Fungal metabolic adaptation in pulmonary aspergillosis (360G-Wellcome-323925_Z_24_Z)

Aspergillus fumigatus is the globally dominant human fungal pathogen, causing a spectrum of pulmonary disease ranging from acute angioinvasive disease to allergic bronchopulmonary aspergillosis. Using high-throughput phenotypic profiling we have discovered two distinct groups of strains based on growth rate on specific carbon and nitrogen sources. Exploiting high-throughput innate immune receptor reporter assays we observed that fast growing strains had novel C-type lectin specificities compared to slow growing strains. Furthermore, slow growing strains were mostly from chronic infections, suggesting in-host metabolic adaptation is linked to innate immune modulation. To further dissect the relationship between metabolism, infection and immunity we will: 1: Define the genetic basis for these metabolic phenotypes using clinical and environmental strains and the Wellcome Trust-funded Aspergillus fumigatus gene deletion collection. 2: Systematically characterise the impact of metabolic phenotype on cell wall composition using clinical and environmental strains and selected gene deletion strains. 3: Investigate the impact of metabolic and cell wall phenotypes on survival in clinically- relevant animal and ex-vivo human infection models. These studies will allow us to define the underpinning mechanisms that link genomics, metabolism and cell wall remodelling during fungal adaptation in the lung, and the impact on fungal survival during clinically-relevant lung immune states.