Systematic infectome-phenome profiling reveals cryptococcal infection-associated proteins driving immune system...

Invasive fungal infections are an escalating global health challenge driven by host immune status and antifungal resistance. Here, we present an integrated infectome-phenome platform that combines high-resolution proteomics with systematic phenotypic profiling to map host-pathogen interactions in Cryptococcus neoformans. This approach captures coordinated host immune suppression alongside complementary fungal virulence programs and enables the prioritization of infection-associated proteins. Phenome fingerprinting of targeted mutants resolves functional relevance and therapeutic potential, supported by in vitro assays and a murine model of cryptococcosis. We identify a conserved, previously uncharacterized protein, CipC, that alters extracellular vesicle composition and enhances antigenicity. Immunization with CipC-derived vesicles elicits a robust and diversified host immune response, highlighting a role for fungal vesicles in immune priming. Together, this work establishes a scalable framework to define functional drivers of fungal infection and accelerate discovery of therapeutic and immunological targets across pathogenic fungi.