Dissemination of Cryptococcus neoformans via localised proliferation and blockage of blood vessels

Cryptococcus neoformans is an opportunistic fungal pathogen that can cause life-threatening cryptoccocal meningitis, predominantly within immunocompromised individuals. Cortical infarcts are observed in as many as 30% of cryptococcal meningitis cases, being particularly common in severe infection. Limited clinical case studies suggest infarcts are secondary to vasculitis and blood vessel damage caused by cryptococcal infection. However, the cause of infarcts in cryptococcal infection has not been determined. To examine potential causes of vascular damage and cryptococcal dissemination in cryptococcal infection, the zebrafish C. neoformans infection model was used. We demonstrate that spread of cryptococci from the vasculature occurs at sites where cryptococci grow within the blood vessels, originating from a single or small number of cryptococci. We find that cryptococcal cells become trapped within the vasculature and can proliferate there resulting in vasodilation. Localised cryptococcal growth in the vasculature is also associated with sites of dissemination - in some cases simultaneously with a loss of blood vessel integrity. Using a cell-cell junction protein reporter (VE-cadherin) we identified sites dissemination associated with both intact blood vessels and where vessel rupture occurred. Thus, we have identified a mechanism for blood vessel damage during cryptococcal infection that may represent a cause of the vascular damage and cortical infarction observed in cryptococcal meningitis.