Trained immunity: a memory for innate host defence
Professor Mihai Netea, Radboud University Nijmegen Medical Centre, The Netherlands
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.
Tackling the threat of rice blast disease caused by the fungus Magnaporthe oryzae
Professor Nick Talbot FRS, University of Exeter, UK
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.
Modus operandi of an accidental fungal pathogen
Dr Elaine Bignell, University of Manchester, UK
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.
Mitigating amphibian chytridiomycosis in the wild
Dr Trent Garner, Institute of Zoology, ZSL, UK
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.
Cryptococcal meningitis: new prevention and treatment strategies to reduce the global mortality burden
Professor Thomas Harrison, St George's University of London, UK
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.
Vaccines and vaccinations in yeasts
Professor John Edwards, University of California, Los Angeles, USA
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.