Depletion of alveolar macrophages decreases the dissemination of a glucosylceramide-deficient mutant of Cryptococcus neoformans in Immunodeficient mice

In previous studies we showed that a Cryptococcus neoformans mutant lacking glucosylceramide (Delta gcs1) is avirulent and unable to reach the brain when it is administered intranasally into an immunocompetent mouse and is contained in a lung granuloma. To determine whether granuloma formation is key for containment of C. neoformans Delta gcs1, we studied the role of C. neoformans glucosylceramide in a T- and NK-cell-immunodeficient mouse model (Tg epsilon 26) in which alveolar macrophages (AMs) are not activated and granuloma formation is not expected. The results show that Tg epsilon 26 mice infected with Delta gcs1 do not produce a lung granuloma and that the Delta gcs1 mutant proliferates in the lungs and does disseminate to the brain, although its virulence phenotype is dramatically reduced. Since Delta gcs1 can grow only in acidic niches, such as the phagolysosome of AMs, and not in neutral or alkaline environments, such as the extracellular spaces, we hypothesize that in immunodeficient mice Delta gcs1 proliferates inside AMs. Indeed, we found that depletion of AMs significantly improved Tg epsilon 26 mouse survival and decreased the dissemination of Delta gcs1 cells to the central nervous system. Thus, these results suggest that the growth of Delta gcs1 in immunodeficient mice is maintained within AMs. This study highlights the hypothesis that AMs may exacerbate C. neoformans infection in conditions in which there is severe host immunodeficiency.