Fungi on the Brain: Interrogating Host-Pathogen Interactions during Fungal Meningitis

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Fungi are a major cause of ill-health in humans; hundreds of millions of people suffer from skin and mucosal fungal infections every year, while life-threatening invasive fungal infections cause more deaths around the world than malaria and some types of cancer. These life-threatening invasive fungal infections are a particular cause for concern, because we have limited antifungal drugs to treat them, diagnosis is very difficult and there are no fungal vaccines. Knowledge of how protective immune responses against fungi are controlled can help us to design vaccines and immune-based treatments for these infections. Yet, compared to bacteria and viruses, fungi are poorly studied and only a few research groups in the world have the expertise to understand how the immune system deals with fungi. Fungal infection of the brain and central nervous system (meningitis) is the most lethal form of invasive fungal disease. The most common fungal brain infection is cryptococcal meningitis, caused by the fungus Cryptococcus neoformans, which mostly affects people with weakened immune systems in low and middle-income countries in sub-Saharan Africa. Cryptococcal meningitis is not easily treated; 4 out of every 5 patients with this disease die from it. New treatment strategies and diagnostics are therefore urgently needed, which in turn could potentially improve the social and economic performance of these low/middle-income countries by improving the population's health. The goal of my research is to better understand immunity to Cryptococcus specifically in the brain. Each organ has its own specialised immune cells that are involved in surveillance and alarming other cells of the immune system to the presence of an invader. Microglia are the specialised cells of the brain's internal immune system. We've known about them for a long time but they are still mysterious since, until recently, we didn't have the tools needed to understand them. These new tools include animal models that enable us to delete microglia from the brain so we can determine how the absence of microglia affects disease progression and resolution. Using my background in fungal immunology and microglia biology, I have adapted these microglia-depleting mice with animal models of fungal infection to allow me to understand what microglia do when confronted with a fungal invader. Answering this fundamental question will then help us to determine what treatments will work best for fungal CNS infection so we can reduce the impact of this devastating disease on human health.