MyD88-dependent signaling and the host response to the human fungal pathogen Histoplasma capsulatum

Histoplasma capsulatum, the causative agent of the disease histoplasmosis, is an intracellular dimorphic fungal pathogen. The organism exists in the environment in a sporulating filamentous form that is easily aerosolized and inhaled by a mammalian host. Inside host lungs, fungal cells convert into a pathogenic yeast form that is able to evade immune defenses by replicating within macrophages. How Histoplasma survives and replicates inside a host cell that has evolved to detect and kill invading pathogens is an area of active inquiry. In addition to studying fungal pathogenesis, complementing studies of the host response to this intracellular eukaryotic pathogen allows full understanding of how fungal infection progresses to serious disease, informing the development of treatment options that can both target the pathogen and boost inherent host responses to control fungal growth. This work describes approaches taken to understand both fungal pathogenesis and host response. First, a high-throughput unbiased screen to identify Histoplasma mutants that are unable to lyse macrophages was performed collaboratively, allowing the identification of 26 lysis defective mutants, including a mutant in the HCL1 gene. The HCL1 gene encodes an HMG-CoA lyase. Mutants in this gene are unable to grow inside macrophages, exist in an acidified phagosome and display a virulence defect in mice. Finally, research was undertaken to understand the role of MyD88, a central mediator of the innate immune response, in the response to Histoplasma infection. We show that MyD88 signaling is important for host survival, control of fungal growth, cytokine production and appropriate T cell responses, including cytokine production and activation. Using in vivo cell-specific MyD88 deficient mice, we determined that MyD88 signaling plays an important role in the production of cytokines by alveolar macrophages and dendritic cells, potentially influencing the interaction of these cell types with activated T cells