Title: Dynamics of brain invasion by the pathogenic fungus Cryptococcus neoformans
Funder: The Academy of Medical Sciences

Abstract: The pathogenic fungus Cryptococcus neoformans invades the mammalian brain to cause meningoencephalitis, resulting in ~180,000 deaths worldwide each year. To tackle this major health burden, we need a better understanding of this critical question: how does C. neoformans reach the mammalian brain? C.neoformans quickly and efficiently crosses a series of tissue barriers – and in particular, the blood-brain barrier and the blood-cerebrospinal-fluid barrier – which normally provide vital protection of the brain from microbes. My goal is to understand how C. neoformans overcomes these protective tissue barriers, and which fungal molecules enable this invasion. Based on my previous work, I propose to: Aim 1: Map the dynamics of fungal brain-tissue invasion in animal models, using state-of-the-art microscopy tools. I will obtain vital clues about the mechanisms by which C. neoformans rapidly invades the brain. Then, I will use key insights to establish relevant in vitro models to gain a deeper understanding of the mechanisms involved. Aim 2: Decipher the molecular mechanisms of fungal invasion. Initially, I will focus on the transcription factor, Pdr802, already known to be central player in brain invasion. I will reveal the molecular mechanisms by which this important regulator controls invasion, by identifying key downstream effectors of Pdr802. Ultimately, this project will define the routes and mechanisms by which C. neoformans rapidly invades the mammalian brain. This knowledge is vital to understand the pathogenesis of this deadly disease. This fertile research avenue will carve a research niche for my career.

Lay abstract: I study a deadly microbial killer – the fungal pathogen Cryptococcus neoformans. This microbe kills about 180,000 people each year, by infecting the human lungs (pneumonia) and brains (meningitis). However, it is not clear how Cryptococcus invades the human body, how it travels from the lungs via the air we inhale, into the bloodstream, to reach the human brain. I recently discovered that Cryptococcus can transit from the lungs to the brain extremely quickly (within hours). My goal is to discover how the fungus can invade the brain so quickly. Microbes which cause disease developed sophisticated arsenals to invade human tissues. These arsenals work in different ways, for example by binding, or damaging human tissue. By identifying key components of this arsenal in Cryptococcus, I will be able to devise ways to block invasion, and counterattack the microbe’s invasion. This is a first step towards the development of novel drugs or vaccines that will, ultimately, reduce the burden of this deadly disease. Therefore, in this project, I will map exactly when and where this fungal microbe reaches the brain using state-of-the-art microscopy and imaging technologies to visualise the fungus in the act of invasion. Next, I will identify key components used by Cryptococcus to bind and damage our tissues in the critically-invaded sites. Together, these two objectives will greatly enhance our knowledge of fungal invasion – a critical step in the progression of this deadly disease – with a view to developing better ways to prevent this disease.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION