Fungal Metabolic Adaptation and Inflammatory Lung Disease

Project Leader

Robert A Cramer, Ph.D.
Assistant Professor
Department of Microbiology & Immunology
Geisel School of Medicine at Dartmouth

The long-term goal of our COBRE pilot project research is to define how Aspergillus fumigatus-Pseudomonas aeruginosa interactions in the lung impact disease outcome as a step towards determining which treatment regimes would be most beneficial for patients experiencing these super-infections. Our objectives in this proposal include determining how P. aeruginosa-produced phenazines alter immunopathogenesis and whether these changes occur through effects on fungal metabolism that allow fungal host colonization. Our central hypothesis, based on strong preliminary data, is that phenazines induce increased exposure of fungal cell wall pathogen associated molecular patterns (PAMPs), thereby increasing inflammation and pulmonary damage that contributes to fungal colonization and poor disease outcomes. These data are expected to help clinicians decide in what context antifungal drug therapy is warranted in these patients. Through collaborative studies performed by the Cramer and Hogan Laboratories, we aim: (1) To test the hypothesis that Pseudomonas aeruginosa phenazines induce pro-inflammatory fungal PAMP exposure on the cell wall and generate an inflammatory environment in the lung that promotes fungal growth. Expected outcomes from the proposed research will provide significant insight into fungi's role in chronic lung disease, and are expected to provide a rationale for treating fungi in chronic lung disease. Two exciting anticipated future directions include addressing the effects of phenazine-mediated alterations in fungal metabolism on antifungal drug efficacy and phenazine affects on immune effector cell antifungal activity. Together, we believe our collaboration will begin to close the gap in knowledge regarding fungi's role in chronic lung disease poor outcomes.

Cramer Laboratory Students/Trainees

Dr. Dawoon Chung, Post-doctoral Fellow - Role of fungal Sterol Regulatory Element Binding Proteins in virulence and hypoxia adaptation

Dr. Sourabh Dhingra, Post-doctoral Fellow - Role of Hyperbaric Oxygen in fungal growth inhibition

Kelly Shepardson, PhD. Candidate - Role of Hypoxia Inducible Factor 1 in the innate immune response to Aspergillus fumigatus

Arsa Thammahong, PhD. Student - Role of trehalose biosynthesis in fungal metabolism and virulence

Sarah Beattie, PhD Student - Role of fungal kinases in fungal hypoxia adaptation and virulence