Host-Microbe Interactions : Fungi

Peer reviewedPostprin

The Cryptococcus gattii species complex:Unique pathogenic yeasts with understudied virulence mechanisms

Members of Cryptococcus gattii/neoformans species complex are the etiological agents of the potentially fatal human fungal infection cryptococcosis. C. gattii and its sister species cause disease in both immunocompetent and immunocompromised hosts, while the closely related species C. neoformans and C. deneoformans predominantly infect immunocompromised hosts. To date, most studies have focused on similarities in pathogenesis between these two groups, but over recent years, important differences have become apparent. In this review paper, we highlight some of the major phenotypic differences between the C. gattii and neoformans species complexes and justify the need to study the virulence and pathogenicity of the C. gattii species complex as a distinct cryptococcal group.</p

In fungal intracellular pathogenesis, form determines fate

For pathogenic microbes to survive ingestion by macrophages, they must subvert powerful microbicidal mechanisms within the phagolysosome. After ingestion, Candida albicans undergoes a morphological transition producing hyphae, while the surrounding phagosome exhibits a loss of phagosomal acidity.For pathogenic microbes to survive ingestion by macrophages, they must subvert powerful microbicidal mechanisms within the phagolysosome. After ingestion, Candida albicans undergoes a morphological transition producing hyphae, while the surrounding phagosome exhibits a loss of phagosomal acidity. However, how these two events are related has remained enigmatic. Now Westman et al. (mBio 9:e01226-18, 2018, https://doi.org/10.1128/mBio.01226-18) report that phagosomal neutralization results from disruption of phagosomal membrane integrity by the enlarging hyphae, directly implicating the morphological transition in physical damage that promotes intracellular survival. The C. albicans intracellular strategy shows parallels with another fungal pathogen, Cryptococcus neoformans, where a morphological changed involving capsular enlargement intracellularly is associated with loss of membrane integrity and death of the host cell. These similarities among distantly related pathogenic fungi suggest that morphological transitions that are common in fungi directly affect the outcome of the fungal cell-macrophage interaction. For this class of organisms, form determines fate in the intracellular environment

Systematic analysis of funding awarded for mycology research to institutions in the UK, 1997–2010

Objectives: Fungal infections cause significant global morbidity and mortality. We have previously described the UK investments in global infectious disease research, and here our objective is to describe the investments awarded to UK institutions for mycology research and outline potential funding gaps in the UK portfolio. Design: Systematic analysis. Setting: UK institutions carrying out infectious disease research. Primary and secondary outcome measures Primary outcome is the amount of funding and number of studies related to mycology research. Secondary outcomes are describing the investments made to specific fungal pathogens and diseases, and also the type of science along the R&D value chain. Methods: We systematically searched databases and websites for information on research studies from public and philanthropic funding institutions awarded between 1997 and 2010, and highlighted the mycology-related projects. Results: Of 6165 funded studies, we identified 171 studies related to mycology (total investment £48.4 million, 1.9% of all infection research, with mean annual funding £3.5 million). Studies related to global health represented 5.1% of this funding (£2.4 million, compared with 35.6% of all infectious diseases). Leading funders were the Biotechnology and Biological Sciences Research Council (£14.8 million, 30.5%) and Wellcome Trust (£12.0 million, 24.7%). Preclinical studies received £42.2 million (87.3%), with clinical trials, intervention studies and implementation research in total receiving £6.2 million (12.7%). By institution, University of Aberdeen received most funding (£16.9 million, 35%). Studies investigating antifungal resistance received £1.5 million (3.2%). Conclusions: There is little translation of preclinical research into clinical trials or implementation research in spite of substantial disease burden globally, and there are few UK institutions that carry out significant quantities of mycology research of any type. In the context of global health and the burden of disease in low-income countries, more investment is required for mycology research

Regulator of G-Protein Signalling-14 (RGS14) Regulates the Activation of αMβ2 Integrin during Phagocytosis

Integrin-mediated phagocytosis, an important physiological activity undertaken by professional phagocytes, requires bidirectional signalling to/from &alpha;M&beta;2 integrin and involves Rap1 and Rho GTPases. The action of Rap1 and the cytoskeletal protein talin in activating &alpha;M&beta;2 integrins, in a RIAM-independent manner, has been previously shown to be critical during phagocytosis in mammalian phagocytes. However, the events downstream of Rap1 are not clearly understood. Our data demonstrate that one potential Rap1 effector, Regulator of G-Protein Signalling-14 (RGS14), is involved in activating &alpha;M&beta;2. Exogenous expression of RGS14 in COS-7 cells expressing &alpha;M&beta;2 results in increased binding of C3bi-opsonised sheep red blood cells. Consistent with this, knock-down of RGS14 in J774.A1 macrophages results in decreased association with C3bi-opsonised sheep red blood cells. Regulation of &alpha;M&beta;2 function occurs through the R333 residue of the RGS14 Ras/Rap binding domain (RBD) and the F754 residue of &beta;2, residues previously shown to be involved in binding of H-Ras and talin1 head binding prior to &alpha;M&beta;2 activation, respectively. Surprisingly, overexpression of talin2 or RAPL had no effect on &alpha;M&beta;2 regulation. Our results establish for the first time a role for RGS14 in the mechanism of Rap1/talin1 activation of &alpha;M&beta;2 during phagocytosis

The Milky Way's external disc constrained by 2MASS star counts

Context. Thanks to recent large scale surveys in the near infrared such as 2MASS, the galactic plane that most suffers from extinction is revealed and its overall structure can be studied. Aims. This work aims at constraining the structure of the Milky Way external disc as seen in 2MASS data, and in particular the warp. Methods. We use the Two Micron All Sky Survey (hereafter 2MASS) along with the Stellar Population Synthesis Model of the Galaxy, developed in Besancon, to constrain the external disc parameters such as its scale length, its cutoff radius, and the slope of the warp. In order to properly interpret the observations, the simulated stars are reddened using a three dimensional extinction map. The shape of the stellar warp is then compared with previous results and with similar structures in gas and dust. Results. We find new constraints on the stellar disc, which is shown to be asymmetrical, similar to observations of HI. The positive longitude side is found to be easily modelled with a S shape warp but with a slope significantly smaller than the slope seen in the HI warp. At negative longitudes, the disc presents peculiarities which are not well reproduced by any simple model. Finally, comparing with the warp seen in the dust, it seems to follow a slope intermediate between the gas and the stars.Comment: 9 pages. Accepted for publication in Astronomy and Astrophysic

Loss of the scavenger receptor MARCO results in uncontrolled vomocytosis of fungi from macrophages

Vomocytosis, also known as nonlytic exocytosis, is a process whereby fully phagocytosed microbes are expelled from phagocytes without discernible damage to either the phagocyte or microbe. Although this phenomenon was first described in the opportunistic fungal pathogen Cryptococcus neoformans in 2006, to date, mechanistic studies have been hampered by an inability to reliably stimulate or inhibit vomocytosis. Here we present the fortuitous discovery that macrophages lacking the scavenger receptor MAcrophage Receptor with COllagenous domain (MARCO), exhibit near‐total vomocytosis of internalised cryptococci within a few hours of infection. Marco−/− macrophages also showed elevated vomocytosis of a yeast‐locked C. albicans strain, suggesting this to be a broadly relevant observation. We go on to show that MARCO's role in modulating vomocytosis is independent of its role as a phagocytic receptor, suggesting that this protein may play an important and hitherto unrecognised role in modulating macrophage behaviour

Cellular Responses in Sea Fan Corals: Granular Amoebocytes React to Pathogen and Climate Stressors

BACKGROUND: Climate warming is causing environmental change making both marine and terrestrial organisms, and even humans, more susceptible to emerging diseases. Coral reefs are among the most impacted ecosystems by climate stress, and immunity of corals, the most ancient of metazoans, is poorly known. Although coral mortality due to infectious diseases and temperature-related stress is on the rise, the immune effector mechanisms that contribute to the resistance of corals to such events remain elusive. In the Caribbean sea fan corals (Anthozoa, Alcyonacea: Gorgoniidae), the cell-based immune defenses are granular acidophilic amoebocytes, which are known to be involved in wound repair and histocompatibility. METHODOLOGY/PRINCIPAL FINDINGS: We demonstrate for the first time in corals that these cells are involved in the organismal response to pathogenic and temperature stress. In sea fans with both naturally occurring infections and experimental inoculations with the fungal pathogen Aspergillus sydowii, an inflammatory response, characterized by a massive increase of amoebocytes, was evident near infections. Melanosomes were detected in amoebocytes adjacent to protective melanin bands in infected sea fans; neither was present in uninfected fans. In naturally infected sea fans a concurrent increase in prophenoloxidase activity was detected in infected tissues with dense amoebocytes. Sea fans sampled in the field during the 2005 Caribbean Bleaching Event (a once-in-hundred-year climate event) responded to heat stress with a systemic increase in amoebocytes and amoebocyte densities were also increased by elevated temperature stress in lab experiments. CONCLUSIONS/SIGNIFICANCE: The observed amoebocyte responses indicate that sea fan corals use cellular defenses to combat fungal infection and temperature stress. The ability to mount an inflammatory response may be a contributing factor that allowed the survival of even infected sea fan corals during a stressful climate event

Microevolutionary traits and comparative population genomics of the emerging pathogenic fungus Cryptococcus gattii

Emerging fungal pathogens cause an expanding burden of disease across the animal kingdom, including a rise in morbidity and mortality in humans. Yet, we currently have only a limited repertoire of available therapeutic interventions. A greater understanding of the mechanisms of fungal virulence and of the emergence of hypervirulence within species is therefore needed for new treatments and mitigation efforts. For example, over the past decade, an unusual lineage of Cryptococcus gattii, which was first detected on Vancouver Island, has spread to the Canadian mainland and the Pacific Northwest infecting otherwise healthy individuals. The molecular changes that led to the development of this hypervirulent cryptococcal lineage remain unclear. To explore this, we traced the history of similar microevolutionary events that can lead to changes in host range and pathogenicity. Here, we detail fine-resolution mapping of genetic differences between two highly related Cryptococcus gattii VGIIc isolates that differ in their virulence traits (phagocytosis, vomocytosis, macrophage death, mitochondrial tubularization and intracellular proliferation). We identified a small number of single site variants within coding regions that potentially contribute to variations in virulence. We then extended our methods across multiple lineages of C. gattii to study how selection is acting on key virulence genes within different lineages. This article is part of the themed issue ‘Tackling emerging fungal threats to animal health, food security and ecosystem resilience’