Proteome and polysaccharidome of Aspergillus fumigatus in early stage of infection – AfuInf

Although they do not convey the attribute epidemics, fungal infections are an increasingly significant medical problem. Humans contract fungal diseases that cause severe damage or kill at least as many people as tuberculosis or malaria. Among them, Aspergillus fumigatus is the most important airborne fungal mould that is responsible for diseases in immunocompetent as well as immunocompromised hosts with unacceptably high mortality rates in the latter cohort.

The threat posed by A. fumigatus to hospital patients is attributable to a very poor understanding of the pathobiology of aspergillosis. Therefore, the major objective of this research programme will be to investigate the spore (conidium), which is the infectious morphotype. A special focus will be on the cell wall of the resting and germinating conidium since we have identified several molecules of the cell wall, which are essential either for fungal virulence by modulating the host immune system but also for resistance against external insults. Until today, however, there is no comprehensive biochemical and genetic analysis of conidia, which is urgently required to understand the early stages of A. fumigatus infection. To address this fundamental problem, we have defined three tasks:

In task 1, the landscape of the cell wall components of the dormant conidium and their structural organization will be deciphered by proteome and polysacchridome analyses as well as structural studies.

In task 2, the cell wall modifications and newly secreted proteins occurring during the early stages of germination will be identified.

In task 3, the effect of cell wall-associated components from resting and germinating conidia on macrophages including the analysis of the phagolysosomal proteome will be deciphered and virulence of the respective mutants will be evaluated in a mouse infection model.

The consortium is composed of the Aspergillus unit of the Institut Pasteur (head: J.-P. Latgé) and the Department of Microbiology and Molecular Biology, University of Jena and the Department of Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology, Jena (head: A. Brakhage). Since many years, these partners have been having an intense and fruitful collaboration on the study of A. fumigatus and have complementary expertise in, e.g., biochemistry, glycobiology, proteomics, bioinformatics, genetics and infection biology, all technologies required to work to together to tackle the analysis of the decisive early steps in the infection of A. fumigatus.

Our project addresses the important question which has not been answered yet: How can an airborne fungus become a human pathogen? Characterizing the infectious propagules in their dormant and early germinating stage is a key for the understanding of the establishment of the disease and the development of new antifungal prophylactic therapies. Results obtained during this project with A. fumigatus can be expected to be of great benefit for the whole scientific field of fungal pathogenicity.