Organ-specific immune responses are strain-dependent in a mouse model of Cryptococcus neoformans brain infection

Cryptococcal meningitis remains the top cause of death from an invasive fungal infection in humans, responsible for ~100,000 deaths annually of vulnerable patients with underlying immune deficiencies. Animal models of cryptococcal meningitis are important for understanding the immune parameters that correlate with protection. However, modeling this infection in mice is challenging. There is wide variability in infection routes, doses, and mouse background used in the field, which makes understanding phenotypes of mutants and immune interventions difficult to broadly apply. Our intention was to create an observational data set for the field on how Cryptococcus neoformans strain influences analysis of organ-specific immune responses in an intravenous mouse model of cryptococcal meningitis, focusing on impact of the fungal strain while keeping mouse genetic background (C57BL/6J) and infection route constant. We quantified myeloid and lymphoid cell recruitment and fungal-specific CD4 T-cell activation, correlating these results with fungal burdens in mice infected with the commonly used reference strain H99 or with two recently isolated clinical strains that were the same molecular type (VNI) or an unrelated type (VNB). We also analyzed how dose used in murine infection models affected brain immune responses during C. neoformans infection. Our work reveals intriguing patterns of organ-specific immunity that are dependent on C. neoformans strain but not always explained by virulence potential, raising important future questions for the field regarding the impact of C. neoformans strain on cellular immune responses in experimental animal models.IMPORTANCECryptococcal meningitis is a fungal infection that causes a wide variation of clinical disease in patients. This variation is thought to be partly due to the diversity of fungal strains that cause the infection. In this work, we have provided an in-depth analysis of immune responses to different clinical isolates of the fungus using mouse models of the infection. Our work reveals intriguing patterns of organ-specific immunity that are dependent on C. neoformans strain but not always explained by virulence potential, raising important future questions for the field regarding the impact of C. neoformans strain on cellular immune responses in experimental animal models.