(6ai) Improved Treatment of Fungal Infections through Targeted Drug Delivery: How Can Biomembranes Help?

Fungal infections are a significant cause of morbidity and mortality especially in immune-compromised individuals. Fungal diseases are hard to eradicate as fungal cells develop resistance to most available antifungal drugs and are hard to target inside mammalian cells. Several life threatening fungal infections such as cryptococcosis and histoplasmosis are contracted by inhalation of spores, which then proliferate inside the macrophages of the alveolar region and disseminate throughout the body. The macrophage-pathogen interaction is the first step in these diseases and provides a suitable target for early treatment of the disease. Recent evidence suggests that microdomains composed of saturated phospholipids and sterols (i.e. lipid rafts) play an important role in macrophage-pathogen interaction. Abolishing lipid rafts in fungal cells is shown to drastically reduce their virulence. Also, many pathogens use lipid rafts as the site of entry to the host cell, suggesting that rafts can be used for targeted treatment of fungal diseases. However, understanding the role of lipid rafts in modulating infections and utilizing them for targeted therapy of fungal infections is a complicated research problem requiring knowledge in various fields such as engineering, biophysics and microbiology. 

My graduate and post-doctoral experiences in chemical engineering and microbiology have uniquely prepared me to investigate this challenging research problem. In my graduate work, I have studied the interactions between phospholipid microdomains and polymeric nanoparticles. I have examined the effects of particles on microdomain size and surface properties. I have also studied the interactions between aerosolized particles and lung surfactant interfaces to gain knowledge on the potential adverse effects of inhaled particles used for pulmonary delivery. In my post-doctoral research, I have studied the role of plasma membrane biophysics in the virulence properties of Cryptococcus neoformans (the causative agent of the disease cryptococcosis). Using a number of fluorescence spectroscopy methods, I have shown that the structure of lipids in the plasma membrane of C. neoformans plays an important role in its ability to form a rigid membrane and cause life threatening infections. I have also examined the relationship between lipid rafts in mammalian cells and their infectivity by C. neoformans.

My future research interests combine my expertise in characterizing plasma membrane physical properties and the interactions between lipid rafts and nanoparticles. Through modulating the physical properties of plasma membrane, I aim to design strategies to increase the uptake of drugs or drug containing nanoparticles in mammalian cells. Also, I aim to use particle engineering to target fungal cells inside macrophages and treat the disease at the site of infection. I plan to use the knowledge provided by these research directions to develop new and more effective inhalable drugs against fungal infections for pulmonary drug delivery.