Organ atlas proteome mapping of cryptococcosis defines novel putative biomarkers and promising druggable targets for personalized health management

The ability to profile changes in both host and pathogen proteomes during infection provides a unique opportunity to identify novel mechanisms of interplay driving disease. Such information supports an improved understanding of a diseased state and promotes novel strategies for disease detection and treatment. Here, we profiled the interplay between the human fungal pathogen, Cryptococcus neoformans, and the mammalian host using high-resolution mass spectrometry-based proteomics to demonstrate the dynamic nature of infection and to define novel diagnostic biomarkers of disease. We established an in vivo murine model of cryptococcosis and profiled 13 clinically relevant organs, tissues, and fluids across a temporal continuum of disease. Tandem mass tags combined with high pH fractionation improved protein quantification and increased proteome coverage across 780 samples with the proteomic data curated and publicly available through our development of the "CProteo Atlas". We demonstrate the value of this resource by defining novel putative dual species biomarker signatures for detecting and monitoring progression of infection, as well as provide organ and temporal-specific drivers of disease. We also leverage our findings to reveal a novel putative druggable target with a key role in blood brain barrier crossing through in vitro and in vivo assays. Overall, we demonstrate dynamic proteome remodelling of cryptococcosis in a temporal and spatial-dependent manner to uncover new putative biomarkers and druggable targets of infection for informed detection, monitoring, and treatment of disease.