When molds go viral: Dissecting the pathogenesis of post-viral Aspergillus pneumonias to guide immunomodulatory therapy in immunocompromised hosts

PROJECT SUMMARY Research objectives: Influenza- and respiratory syncytial virus-associated pulmonary aspergillosis (IAPA/RSV- APA) are deadly secondary mold infections, especially in immunocompromised patients. Promising preliminary data suggest that restoration and enhancement of epithelial resilience and attenuation of post-viral immune pa- ralysis with locally delivered (inhaled) immunomodulators may provide an innovative therapeutic avenue to im- prove the often-detrimental outcomes of post-viral mold pneumonias. This approach will be studied using nu- anced sequential infection models in mice with underlying immunosuppressive conditions, i.e., remission-induc- tion chemotherapy for acute myeloid leukemia or high-dose glucocorticosteroids. Aim 1 will provide a temporally and spatially resolved characterization of host-associated, global post-viral, and virus-specific (RSV- or influ- enza-specific) impairment of pulmonary and systemic anti-Aspergillus immune defense. Aim 2 will characterize protective immunity against IAPA and RSV-APA after nebulized immunotherapy (TLR2/6/9 agonists or GM-CSF) given at different timepoints, with or without systemic antiviral or antifungal therapy. Detailed immunologic studies and dual-RNA sequencing will unveil key components of protective immune augmentation, fungal adaptation to an altered host environment after multimodal therapy, and host biomarkers associated with favorable therapeutic outcomes. Collectively, these studies will provide comprehensive preclinical data to facilitate future clinical trans- lation of nebulized immunomodulators to protect high-risk patients from deadly secondary mold pneumonias. Candidate and career development plan: Dr. Wurster’s postgraduate training in molecular oncology combined with his postdoctoral and junior faculty experience in experimental mycology and translational immunology pro- vides him with an ideal and unique background to study fungal pathogenesis, host defense, and immunomodu- latory therapy in the context of underlying malignancy, virus-induced immune dysfunction, and opportunistic mold infection. Supported by an outstanding team of mentors and advisors with internationally recognized expertise in fungal pathogenesis and preclinical infection models (Dr. Kontoyiannis), pulmonary immunobiology and im- munotherapy (Dr. Evans), viral immunology (Dr. Chemaly), spatial transcriptomics (Dr. Wang), and dual host/fun- gal transcriptomics (Dr. Bruno), this data science-focused K01 project will provide an ideal setting for thorough training in state-of-the-art transcriptomics techniques and advanced immuno-informatics approaches for multidi- mensional data integration. These training objectives, along with dedicated leadership training, will substantially enhance Dr. Wurster’s competitiveness as an emerging independent investigator and future thought leader in experimental and translational mycology. Moreover, the strategic alignment of this K01 project with Dr. Wurster’s career goal of establishing a host-targeted precision medicine program for fungal and polymicrobial infections in immunocompromised patients, and the institutional focus on personalized care programs, will provide an optimal framework for him to succeed as a future independent group leader at MD Anderson Cancer Center.