Interrogating Host-Pathogen Interactions during Fungal Meningitis

My lab is focused on understanding the pathogenesis of the invasive fungal infection, cryptococcal meningitis, which was recently named as the number one priority fungal disease requiring urgent attention by the World Health Organisation. Despite that, there is little understood about how immune responses are regulated in the brain during this infection. The major immune cells resident in the brain are macrophages called microglia. It was not clear how these cells responded to Cryptococcus neoformans, the main causative agent of cryptococcal meningitis. It was also not known whether these cells play a protective or deleterious role during infection, since macrophages can act as intracellular infection reservoirs for this fungus, but the relevance of this in the brain had not been studied. We have shown that brain-resident immune cells called microglia are an important reservoir for intracellular fungal infection. Moreover, we have found that microglia are important drivers of heterogeneity within the fungal population by shaping their nutrient scavenging responses, and that these fungal-microglia interactions can be modulated by the protective cytokine IFNg. This is important, because IFNg is a promising immune-based therapy for cryptococcal meningitis and there is significant interest and translational potential in understanding how this cytokine exerts its protective effects in the brain.