Cryptococcus gattii in North American Pacific Northwest: Whole-Population Genome Analysis Provides Insights into Species Evolution and Dispersal

Abstract

The emergence of distinct populations of Cryptococcus gattii in the temperate North American Pacific Northwest (PNW) was surprising, as this species was previously thought to be confined to tropical and semitropical regions. Beyond a new habitat niche, the dominant emergent population displayed increased virulence and caused primary pulmonary disease, as opposed to the predominantly neurologic disease seen previously elsewhere. Whole-genome sequencing was performed on 118 C. gattii isolates, including the PNW subtypes and the global diversity of molecular type VGII, to better ascertain the natural source and genomic adaptations leading to the emergence of infection in the PNW. Overall, the VGII population was highly diverse, demonstrating large numbers of mutational and recombinational events; however, the three dominant subtypes from the PNW were of low diversity and were completely clonal. Although strains of VGII were found on at least five continents, all genetic subpopulations were represented or were most closely related to strains from South America. The phylogenetic data are consistent with multiple dispersal events from South America to North America and elsewhere. Numerous gene content differences were identified between the emergent clones and other VGII lineages, including genes potentially related to habitat adaptation, virulence, and pathology. Evidence was also found for possible gene introgression from Cryptococcus neoformans var. grubii that is rarely seen in global C. gattii but that was present in all PNW populations. These findings provide greater understanding of C. gattii evolution in North America and support extensive evolution in, and dispersal from, South America.

Cryptococcus gattii Infections

“…The WGST data showed clearly that the VGIIc genotype responsible for the most recent infections in the Pacific Northwest is genetically distinct from both VGIIa and VGIIb Vancouver Island outbreak subtypes and suggest that all three subtypes are equally distinct from each other (52). Similar findings based on multilocus sequence typing (MLST) and MLMT analyses, which have been confirmed based on WGST, have been reported recently (53)(54)(55). All studies suggest that the three subtypes have arisen as a result of recombination events that took place prior to their introduction into the Pacific Northwest.…”

“…More recent studies support the proposal that C. gattii molecular type VGII originated in South America (46,72) and that Australia and Thailand are possible "stepping stones" in the global spread of VGIIb from South to North America (88,89). The introduction of VGIIb from its ancestral origin in South America, via different parts of the world, has recently been confirmed by using WGST (54). These findings agree with a recent comprehensive, global study of VGII strains, which traced the origin of both outbreak subgenotypes VGIIa and VGIIb back to an ancestral C. gattii strain, LMM645, from the Amazon rainforest.…”

Advances in the understanding of the Cryptococcus neoformans and C. gattii species complexes and cryptococcosis

“…Although the VGII subtypes were found to be completely clonal, the overall VGII population showed a high genetic diversity. In addition, several mutations, deletions, transpositions and recombination events have been identified within VGII strains, and this pointed to a South American origin 30 . Using WGS to compare subtypes, various genetic differences have been recognised, which are potentially related to habitat adaptation, virulence, and pathology 30 .…”

“…In addition, several mutations, deletions, transpositions and recombination events have been identified within VGII strains, and this pointed to a South American origin 30 . Using WGS to compare subtypes, various genetic differences have been recognised, which are potentially related to habitat adaptation, virulence, and pathology 30 . For example, a set of~50 genes has been identified being either present or absent in lung or brain infecting strains …”

You are what you secrete: extracellular proteins and virulence in Cryptococcus

“…Comparative genomic studies have identified genes that are particular to the high virulence strains but their role in virulence is yet to be verified 11,12 . As secreted biomolecules are mediators of contact between the host and the pathogen, differences in these are likely to influence whether a pathogen will be rapidly recognized and eliminated, or will be able to bypass the host response and use host resources to establish an active infection.…”