Dynamics of Fungal Stress Responses in the Host Environment

SUMMARY Fungi can adapt and grow in a wide range of quickly changing environments, especially under harsh conditions inside a host. However, the fundamental mechanisms underlying fungal fitness and survival inside a host remain poorly understood. Stress responses during host colonization are relevant to human health, since pathogenic fungi with activated stress-responses are better colonizers and less susceptible to antimicrobial treatments. This results in more than 1 million deaths associated with fungal diseases each year globally. Along with antifungal compounds, these species have also evolved and adapted to elevated temperature (37oC), low O2 level, elevated CO2 level, and other stresses derived from the host immune system. This phenomenon raises several fundamental questions. How do fungi adapt and grow within a host’s environment during colonization? What are effects of the host immune system on fungal fitness, and how do fungi respond against these stimuli? Finally, how do shifts in growth environment, and negative effects of the immune system and antifungal compounds, have an impact on fungal plasma membrane biology? The proposed research program tackles these questions by taking advantage of the fungus Nakaseomyces glabratus as a tractable model organism. With the uses of fungal genetics, molecular biology techniques, next-generation sequencing, proteomics, lipidomics, and an in vivo mouse model, these studies will yield a new and more mechanistic understanding of how fungal cells sense and adapt to environmental stress during host colonization. The results will have broad implications for understanding the basic principle of stress response across many biological systems. They will also bring forth foundational knowledge that will be useful for human health improvement, in terms of future antifungal development and diagnostic strategies targeting environmental stress sensing and response.