Mammalian-evolved strains of the fungal pathogen Cryptococcus neoformans show adaptation via heritable transcript level differences specific to mouse MHC haplotype

BACKGROUND: Organisms adapt to novel environments using changes to genome, gene expression, and protein functions. This study focused on changes that had occurred when a fungal pathogen previously encountered hosts that differed only at the major histocompatibility complex (MHC) region, loci that control immune recognition during the adaptive immune response. To investigate how this fungal pathogen adapted to the host environment, next generation sequencing data were examined from strains of Cryptococcus neoformans (C. neoformans) that had been previously passaged eight times through congenic mice that specifically differed at the MHC locus, H2. Transcript levels and the genomic sequence for each post-adapted fungal strain were examined to identify molecular adaptation strategies via heritable gene expression changes (epigenetic changes) and mutation (DNA changes). RESULTS: The post-adapted strains displayed repeated changes in transcript levels, as determined by RNA-sequencing. Some of these epigenetically regulated genes (ERGs) only occurred in strains passaged in MHC specific hosts, suggesting possible prior adaptations to specific host MHCs. To our knowledge, this is the first time ERGs have been reported as possible pathogen adaptations to specific host MHC alleles. Additionally, of the total 47 single nucleotide polymorphisms (SNPs) identified, 7 SNPs each were found in 2 or more fungal strains (of the 6 analyzed strains) passaged through different MHC congenic hosts, suggesting much of the fungal mutation-based adaptation was to the mouse host, and not MHC-specific. CONCLUSIONS: These data demonstrated that these passaged C. neoformans strains adapted to the MHC haplotype of a novel mammalian host environment primarily via epigenetic rather than mutation-based mechanisms.