Histoplasma capsulatum (Hc) is a dimorphic fungus that is distributed globally. The lung is the portal of entry of the fungus. Cellular immunity is the critical host defense mechanism activated in response to infection and is the key factor in limiting the progression of infection. Antigen-specific T-cells and their cognate cytokines arm macrophages (MΦ) to restrict intracellular growth. The transcription factors that regulate the behavior of MΦ response to Hc are largely unknown. We have for the past 3 years collected data that the hypoxia-induciable factor (HIF)-1α is a key regulator of MΦ function in response to this fungal pathogen.  

Aims

1. To elucidate the underlying mechanism on how stabilization of HIF-1α promotes the antifungal activity of MΦ  

2. To investigate the role of autophagy/xenophagy and the generation of toxic oxygen or nitrogen intermediates in this process

3. To examine the impact of HIF-1α on the metabolic profile of Hc-infected human and murine MΦ

4. To determine the HIF-1 inducing properties of different cell wall components of Hc