The unexpected consequences of antifungals on innate immune interactions

Drug-resistant fungi are an emerging clinical problem whose interactions with the immune system are poorly understood.

Candida glabrata is a facultative intracellular emerging fungal pathogen that is responsible for ~24% of life-threatening candidiasis cases in the UK. C. glabrata is intrinsically resistant to azole antifungals, such as fluconazole.

However, little is known regarding how antifungals influence C. glabrata host-pathogen interactions and innate immune evasion. Furthermore, we have very limited high-throughput tools to study intracellular fungal-host interactions. Therefore, I will leverage my years of expertise in fungal-host interactions to address this problem.

Specifically, I will determine the mechanisms driving immune evasion in a drug-resistant fungus and establish a crucial high-throughput platform to evaluate intracellular pathogenesis that facilitates future drug development applications.

The fungal cell wall is the first point of contact with the immune system, with several epitopes that influence immune recognition and fungal killing. I have shown that fluconazole treatment promotes epitope remodelling and enhances C. glabrata survival in macrophages. Thus, this proposal will establish how C. glabrata antifungal resistance impacts immune evasion and pathogenesis.

I will use my expertise in epitope exposure profiling and macrophage challenge assays to establish how antifungals influence innate immune recognition and fungal killing.

I will also establish an imaging cytometry method to address the need for a robust tool to investigate intracellular virulence and identify novel therapeutics.

The data and tools developed by this proposal will support MRC and Wellcome Trust Investigator applications and generate impact through academic and drug discovery collaborations.