The Section has achieved significant advances in the areas of augmentation of host defense, molecular detection and pharmacology of these life-threatening infections. Augmentation of Host Defenses. Immunopharmaocological interactions between innate host defenses and antimicrobial agents are a key component of developing new strategies for augmenting host response against emerging or resistant pathogens. We have extensively characterized the immunopharmacological interactions between phagocytic effector cells (pulmonary alveolar macrophages, monocytes, and neutrophils) of the innate host defense and antifungal agents (polyenes, echinocandins, and triazoles) with and without immunomodulators (IFN-g, GCSF, GMCSF) against several of the key pathogens infecting oncology patients: Aspergillus fumigatus, Fusarium solani, Scedosporium spp., and Zygomycetes. We have further extended our work in Th1/Th2 dysimmunoregulation of invasive candidiasis to the filamentous fungi (Aspergillus spp., Fusarium spp., Scedosporium spp., and Zygomycetes) with particular focus on IL-15, IL-4, and TGF-beta. Reversal of the Th2 immunophenotypic expression augments host response against these organisms. We have completed the first known kinetic studies of the functional genomic response of innate host defenses of human monocytes to Candida albicans, Aspergillus fumigatus, Rhizopus oryzae, and Fusarium solani. These studies will provide fundamental guidance to investigators worldwide in understanding the coordinated transcriptional responses of their selected genes of interest for further exploration. In order to further understand the host factors contributing to infections in pediatric and adult oncology and HSCT patients, we have completed a series of complementary targeted population-based studies in collaboration with the Centers for Disease Control, Roswell Park Cancer Center, and Children's Hospital al of Philadelphia. Molecular Detection. Following an extensive series of correlative laboratory animal studies with iterative platforms for detection of galactomannan an (GM) antigenemia, as well as subsequent clinical evaluation, as EIA was recently approved in the US for detection of invasive aspergillosis. The laboratory animal findings correlated with and were predictive of the results of expression of GM antigenemia in oncology and HSCT patients with invasive aspergillosis. As little is known about the pathogenesis of invasive pulmonary aspergillosis, and its relationship between the kinetics of diagnostic markers and the outcome of antifungal therapy, we developed an in vitro model of the human alveolus, consisting of a bilayer of human alveolar epithelial and endothelial cells. An A. fumigatus strain expressing green fluorescent protein was used to study the invasion of the cell bilayer was studied using confocal and electron microscopy. The kinetics of culture, PCR and galactomannan were determined by a series of differential equations. Galactomannan was used to measure the antifungal effect of macrophages and amphotericin B. A mathematical model was developed and results bridged to humans. Galactomannan levels were found to be inextricably tied to Aspergillus invasion, and were a robust measure of the antifungal effect of macrophages and amphotericin B. Neither amphotericin nor macrophages alone was able to suppress growth of A. fumigatus; rather, the combination was required. This new model provides a strategy by which relationships between pathogenesis, immunological effectors and antifungal drug therapy for invasive pulmonary aspergillosis may be further understood. Finally, in order to improve the design and implementation of qPCR for the detection of deeply invasive candidiasis, we sought to develop a more comprehensive understanding of the kinetics of DNA from C. albicans in vitro and in vivo.
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