Inflammation and immune cell recruitment in the CNS following disseminated Cryptococcus neoformans infection

Mortality in Cryptococcus neoformans (Cn) infection is chiefly associated with CNS infection but little is known about immune responses against Cn within the CNS. We established an i.v. model of disseminated cryptococcosis that leads to a rapid expansion of Cn in the CNS in order to compare inflammatory readouts in resistant CBA/J with susceptible C57BL/6 mice. Fungal burdens peaked (u003e10 7 CFU) in the brain by d7 post infection in both models, but in CBA/J mice fungal burden significantly declined between d14 to d21. In contrast, C57BL/6 mice developed persistently high fungal burdens through d21. Consistent with these findings CBA/J mice showed gradual increases in Ly6C + myeloid, CD4 + and CD8 + T cell infiltration along with production of CCL2, IFNγ and CXCL10, reaching maximum or near maximum levels by day 14. In C57BL6, the development of inflammatory responses was significantly delayed. Production of cytokines and influx of Ly6C + , CD4 + and CD8 + cells was almost absent until d21, but prominently exceeded all readouts from CBA/J at day 21 by several fold. Significant increases in iNOS hi CD11b hi MHCII hi CD11c + cells and an overabundance of highly activated CD11c + MHCII + microglia, hallmarks of rapidly developing CNS pathologies, were also more evident in the brains of C57BL/6 mice at d21. In summary, our findings are consistent with the hypothesis that early recruitment and activation of inflammatory cells in the CNS post-Cn infection, presumably in response to early CCL2-induction, along with subsequent early induction of IFNγ and CXCL10 promotes fungal clearance. In contrast, delayed responses found in C57BL6 mice were ineffective at removing fungal organisms while leading to over exuberant inflammation and detrimental CNS pathology.