Cryptococcus deuterogattii Lung Infection Leads to a Prothrombotic State Revealed by Proteomics and Functional Analysis

Abstract Cryptococcosis caused by Cryptococcus deuterogattii is a life-threatening fungal infection increasingly reported in immunocompetent individuals. Although clinical evidence suggests that invasive fungal diseases could impact coagulation, the molecular mechanisms linking cryptococcal infection to hemostatic dysregulation remain unexplored. In this study, we employed an integrative approach combining in vivo rat lung infection model, proteomics, and in vitro assays to investigate alterations in coagulation and hemostasis induced by C. deuterogattii R265. Morphological and histological evaluations revealed progressive lung damage and cryptococcoma formation. Functional assays showed early thrombocytopenia, increased thrombin activity, reduced prothrombin time, and enhanced platelet aggregation, indicating a procoagulant state in the infection. Proteomic analysis identified the upregulation of platelet activation pathways and key prothrombotic proteins at 3 days post-inoculation (dpi), along with downregulation of anticoagulant regulators such as thrombomodulin and antithrombin III. At 14 dpi, a widespread protein downregulation suggests systemic collapse of host functions. Data are available via ProteomeXchange with identifier PXD077765. Coculture of A7R5 cells with C. deuterogattii confirmed increased tissue factor expression, reinforcing the role of the fungus in triggering thrombo-inflammatory responses and validating proteomics data. Our results provide the first molecular evidence linking cryptococcal infection to a dysregulated hemostatic profile, shedding light on host–pathogen interaction and suggesting that targeting coagulation pathways may offer novel therapeutic avenues in cryptococcosis management.