion was dependent on regiospecific methylation of the flavonol scaffold with a rank order of quercetin-3,4'-dimethylether > quercetin-3-methylether > casticin. The mechanism underpinning this costimulation did not involve enhanced inflammasome activation. In contrast, the methylated flavonols enhanced IL-1β gene expression through transcriptional regulation, involving mechanisms that operate downstream of the initial NF-κB and STAT1 activation events. These studies demonstrate an exquisite level of control of scaffold bioactivity by regiospecific methylation, with important implications for understanding how natural products affect innate immunity and for their development as novel immunomodulators for clinical use.
    Journal of Biological Chemistry 06/2013; · 4.65 Impact Factor
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    ABSTRACT: Myeloid and non-myeloid cells express members of the C-type lectin-like receptor (CTLR) family, which mediate crucial cellular functions during immunity and homeostasis. Of relevance here is the dendritic cell-associated C-type lectin-2 (Dectin-2) family of CTLRs, which includes blood dendritic cell antigen 2 (BDCA-2), dendritic cell immunoactivating receptor (DCAR), dendritic cell immunoreceptor (DCIR), Dectin-2, C-type lectin superfamily 8 (CLECSF8) and macrophage-inducible C-type lectin (Mincle). These CTLRs possess a single extracellular conserved C-type lectin-like domain and are capable of mediating intracellular signalling either directly, through integral signalling domains, or indirectly, by associating with signalling adaptor molecules. These receptors recognize a diverse range of endogenous and exogenous ligands, and can function as pattern recognition receptors for several classes of pathogens including fungi, bacteria and parasites, driving both innate and adaptive immunity. In this review, we summarize our knowledge of each of these receptors, highlighting the exciting discoveries that have been made in recent years.
    International Immunology 05/2013; 25(5):271-7. · 3.14 Impact Factor
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    ABSTRACT: The β-glucan receptor Dectin-1 is a member of the C-type lectin family and functions as an innate pattern recognition receptor in antifungal immunity. In both mouse and man, Dectin-1 has been found to play an essential role in controlling infections with Candida albicans, a normally commensal fungus in man which can cause superficial mucocutaneous infections as well as life-threatening invasive diseases. Here, using in vivo models of infection, we show that the requirement for Dectin-1 in the control of systemic Candida albicans infections is fungal strain-specific; a phenotype that only becomes apparent during infection and cannot be recapitulated in vitro. Transcript analysis revealed that this differential requirement for Dectin-1 is due to variable adaptation of C. albicans strains in vivo, and that this results in substantial differences in the composition and nature of their cell walls. In particular, we established that differences in the levels of cell-wall chitin influence the role of Dectin-1, and that these effects can be modulated by antifungal drug treatment. Our results therefore provide substantial new insights into the interaction between C. albicans and the immune system and have significant implications for our understanding of susceptibility and treatment of human infections with this pathogen.
    PLoS Pathogens 04/2013; 9(4):e1003315. · 8.14 Impact Factor
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    ABSTRACT: β-Glucans are known for their ability to trigger both protective and damaging immune responses. Here we have explored the role of the beta-glucan receptor Dectin-1 in archetypical models of protective and non-protective immuno-modulation by beta-glucan rich ligands. In the first model, we explored the role of Dectin-1 in the ability of soluble purified β-glucans to mediate protection against systemic Staphylococcus aureus infection in mice. In the second model, we explored the role of Dectin-1 in zymosan induced multiple organ dysfunction syndrome. In both cases, these β-glucan rich compounds had marked effects in vivo which were unaltered by Dectin-1 deficiency, suggesting that this receptor has a redundant role in these murine models.
    Microbes and Infection 03/2013; · 2.92 Impact Factor
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    ABSTRACT: The role of Group IVA cytosolic phospholipase A2 (cPLA2α) activation in regulating macrophage transcriptional responses to Candida albicans infection was investigated. cPLA2α releases arachidonic acid for the production of eicosanoids. In mouse resident peritoneal macrophages, prostacyclin, prostaglandin E2 and leukotriene C4 were produced within minutes of C. albicans addition before cyclooxygenase 2 expression. The production of TNFα was lower in C. albicans-stimulated cPLA2α(+/+) than cPLA2α(-/-) macrophages due to an autocrine effect of prostaglandins that increased cAMP to a greater extent in cPLA2α(+/+) than cPLA2α(-/-) macrophages. For global insight, differential gene expression in C. albicans-stimulated cPLA2α(+/+) and cPLA2α(-/-) macrophages (3 h) was compared by microarray. cPLA2α(+/+) macrophages expressed 86 genes at lower levels and 181 genes at higher levels than cPLA2α(-/-) macrophages (≥2-fold, p<0.05). Several pro-inflammatory genes were expressed at lower levels (Tnfα, Cx3cl1, Cd40, Ccl5, Csf1, Edn1, CxCr7, Irf1, Irf4, Akna, Ifnγ, several IFNγ-inducible GTPases). Genes that dampen inflammation (Socs3, Il10, Crem, Stat3, Thbd, Thbs1, Abca1) and genes involved in host defense (Gja1, Csf3, Trem1, Hdc) were expressed at higher levels in cPLA2α(+/+) macrophages. Representative genes expressed lower in cPLA2α(+/+) macrophages (Tnfα, Csf1) were increased by treatment with a prostacyclin receptor antagonist and protein kinase A inhibitor, whereas genes expressed at higher levels (Crem, Nr4a2, Il10, Csf3) were suppressed. The results suggest that C. albicans stimulates an autocrine loop in macrophages involving cPLA2α, cyclooxygenase 1-derived prostaglandins and increased cAMP that globally effects expression of genes involved in host defense and inflammation.
    PLoS ONE 01/2013; 8(7):e69002. · 3.73 Impact Factor
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    ABSTRACT: In response to infection by fungal pathogens, the innate immune system recognises specific fungal pathogen associated molecular patterns (PAMPs) via pattern recognition receptors including the C-type lectin dectin-1 and members of the Toll Like Receptor (TLR) family. Stimulation of these receptors leads to the induction of both pro- and anti-inflammatory cytokines. The protein kinases MSK1 and 2 are known to be important in limiting inflammatory cytokine production by macrophages in response to the TLR4 agonist LPS. In this study we show that MSKs are also activated in macrophages by the fungal derived ligand zymosan, as well as the dectin-1 specific agonists curdlan and depleted zymosan, via the ERK1/2 and p38α MAPK pathways. Furthermore, we show that MSKs regulate dectin-1 induced IL-10 production, and that this regulation is dependent on the ability of MSKs to phosphorylate the transcription factor CREB. IL-10 secreted in response to zymosan was able to promote STAT3 phosphorylation via an autocrine feedback loop. Consistent with the decreased IL-10 secretion in MSK1/2 knockout macrophages, these cells also had decreased STAT3 tyrosine phosphorylation relative to wild type controls after stimulation with zymosan. We further show that the reduction in IL-10 production in the MSK1/2 macrophages results in increased secretion of IL-12p40 in response to zymosan relative to wild type controls. The production of high levels of IL-10 but low levels of IL-12 has previously been associated with an M2b or 'regulatory' macrophage phenotype, which was initially described in macrophages stimulated with a combination of immune complexes and LPS. We found that zymosan, via dectin-1 activation, also leads to the expression of SphK1 and LIGHT, markers of a regulatory like phenotype in mouse macrophages. The expression of these makers was further reinforced by the high level of IL-10 secreted in response to zymosan stimulation.
    PLoS ONE 01/2013; 8(3):e60086. · 3.73 Impact Factor

Publication Stats

9k Citations
1,265.06 Total Impact Points

Institutions

  • 2004–2014
    • University of Aberdeen
      • • Institute of Medical Sciences
      • • Division of Applied Medicine
      Aberdeen, Scotland, United Kingdom
  • 2002–2014
    • University of Cape Town
      • • Institute of Infectious Disease & Molecular Medicine (IIDMM)
      • • Division of Immunology
      • • Faculty of Health Sciences
      • • Division of Medical Biochemistry
      Kaapstad, Western Cape, South Africa
  • 2012
    • Universität zu Lübeck
      • Department of Dermatology
      Lübeck, Schleswig-Holstein, Germany
  • 2009–2012
    • University of Alabama at Birmingham
      • Department of Medicine
      Birmingham, AL, United States
    • Radboud University Nijmegen
      • Nijmegen Institute for Infection, Inflammation and Immunity
      Nijmegen, Provincie Gelderland, Netherlands
  • 2008–2012
    • Cardiff University
      • • Cardiff Institute of Infection & Immunity
      • • Department of Medical Biochemistry and Immunology
      Cardiff, WLS, United Kingdom
    • Radboud University Medical Centre (Radboudumc)
      • Department of Human Genetics
      Nymegen, Gelderland, Netherlands
  • 2005–2009
    • East Tennessee State University
      • Department of Surgery
      Johnson City, TN, United States
    • London Research Institute
      • Laboratory of Immunobiology
      Londinium, England, United Kingdom
  • 2002–2009
    • University of Oxford
      • Sir William Dunn School of Pathology
      Oxford, ENG, United Kingdom
  • 2006
    • Childrens Hospital of Pittsburgh
      • Department of Pediatrics
      Pittsburgh, Pennsylvania, United States
  • 2000–2002
    • Stellenbosch University
      Stellenbosch, Western Cape, South Africa