Abstract Microglia provide protection against a range of brain infections, but how these glial cells respond to fungi is poorly understood. We investigated the role of microglia in the context of cryptococcal meningitis, the most common cause of fungal brain infections in humans. Using a series of transgenic- and chemical-based microglia depletion methods we found that, contrary to their protective role during other infections, microglia supported cryptococcal fungal brain infection. We show that microglia become hosts for intracellular fungal growth and are a site in which the fungus accesses the restricted micronutrient copper. We developed a reporter fungal strain to track copper starvation responses by the fungus and found that yeast were protected from copper starvation within microglia. Lastly, we show that stimulation of microglia with IFNγ causes restriction of phagosomal copper to intracellular fungi. These data provide a mechanistic explanation for why microglia depletion has a therapeutic effect in the context of this life-threatening fungal infection and is one of the few examples of microglia acting to promote infection. Our data demonstrate how tissue-resident phagocytes can support cryptococcal infections by acting as intracellular reservoirs and sites of microbial nutrient acquisition, and how these mechanisms may be blocked by IFNγ immunotherapy.

Microglia protect fungi against copper starvation and promote brain infection