Award Title: Investigating the pleiotropic effects of aneuploidy in antifungal resistance.
Funder: The Academy of Medical Sciences

Abstract: Antifungal resistance is a rapidly emerging global problem, and the fact that fungal pathogens can leverage genome instability (e.g., aneuploidy) to evolve resistance is a major impediment to developing effective antifungal drugs. My research proposal aims to address the multi-scale effects of aneuploidy in antifungal resistance. The goal is to define predictable, targetable changes in fungal cells and at the host-fungal interface during the evolution of antifungal resistance.
Aneuploidy, a genome with gain or loss of chromosomes, is detrimental for cellular fitness; however, it is also associated with hyperproliferative diseases, including cancer. In clinical fungal isolates, aneuploidy is frequently observed to confer phenotypic variation and drives resistance by overcoming antiproliferative stress. Despite its clinical importance, no direct strategies are available against aneuploid diseases. My recent work, for the first time, identified a hypo-osmotic signature commonly associated with the aneuploid state, independent of its random karyotypes, and this biophysical property may underlie the high adaptability of aneuploidy to antifungals. Here, I propose to investigate how aneuploid fungi leverage their unique biophysical changes to provide a permissive extracellular (Aim 1) and intracellular (Aim 2) environment for tolerating the host and antifungal stress. Furthermore, evolutionary genomics approaches will be used to elucidate the genetic basis of acquired antifungal resistance (Aim 3). My discoveries in this research program will not only improve our understanding of diseases associated with large-scale genome instability but also provide a paradigm shift for antifungal designs based on distinctive host-fungal interactions and physical-chemical properties triggered by aneuploidy.

Lay Abstract: Fungal infections affect billions of people worldwide and cause >1.5 million deaths each year. Despite the high mortality, over the past 30 years, only three classes of antifungal drugs are available to treat patients, and the unmet clinical needs of new antifungals remains unsolved. Consequently, life-threatening multidrug-resistant fungal pathogens (“superbugs”) have emerged rapidly in the past decade. The CDC has listed two common human fungal pathogens, both Candida species, as major antibiotic-resistance threats. 
A common challenge to thwart antifungal resistance is that fungi survive antifungal therapies by frequently altering their genome contents, such as aneuploidization (gaining or losing chromosomes), through erroneous cell divisions. This is commonly observed in clinical fungal isolates as fungi can immediately become aneuploid after entering the host due to the host stress. To stop this process, my work aims to identify key mechanisms underlying the development of antifungal resistance in aneuploid fungi. 
I recently discovered a general stress state caused by excessive water inflow in aneuploid cells, and this observation establishes a causal link between biophysical changes and cellular adaptability, enabling antifungal resistance. Here, I will first identify protein factors from aneuploid fungi that protect fungal populations from the host and antifungal stress. Then, I will investigate how aneuploid fungi “buffer” stress to survive antifungal therapies. Lastly, I will evolve fungal pathogens under antifungal stress to track genomic changes and further predict the onset of antifungal resistance. Together, the research outputs from this project will significantly improve our understanding of aneuploid diseases to combat antifungal resistance.

Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health Categories: INFECTION