Yeasts

Event Date: 
Wednesday, September 24, 2014 - 18:15 - 18:30
Institution: 
University of Sydney
Title: 

Cathelicidins in the Tasmanian devil (Sarcophilus harrisii)

Abstract: 

Antimicrobial resistance is increasing, posing a threat to human and animal health. A lack of new antibiotics means alternatives such as antimicrobial peptides are urgently required. Antimicrobial peptides are a primitive component of the innate immune system. Cathelicidins are a predominant family within mammals, contributing to host immunity through antimicrobial and immunomodulatory functions. They have been studied extensively in eutherian mammals but marsupials are relatively unexplored. Marsupials give birth to altricial young which are immunologically naïve. During development the young are protected from infection by mechanisms such as cathelicidins within the pouch. This unique reproductive physiology has encouraged lineage specific expansion of the cathelicidin gene family within marsupials, resulting in numerous diverse peptides.
 
The Tasmanian devil (Sarcophilus harrisii) is the largest remaining carnivorous marsupial and is currently under threat from a contagious cancer, devil facial tumour disease (DFTD). Human and bovine cathelicidins exhibit anti-tumour activity against a number of cancers. Furthermore, studies in the tammar wallaby have revealed the potency of marsupial cathelicidins against multi-drug resistant bacteria. As such, release of the Tasmanian devil genome in 2012 provides new avenues in the search for cathelicidins with the therapeutic potential to treat DFTD and resistant pathogens.
 
We identified 7 cathelicidins in the Tasmanian devil genome which were highly variable and distantly related to eutherian cathelicidins. Six Tasmanian devil cathelicidins have been synthesised and will be tested against a range of bacteria and fungi. Preliminary antifungal testing of two cathelicidins revealed that one peptide was more effective at killing Candida krusei, Candida parapsilosisCryptococcus gattii and Cryptococcus neoformans than the antifungal drug fluconazole. Cytotoxic and haemolytic activity of all six cathelicidins has also been determined. Four cathelicidins did not kill human lung epithelial cells or red blood cells, and only two showed moderate cytotoxic and haemolytic activity. This study highlights the potential for marsupials such as the Tasmanian devil to provide new drugs to treat human and animal disease.

Event Date: 
Wednesday, May 28, 2014 - 19:00 - 20:00
Institution: 
USyd
Title: 

Population genetics and evolution of Cryptococcus gattii : an environmental pathogen

Abstract: 

The yeast species Cryptococcus neoformans and C. gattii cause cryptococosis in humans and a range of animal. Although research on Cryptococcus is generally structured in terms of its importance as a fungal pathogen, human infection is accidental and the fungus mostly lives as an environmental saprotroph. C. neoformans and C. gattii each comprise a number of distinct molecular genotypes that vary in their ecology, their geographic distribution, and various virulence-associated phenotypes. In particular, C. gattii molecular type VGII is responsible for outbreaks that have expanded the fungus beyond its normal geographic range. Our interests lie in understanding the ecology and evolution of C. gattii in the environment, and how these relate to its ability to cause disease. We have found the level of sexual recombination varies by molecular type, and that while in general C. gattii population structure is sexual, this is punctuated by periodic clonal lineages that may be associated with disease outbreaks. Here we refine our analysis using MLST data, haplotype networks and coalesence theory. We find the level of diversity within genotypes to be highly constrained and comparable to some recently evolved plant pathogens, and evidence for purifying selection at the master regulator of mating type. Comparison with other fungi that are causing major outbreaks suggests C. gattii outbreaks may be due to a “perfect storm”, where range expansion and elevated transmission combined with high virulence bring the fungus to new areas with deadly consequences. 

Event Date: 
Wednesday, February 26, 2014 - 15:45 - 16:15
Institution: 
University of Perugia, Italy
Title: 

The intricate cross-talk of the microbiome in Resistance and Tolerance to pathogens

Abstract: 

The diverse microbial population characterizing the human host represents the result of different complex scenarios impacting the human microbiome assembly. The variety of the microbial species involved plays an important role on the human health by affecting the tissue differentiation, the modulation of the immune system as well as the general response against infectious pathogens, which has been recently revised and divided into two different strategies named Resistance and Tolerance. Resistance being the strategy where the host protects himself by reducing the pathogen load whereby the Tolerance being the opposite strategy, which consists in tolerating the pathogen to avoid tissue damage due to the occurrence of subsequent inflammatory pathologies. The host microbiome seems to play a crucial role in determining which strategy the host will exploit to avoid infection. We recently found that highly adaptive lactobacilli, switching from sugar to Tryptophan (Trp) as an energy source  are expanded and produce an aryl hydrocarbon receptor (AhR) ligand—indole-3-aldehyde—that contributes to AhR-dependent IL-22 transcription, which then trigger the release of antimicrobial peptides by the gut epithelium. Importantly, innate lymphocytes IL-22 producers were already described as a typical innate Resistance strategy to protect the host from intragastrical Candida albicans infections in mice. Thus, the resulting IL-22-dependent balanced mucosal response allows for survival of mixed microbial communities yet provides colonization resistance to the fungus Candida albicans. Therefore, the microbiota-AhR axis might represent an important strategy pursued by co-evolutive commensalism for fine-tuning host mucosal reactivity contingent on Trp catabolism.

Event Date: 
Wednesday, November 30, 2011 - 18:15 - 18:30
Institution: 
University of Sydney
Title: 

The fungal secretome and virulence: analysis of the proteins secreted by Cryptococcus gattii strains with different virulence profiles.

Abstract: 
Cryptococcus gattii is a ubiquitous environmental yeast-like fungus capable of causing disease in a wide range of animal hosts. In humans, disease progression begins after inhalation of the infectious propagule leading to infection of the lung. The infective yeast cells can then disseminate to the central nervous system, resulting in meningoencephalitis, which can be fatal if left untreated.

Closely related strains of C. gattii exhibit significantly different degrees of virulence in the mammalian host. Fungi utilize absorbtive nutrition and produce a range of secreted degrative enzymes, and as these may invoke a host response, the fungal secretome is likely to be very important in modulating the host-pathogen interaction. In this study, we compare the secretomes of two C. gattii strains, one categorized as hypervirulent (R265) and the other exhibiting low-level virulence (R272). C. gattii was grown under conditions designed to be as similar as possible to those encountered in vivo. Secreted proteins were captured from the culture supernatant by re-circulating across ProteominerTM beads using a closed peristaltic pump system. Concentrated protein was analysed via 1D nanoLC-MS/MS. A total of 27 proteins were identified with only four protein identifications being shared by both strains. The secretome of R265 primarily included uncharacterized proteins containing catalytic cores with roles in carbohydrate degradation as well as the antioxidant superoxide dismutase and a GTPase. R272 secreted a more diverse set of proteins including enolase and transaldolase, enzymes canonically involved in glycolysis and the pentose phosphate pathway respectively, but both also described as fungal allergens that bind IgE.

This work indicates that very different cohorts of proteins are secreted by closely related strains of C. gattii exhibiting different levels of virulence. By enhancing our understanding of the fungal secretome and unraveling these differences it may suggest novel therapeutic strategies or help devise diagnostic markers predicting for disease progression.
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