Meta-analysis of published molecular epidemiology data of the Cryptococcus neoformans and C. gattii species complexes using the ISHAM MLST consensus
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Objective: Cryptococcosis is a life-threatening systemic mycosis affecting humans and animals. A standardized MLST scheme has been established by the ISHAM working group on “Genotyping of Cryptococcus neoformans/C. gattii “, which is used globally for typing the agents of cryptococcosis. This scheme includes seven unlinked genetic loci, the genes CAP59, GPD1, LAC1, PLB1, SOD1, URA5, and the IGS1 region. The allele and sequence types are recorded in theMLST database: http://mlst.mycologylab.org/. We present a meta-analysis to discuss the worldwide molecular epidemiology of the C. neoformans/C. gattii species complexes based on the currently published data. Methods: At least 47 papers have puclished data using the ISHAM MLST consensus scheme and/or the MLST database until 2017. From those, only 23 papers included the list of strains, accounting for 1849 C. neoformans and 1141 C. gattii species complex strains from 51 countries. Results: Most of the strains analyzed by MLST are reported to be VNI (51%) followed by VGII (25%), VGI (8%), VGIII (6%), VNIV (5%), VNII (3%), VNB and VNIV (1% each). A total of 465 sequence types (STs), 241 for C. neoformans species complex and 224 for C. gattii species complex, were identified. Haplotype (Hd) and nucleotide (Pi) diversity of the concatenated seven loci varied according to the major molecular type and the continent of origin of the strains. The most genetically diverse population was found among VNB strains in Africa. VNIV in Europe, VGII in South America and VGIII in North America also showed high genetic diversity. Minimum spanning tree analysis shows that VNI population includes two main clusters, one containing predominantly STs from Asia and the other containing STs from Europe. Some STs are exclusive of a specific continent and others are present worldwide, but predominating in different regions, e.g. for C. neoformans STs 4, 5, 6 and 31 are more prevalent in Asia; STs 1, 71, 77 and 93 predominate in South America; STs 32 and 69 in Africa; and STs 23, 59, and 63 in Europe. VNB is almost exclusively from Africa and VNIV from Europe, but they are also occasionally reported in other continents. Similar regional patterns are observed among C. gattii species complex subtypes, ST156 is exclusive to Europe, ST6 to North America, but STs 51 and 7 are found in several continents. The majority of C. neoformans species complex strains (51%) had risk factor data, with the presence of risk factors to acquire cryptococcosis varying greatly, from 100% (for all VNB STs) to 9% (for VNIV, ST324). Only 7.7% of C. gattii cases have risk factor data, and the numbers per ST are too small to make any association. Statistical analysis demonstrates that populations with a higher genetic diversity are associated with a higher rate of mating type a strains, suggesting sexual reproduction as the main way of recombination within the C. neoformans and C. gattii species complexes. Conclusion: This work highlights the significant progress that has been made worldwide towards the typification of cryptococcal isolates, which contribute to understand the population structure of these medically important yeasts.