Opportunistic fungal pathogens can cause infection in immunocompromised patients with high mortality rate. These fungi produce a tremendous number of secondary metabolites with myriad biological activities, which allow them to adapt and thrive in diverse ecological niches. Recent advances in genome sequencing have revealed that opportunistic fungal pathogens harbor a large number of secondary metabolite biosynthetic gene clusters. However, our knowledge of their biological roles is limited, especially for less-studied species.
My research is focusing on investigating the roles of secondary metabolites in host-pathogen interactions in Scedosporium aurantiacum, which is the second most isolated fungi from Cystic fibrosis patients. An in vitro lung epithelial infection model with using an air-liquid interface (ALI) culture was developed. To interrogate the S. aurantiacum response to a mucosal surface, transcriptomics and metabolomics analysis were performed on samples collected from ALI cultures at different time points. Transcriptomic analysis showed that seven gene clusters are upregulated during the host-pathogen interaction. Simultaneously, we have isolated cytotoxic epipolythiodiketopiperazine (ETP) compounds from cultures of S. aurantiacum in different media. These compounds can be detected in the metabolomics samples from ALI cultures and allow us to correlate to one of the upregulated biosynthetic gene clusters. Currently, heterologous expression and genetic knockout are being carried out to link the upregulated gene clusters to metabolites. The virulence of the knockout mutants will also be compared against WT in the in vitro infection model to shed light into the role of secondary metabolites in the disease development.
Studying the human/animal fungal pathogens secondary metabolites could lead us to discover how these compounds facilitate infection, help develop new metabolite-based diagnostics, and potentially identify therapeutic purposes.