Cryptococcal meningitis is an infection with Cryptococcus species; almost all disease occurs in immunosuppressed patients due to C. neoformans. Cryptococcus spp are environmental saprophytes; the ability to cause disease is considered an accident of adaptation to their ecological niche.
In Southeast Asia, cryptococcal meningitis in immunocompetent individuals is well-described and is almost always due to the C. neoformans ST5 (VNIa-5) lineage. I hypothesize this lineage has relative increased pathogenicity. The aims of this thesis were to: identify the ecological niche of C. neoformans; define the diversity of C. neoformans in Vietnam; compare the virulence of different genotypes, and; define transcriptional differences associated with virulence.
I identified spatial clustering of lineages VNIa-4, VNIa-5 and VNIa-32. Environmental sampling yielded 123 cryptococci the majority of which were non-pathogenic.
Using the G. mellonella infection model I identified an ‘ecological imprint’ on isolates. Within a lineage, the virulence of an isolate is determined by its source – environmental, immunosuppressed or immunocompetent patient. Moreover, the virulence of environmental C. neoformans can be upregulated by clinical strains of that lineage. This ‘induction’ effect is regulated by a protein/peptide signaling system. Comparative transcriptomics revealed 1700 genes differentially expressed between clinical and environmental isolates. Gene ontology (GO) terms relevant to metabolism and cellular biosynthesis were enriched in clinical isolates; GO terms relevant to cell cycle and cell division were significantly enriched in induced environmental isolates. Clinical and induced environmental isolates had highly similar transcriptomes. A number of genes previously confirmed as virulence determinants were upregulated in clinical and induced environmental isolates; a third of differentially expressed genes between the induced and `naive' isolates were hypothetical proteins. These are novel candidates implicated in the upregulation of virulence. My findings provide insight into ecology of C. neoformans in Vietnam and the genetic control of virulence
