Anna Mackey, 2025 MGM Distinguished Fellows Travel Award Recipient

Anna Mackey
Gusa Lab
Cellular and Molecular Fungal Biology Gordon Research Conference, New Hampshire
June 21-26, 2026

Abstract

With mortality rates reaching 60%, invasive fungal infections pose a major threat to immunocompromised individuals, including patients with cancer, autoimmune disorders, organ transplants, and HIV/AIDS, because these infections tend to rapidly acquire drug resistance and recur. The environmental yeast Cryptococcus neoformans, classified as one of four critically important human fungal pathogens by the World Health Organization, exemplifies this threat due to its ability to develop antifungal resistance and persist in the host. Recurrent cryptococcosis can last for years, severely impacting quality of life and reducing life expectancy, contributing to an estimated 147,000 deaths caused by C. neoformans annually. During the environment-to-host transition, C. neoformans encounters multiple stressors, including the substantial heat stress imposed by human body temperature (37°C). In the less pathogenic sister species, Cryptococcus deneoformans, heat stress has been shown to increase mutation rates and drive antifungal resistance through transposable element (TE) mobilization. Importantly, TEs were shown to be mutagenic during murine infection and can mediate resistance to 5-fluorocytosine (5-FC), a first-line antifungal treatment. New findings from our laboratory demonstrate that heat stress dramatically increases TE mobilization in C. neoformans, which is responsible for approximately 95% of cryptococcal infections, leading to elevated antifungal resistance rates. The underlying mechanisms of heat stress-induced TE mobilization in fungi remain unknown. We are pursuing two lines of investigation: (1) whether heat stress disrupts TE suppression systems, and (2) whether TEs exploit the host heat shock response to drive transcriptional activation and mobilization. We are addressing these questions using a combination of next- generation sequencing and molecular analyses. Elucidating the mechanisms underlying heat stress-induced TE mobilization will provide critical insights into stress-driven genome evolution and adaptation in C. neoformans.