Whole Blood Proteome Dynamics Defines Predictive Diagnostic and Prognostic Signatures of Cryptococcal Infection

Across the globe, fungi are impacting the lives of millions of people through the development of infections ranging from superficial to systemic with limited treatment options. To effectively combat fungal disease, rapid and reliable diagnostic methods are required, including current methodologies using antigen detection, culturing, microscopy, and molecular tools. However, the flexibility of these platforms to diagnose infection using non-invasive methods and predict the outcome of disease are limited. In this study, we apply state-of-the-art mass spectrometry-based proteomics to perform dual perspective (i.e., host and pathogen) profiling of cryptococcal infection. Whole blood collected over a temporal scale following murine model challenged with the human fungal pathogen, Cryptococcus neoformans, detected >3000 host proteins and 160 fungal proteins. From the host perspective, temporal regulation of known immune-associated proteins, including eosinophil peroxidase and lipocalin-2, along with suppression of lipoproteins, demonstrated infection- and time-dependent host remodeling. Conversely, from the pathogen perspective, known and putative virulence-associated proteins were detected, including proteins associated with fungal extracellular vesicles and host immune modulation. We also observed and validated a new mechanism of immune system response to C. neoformans through modulation of haptoglobin. Furthermore, we assessed the predictive power of dual perspective proteome profiling toward prognostics of cryptococcal infection and report a previously undisclosed integration among virulence factor production, immune system modulation, and individual model survival. Together, our findings pose novel biomarkers of cryptococcal infection from whole blood and highlight the potential of personal proteome profiles to determine the prognosis of cryptococcal infection, a new parameter in fungal disease management.