The virulence of the Cryptococcus neoformans VNIa-5 lineage is highly plastic and associated with isolate background.

Cryptococcus neoformans most frequently causes disease in immunocompromised patients. However, in Vietnam and east Asia, disease is frequently reported in apparently immunocompetent patients. We have previously shown that almost all such disease is due to the specific lineage of C. neoformans VNIa-5. However, in HIV-infected patients, infections due to this lineage are not associated with worse outcomes. Here, we demonstrate that the VNIa-5 lineage presents different virulence phenotypes depending on its source. Isolates derived from immunocompetent patients are more virulent than those from HIV-infected patients or the environment. Moreover, the virulence phenotype is plastic: sterile culture filtrate from highly virulent VNIa5 strains can induce increased virulence in less virulent VNIa-5 isolates, which in turn can then induce increased virulence in their low virulence states. We present evidence that this phenomenon is driven by secreted proteins associated with extra-cellular vesicles.