Macrophages alone seem unable to clear infection and an adaptive immune response leading to a self-resolving granuloma is required 7. neoformans is thought to occur through the lungs where, in the immunocompetent, the first immune cells to encounter cryptococci will most likely be alveolar macrophages. However, there are a number of unifying features in susceptibility to cryptococcal disease, notably a failure in a pro-inflammatory immune response to primary infection 4, 5, 6. Cryptococcal meningitis is also found associated with a large variety of other immune deficient states, including in patients on immunosuppressive therapies 2, 3, those with hematological malignancy and other more oblique disorders 4. Thus, high-content imaging of cryptococcal infection in vivo demonstrates how very early interactions between macrophages and cryptococci are critical in the outcome of cryptococcosis.Ĭryptococcus neoformans is a fungal pathogen of humans that causes life-threatening cryptococcal meningitis in immunocompromised patients, in particular those with advanced AIDS 1. We show that macrophages preferentially phagocytose cryptococci with smaller polysaccharide capsules and that capsule size is greatly increased over twenty-four hours of infection, a change that is sufficient to severely limit further phagocytosis. We find phagocytosis is restrained very early in infection and that increases in cryptococcal number are driven by intracellular proliferation. neoformans, a failure of macrophage response is not the limiting defect in fatal infections. Using this approach we demonstrate that, while macrophages are critical for control of C. Here we describe a high-content imaging method in a zebrafish model of cryptococcosis that permits the detailed analysis of macrophage interactions with C. Two current limitations are: 1) The difficulties in interpreting studies using isolated macrophages in the context of the progression of infection, and 2) The use of high resolution imaging in understanding immune cell behavior during animal infection. Many questions remain regarding the function of macrophages in normal clearance of cryptococcal infection and the defects present in uncontrolled cryptococcosis. Cryptococcus neoformans is a significant fungal pathogen of immunocompromised patients.
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