Chairs
Professor John W. Taylor, University of California, Berkeley, USA
Professor John W. Taylor, University of California, Berkeley, USA
John W. Taylor is professor of Plant and Microbial Biology at UC Berkeley. He and his group use DNA variation to study fungal evolution from phylogeny to population genomics. He has served as Chair of his Division at Berkeley, President of the Mycologial Society of America (MSA) and the International Mycological Association. He has received the Lucile Georg Medal of the International Association of Human and Animal Mycology, the Rhoda Benham Medal of the Medical Mycological Society of the Americas, the Alexopoulos Prize and Distinguished Mycologist Award of the Mycological Society of America and the J. A. von Arx Award for Research of the Centraalbureau voor Schimmelcultures. He has received awards for excellence in teaching from the MSA and his college. He is a fellow of the MSA, the California Academy of Science, the American Association for the Advancement of Science and the American Academy of Microbiology.
13:30-14:00
Trained immunity: a memory for innate host defence
Professor Mihai Netea, Radboud University Nijmegen Medical Centre, The Netherlands
Abstract
The inability of innate immunity to build an immunological memory, considered one of the main characteristics differentiating it from adaptive immunity, has been recently challenged by studies in plants, invertebrates, and mammals. Long-term reprogramming of innate immunity, that induces adaptive traits and has been termed trained immunity characterises prototypical innate immune cells such as natural killer cells and monocytes, and provides protection against reinfection in a T/B-cell-independent manner. In contrast, trained immunity has been shown to be able to induce protection against reinfection in a monocyte-independent manner. Non-specific protective effects dependent on trained immunity have also been shown to be induced after BCG vaccination in humans. Specific signaling mechanisms including the dectin-1/Raf1 and NOD2-mediated pathways induce trained immunity, through induction of histone methylation and epigenetic reprogramming of monocyte function. Complex immunological and metabolic circuits link cell stimulation to a long-term epigenetic reprogramming of its function. The concept of trained immunity represents a paradigm change in immunity and its putative role in infection and inflammation may represent the next step in the design of future vaccines and immunotherapeutic approaches.
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Professor Mihai Netea, Radboud University Nijmegen Medical Centre, The Netherlands
Professor Mihai Netea, Radboud University Nijmegen Medical Centre, The Netherlands
Mihai Netea was born and studied medicine in Cluj-Napoca, Romania. He completed his PhD at the Radboud University Nijmegen, The Netherlands, on studies investigating the cytokine network in sepsis. After working as a post-doc at the University of Colorado, he returned to Nijmegen where he finished his clinical training as an infectious diseases specialist, and where he currently heads the division of Experimental Medicine, Department of Internal Medicine, Nijmegen University Nijmegen Medical Center. His main research interests are pattern recognition of fungal pathogens and the induction of antifungal immunity, primary immunodeficiencies in innate immune system, and the study of the memory traits of innate immunity.
14:00-14:30
Tackling the threat of rice blast disease caused by the fungus Magnaporthe oryzae
Professor Nick Talbot FRS, University of Exeter, UK
Abstract
Magnaporthe oryzae is the causal agent of rice blast, one of the most serious diseases affecting rice production. Blast disease, however, also affects more than 50 grass species, including other important crops such as pearl millet, finger millet, oats and barley. Recently, blast disease has spread to wheat in South America and there have been important outbreaks of wheat blast disease in Brazil, Bolivia, and Paraguay. Combatting blast disease of rice and the other cereals it infects is therefore vital to ensuring global food security. In my research group we are investigating the biology of plant infection by M. oryzae and trying to use this information to devise new control strategies for the disease. During plant infection, M. oryzae forms a specialised infection structure called an appressorium. The infection cell generates enormous turgor, which is focused as mechanical force to breach the rice cuticle. We are particularly interested in re-polarisation of the appressorium and how this is controlled by means of a turgor-sensing mechanism that re-organises the actin cytoskeleton at the base of the appressorium to bring about cuticle penetration. Once rice tissue is invaded, the fungus secretes a large repertoire of effector proteins into plant cells. We are trying to understand how M. oryzae effectors facilitate invasion of plant tissue and modulate plant immunity. We are seeking to apply the knowledge gained to develop both short term means of controlling rice blast disease, using existing resistance genes more efficiently, and in the longer term by devising more durable solution to the disease.
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Professor Nick Talbot FRS, University of Exeter, UK
Professor Nick Talbot FRS, University of Exeter, UK
Nick Talbot is Professor of Molecular Genetics and Deputy Vice-Chancellor of the University of Exeter. Nick’s research is focused on the biology of plant diseases. He utilises a range of cell biology, genetics and genomics approaches in his research and, in particular, investigates the biology of plant infection by the rice blast fungus Magnaporthe oryzae. He is interested in fungal infection-related development and understanding how fungi are able to invade plant tissue and suppress plant immunity. Professor Talbot has authored more than 120 scientific papers and reviews. He is currently an ERC Advanced Investigator and also holds grants from the BBSRC, The Bill and Melinda Gates Foundation and the Halpin Trust. He was elected Fellow of the Society of Biology (FSB) in 2010, a Member of EMBO in 2013, and a Fellow of the Royal Society (FRS) in 2014.
14:30-15:00
Modus operandi of an accidental fungal pathogen
Dr Elaine Bignell, University of Manchester, UK
Abstract
Exposure to fungal spores is an unavoidable, and sometimes fatal, consequence of human respiration. Amongst the plethora of species which populate the airborne microflora a single agent, Aspergillus fumigatus, accounts for ~90% of mould-related lung disease in humans. The molecular basis of disease pathology is poorly characterised, and the predominance of a single pathogenic species unexplained. Our recent studies revealed genetic regulation of A. fumigatus traits directing pulmonary tissue invasion and suggest that host damage results from the collateral activity of multiple gene products. We have used transcriptional profiling to gather a panoramic view of fungal gene expression during mould infection of the mammalian lung and used it as a tool with which to dissect avirulent phenotypes. Addressing the behaviour of a non-invasive mutant lacking the pH-responsive transcription factor PacC we discovered a combinatorial mode of tissue entry dependent upon sequential, and mechanistically distinct, perturbations of the pulmonary epithelium. Thus, analysis of the host-infecting transcriptome reveals stage-specific expression of physiologically relevant and co-ordinately regulated pathogen genes including a cohort of species-specific and/or host mimicking traits capable of promoting tissue damage. The implications of these findings with respect to the origin of pathogenicity within the Aspergillus genus will be discussed.
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Dr Elaine Bignell, University of Manchester, UK
Dr Elaine Bignell, University of Manchester, UK
Dr Elaine Bignell is a Reader in Applied Mycology at the University of Manchester (UoM) and Deputy Director of the Manchester Fungal Infection Group (MFIG), a multi-million pound venture funded by UoM in 2013 to strengthen understanding of fungal infection biology. The aim of her research is to deliver, from molecules - through cells - to living animals, the insight required to design and generate the next generation of anti-infective therapeutic entities, which are urgently required for the fight against fungal diseases of man. These might impact pathogen and/or host activities to effect a favourable outcome of disease. Her group is working to identify crucial sensory and signalling proteins used by Aspergillus fumigatus to withstand stress within the host environment. They are also working with mathematicians to derive a fully quantitative understanding of the host pathogen interaction. This will enable us to redefine virulence of this pathogen and also to determine the relative contributions of host and pathogen activities to disease, within a framework conducive to appropriate intervention.
Dr Bignell has more than 20 years of experience in molecular genetic manipulation of model and pathogenic fungi and has accrued a theoretical and practical working knowledge of whole animal infection modelling, epithelial and macrophage infection assays, fungal classical and molecular genetics, analysis of protein-protein interactions in living fungal cells and whole genome transcriptomics analyses. She have worked extensively on transcriptional and post-translational regulation of fungal pH signalling. This work contributed directly to a pioneering body of research published in the late 1990s which described, for the first time in fungi, the mechanistic basis of pH-mediated signalling. Since 2000, initially funded as an MRC New Investigator at Imperial College London, she has developed murine models of invasive fungal infections and used them to identify fungal processes critical to mammalian infection, including the first and only in-host transcriptomic profiles of Aspergillus fumigatus pathogenic activities.
Current research programmes include mechanistic aspects of calcium-mediated signalling in A. fumigatus (Wellcome Trust WT093596MA), structure-function analysis of a pH-responsive molecular switch required for fungal virulence (MRC:MR/L000822/1) and new MRC project: A genome-scale census of pathogenicity factors in the major mould pathogen of human lungs (MR/M02010X/1).
15:30-16:00
Mitigating amphibian chytridiomycosis in the wild
Dr Trent Garner, Institute of Zoology, ZSL, UK
Abstract
It has been almost 20 years since the fungal pathogen Batrachochytrium dendrobatidis was first described as a cause of amphibian mass mortality in captivity and the wild. Since then, it has been implicated in amphibian population declines on five continents, along with its congener (Batrachochytrium salamandrivorans), currently affecting wild caudate amphibians on the European continent. Despite this, there has been an almost complete lack of efforts to mitigate these fungal pathogens in nature, and existing strategies are arguably best suited to managing disease in the captive setting. Several approaches are being investigated, and generally fall into five categories: i) host species-specific manipulations of host and extended immunity; ii) ‘immunisation’ using avirulent forms of the pathogen; iii) antifungal applications; iv) environmental disinfection or reduction of pathogen density, and v) manipulation of host community composition through removal of targeted host species. To date, the only published example of pathogen elimination required combining chemical environmental disinfection (iv) with antifungal treatment (iii), a transferrable but controversial method requiring further investigation of potential environmental impacts. Although research suggests manipulation of immunity (i) may hold some promise, the lack of transferability and high levels of pathogen diversity suggest that these approaches will be difficult, if not impossible, to roll out across amphibian communities in a timely fashion. Attempts at immunising (ii) with killed fungus have failed, and early results investigating competitive interactions amongst pathogen genotypes indicate that avirulent forms are simply outcompeted by more virulent genotypes. Antifungal treatment (iii) alone offers only transient benefits and do not impair reinvasion by amphibian-associated chytrids. Environmental reduction of pathogen density (iv) has been shown to allow coexistence between lethal forms of the chytrids and highly susceptible hosts, and theoretical research suggests that elimination of key host species (v) may reduce pathogen burdens to less virulent levels. These categories are value driven with the primary goal of conserving amphibians and will inevitably involve ethical disputes. It is therefore important that scientific objectivity underpins decision to apply any mitigation action.
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Dr Trent Garner, Institute of Zoology, ZSL, UK
Dr Trent Garner, Institute of Zoology, ZSL, UK
Dr Trent Garner is an experimental ecologist interested in determining when infectious diseases pose conservation threats to amphibian hosts and developing strategies for disease mitigation when they do. He has worked extensively with amphibian-associated chytridiomycete fungi and ranaviruses and developed risk assessments and conservation strategies for disease-affected European amphibian hosts.
16:00-16:30
Cryptococcal meningitis: new prevention and treatment strategies to reduce the global mortality burden
Professor Thomas Harrison, St George's University of London, UK
Abstract
Cryptococcus species are a leading fungal cause of human disease and death worldwide. In Sub-Saharan Africa, HIV-related cryptococcal meningitis, caused by C. neoformans, is associated with a 70% 3-month mortality and around 200,000 deaths per year. Importantly, despite increased availability of antiretroviral drugs, cases have not decreased. Additionally, the emergence of a hypervirulent lineage of C. gattii in British Columbia has demonstrated the threat posed by Cryptococcus sp. in regions outside their usual range and to immunocompetent hosts.
A new point-of-care immunodiagnostic test is now being used to facilitate screening and pre-emptive antifungal treatment as a cost-effective prevention strategy in patients with late-stage HIV infection; as well as enabling earlier, primary care-based, diagnosis for all symptomatic cases. Drug discovery aimed specifically at Cryptococcus species is limited, but one promising new agent, Viamet-1129, is now entering clinical evaluation. Meanwhile, expanding access to current antifungal drugs, and optimising their use in regimens that are sustainable in resource-limited settings, together with earlier diagnosis, and therapeutic lumbar punctures to manage the common complication of raised cerebrospinal fluid pressure, have the potential to significantly reduce the global disease burden.
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Professor Thomas Harrison, St George's University of London, UK
Professor Thomas Harrison, St George's University of London, UK
Tom Harrison is Professor of Infectious Diseases and Medicine, and Deputy Director of the Institute for Infection and Immunity, at St Georges University of London, and Honorary Consultant at St Georges Hospital, London. He trained in Infectious Diseases in London and Boston, USA. His initial research training was in Boston, where he worked on immune responses to Cryptococcus neoformans. He leads a clinical research programme on the prevention and treatment of cryptococcal meningitis, developed first in Thailand, and subsequently across sites in Sub-Saharan Africa. He is also involved in phase II and III clinical trials on the chemotherapy of tuberculosis. He has served on the cryptococcal guidelines panels of the IDSA, The Southern African HIV Clinicians Society, and WHO.
16:30-17:00
Vaccines and vaccinations in yeasts
Professor John Edwards, University of California, Los Angeles, USA
Abstract
Numerous studies of various strategies for vaccination against Candida spp by multiple groups distributed internationally have been performed. Additionally, there has been an extensive effort to develop cryptococcal active and passive vaccines. Antigens used for Candida include heat killed whole organisms, attenuated live organisms, Candida enolase, the Candida cell surface iC3b receptors, mannans, beta-glucan, heat shock protein hsp90, hyphally-regulated protein (Hyr1), proteins from the Sap family (secreted aspartic proteins), and recombinant proteins from the ALS (agglutinin like sequence) gene family. Additionally, several glycoconjugate strategies have been tested experimentally. Differing adjuvant strategies have been explored also. For Cryptococcus, in addition to a variety of antigens, various immunostimulatory strategies, to be used in combination with antigens, have been explored. In nearly all preclinical studies, significant and encouraging efficacy has been found.
Coincident with the ever increasing prevalence of Candida spp in hospitalised patients and the high prevalence rates of cryptococcal infection in patients with HIV, has been a substantive increasing societal/medical interest in the development of vaccines for both of these yeasts. The high costs of human trials have been a considerable road block for robust development of fungal vaccines in general. Several million dollars are needed for a single Phase 1 trial in humans. The Swiss company Pevion completed a Phase 1 clinical trial of vaccination with a recombinant Sap2 protein for patients with recurrent vulvovaginal candidiasis (RVVC). NovaDigm Therapeutics, with a future focus on disseminated candidiasis, has completed two Phase 1 trials, and is conducting a Phase 1b/2a trial in patients with RVVC. The vaccine NDV-3 in these studies contains the recombinant antigen Als3. The results of the first six months of this NovaDigm 1b/2a trial are currently under statistical analysis. In all three of these trials, NDV-3 has elicited robust antibody responses (IgG and IgA) as well as evidence of Th1 and Th17 T-cell activation. The safety profile of NDV-3 has been comparable to similar recombinant vaccines with local site reactions but there have been no serious adverse events due to the vaccine. NovaDigm intends to assess the Hyr1 and Sap2 antigens in a combined vaccine with Als3. To our knowledge, no clinical trials have been conducted with active vaccination strategies for Cryptococcus to date.
Of additional interest is the discovery of a very high level of 3D, structural homology between the rAls3p-N, the antigen used in the NovaDigm trials, and surface adhesins of Staphylococcus aureus. In preclinical murine studies, vaccination with the Candida antigen protects against challenge with Staphylococcus aureus in septicaemic and skin infections. Subjects vaccinated with rAls3p-N in the Phase 1 and 1b/2a trials clinical trials have produced antibodies that are opsonophagocytic for Staphylococcus.
The increasing need for prevention of Candida spp infections, intensive antigen and adjuvant searches, the possible of immuno-enhancement strategies, especially for Cryptococcus, coupled with the development of newer adjuvants, and the growing interest in both governmental and private funding sources, provide considerable optimism for vaccines being successfully developed for these yeasts.
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Professor John Edwards, University of California, Los Angeles, USA
Professor John Edwards, University of California, Los Angeles, USA
Dr Edwards is a Professor of Medicine Emeritus at the David Geffen School of Medicine at Harbor/UCLA Medical Center. He is also member of the Los Angeles Biomedical Research Institute at Harbor/UCLA. He has spent over 30 years conducting basic research funded from the National Institutes of Health on the pathogenesis of opportunistic fungal infections with an emphasis on Candida infections. He has also contributed to clinical research on fungal infections and is the former Chairman of the NIH, Mycosis Study Group, Candida subproject. He and his colleagues have developed a vaccine, based on a cell surface adhesin of Candida, designed to prevent and ameliorate haematogenous candidiasis in hospitalised patients. The vaccine antigen has 3D structural homology with cell surface proteins on Staphylococcus and has preventive capabilities in preclinical models for both skin and soft tissue staphylococcal infections as well has haematogenous staphylococcal infection in visceral organs.