title: MLST and Whole-Genome-Based Population Analysis of Cryptococcus gattii VGIII Links Clinical, Veterinary and Environmental Strains, and Reveals Divergent Serotype Specific Sub-populations and Distant Ancestors.
abstract: The emerging pathogen Cryptococcus gattii causes life-threatening disease in immunocompetent and immunocompromised hosts. Of the four major molecular types (VGI-VGIV), the molecular type VGIII has recently emerged as cause of disease in otherwise healthy individuals, prompting a need to investigate its population genetic structure to understand if there are potential genotype-dependent characteristics in its epidemiology, environmental niche(s), host range and clinical features of disease. Multilocus sequence typing (MLST) of 122 clinical, environmental and veterinary C. gattii VGIII isolates from Australia, Colombia, Guatemala, Mexico, New Zealand, Paraguay, USA and Venezuela, and whole genome sequencing (WGS) of 60 isolates representing all established MLST types identified four divergent sub-populations. The majority of the isolates belong to two main clades, corresponding either to serotype B or C, indicating an ongoing species evolution. Both major clades included clinical, environmental and veterinary isolates. The C. gattii VGIII population was genetically highly diverse, with minor differences between countries, isolation source, serotype and mating type. Little to no recombination was found between the two major groups, serotype B and C, at the whole and mitochondrial genome level. C. gattii VGIII is widespread in the Americas, with sporadic cases occurring elsewhere, WGS revealed Mexico and USA as a likely origin of the serotype B VGIII population and Colombia as a possible origin of the serotype C VGIII population. Serotype B isolates are more virulent than serotype C isolates in a murine model of infection, causing predominantly pulmonary cryptococcosis. No specific link between genotype and virulence was observed. Antifungal susceptibility testing against six antifungal drugs revealed that serotype B isolates are more susceptible to azoles than serotype C isolates, highlighting the importance of strain typing to guide effective treatment to improve the disease outcome.
authors: Molecular Mycology Research Laboratory, Centre for Infectious Diseases and Microbiology, Sydney Medical School - Westmead Hospital, Marie Bashir Institute for Infectious Diseases and Biosecurity, The University of Sydney, Westmead Millennium Institute, Sydney, Australia.|Grupo de Microbiología, Instituto Nacional de Salud, Bogotá, Colombia.
authors: Carolina
authors: C
authors: Firacative
authors: Translational Genomics Research Institute, Flagstaff, Arizona, United States of America.
authors: Chandler C
authors: CC
authors: Roe
authors: Centre for Veterinary Education, The University of Sydney, Sydney, Australia.
authors: Richard
authors: R
authors: Malik
authors: Molecular Mycology Research Laboratory, Centre for Infectious Diseases and Microbiology, Sydney Medical School - Westmead Hospital, Marie Bashir Institute for Infectious Diseases and Biosecurity, The University of Sydney, Westmead Millennium Institute, Sydney, Australia.|Infectious Disease Department, Triangulo Mineiro Federal University, Uberaba, Minas Gerais, Brazil.
authors: Kennio
authors: K
authors: Ferreira-Paim
authors: Grupo de Microbiología, Instituto Nacional de Salud, Bogotá, Colombia.
authors: Patricia
authors: P
authors: Escandón
authors: Department of Medicine and Epidemiology, University of California, Davis, Davis, California, United States of America.
authors: Jane E
authors: JE
authors: Sykes
authors: Departamento de Microbiología y Parasitología, Facultad de Medicina, Universidad National Autónoma de México, Mexico City, Mexico.
authors: Laura Rocío
authors: LR
authors: Castañón-Olivares
authors: Instituto Nacional de Diagnóstico y Referencia Epidemiológicos, Mexico City, Mexico.
authors: Cudberto
authors: C
authors: Contreras-Peres
authors: Hospital San Juan de Dios, Guatemala City, Guatemala.
authors: Blanca
authors: B
authors: Samayoa
authors: Molecular Mycology Research Laboratory, Centre for Infectious Diseases and Microbiology, Sydney Medical School - Westmead Hospital, Marie Bashir Institute for Infectious Diseases and Biosecurity, The University of Sydney, Westmead Millennium Institute, Sydney, Australia.
authors: Tania C
authors: TC
authors: Sorrell
authors: Grupo de Microbiología, Instituto Nacional de Salud, Bogotá, Colombia.
authors: Elizabeth
authors: E
authors: Castañeda
authors: Mycotic Diseases Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America.
authors: Shawn R
authors: SR
authors: Lockhart
authors: Translational Genomics Research Institute, Flagstaff, Arizona, United States of America.
authors: David M
authors: DM
authors: Engelthaler
authors: Molecular Mycology Research Laboratory, Centre for Infectious Diseases and Microbiology, Sydney Medical School - Westmead Hospital, Marie Bashir Institute for Infectious Diseases and Biosecurity, The University of Sydney, Westmead Millennium Institute, Sydney, Australia.
authors: Wieland
authors: W
authors: Meyer
mesh_terms: D000569:Americas / Q000453:epidemiology; D000818:Animals; D001315:Australia / Q000453:epidemiology; D003453:Cryptococcosis / Q000453:epidemiology / Q000382:microbiology*; D056285:Cryptococcus gattii / Q000145:classification* / Q000235:genetics* / Q000276:immunology / Q000472:pathogenicity; D014644:Genetic Variation; D016681:Genome, Fungal; D005838:Genotype; D006166:Guatemala / Q000453:epidemiology; D006801:Humans; D056186:Metagenomics; D008800:Mexico / Q000453:epidemiology; D058885:Multilocus Sequence Typing; D010802:Phylogeny; D065288:Serogroup; D014687:Venezuela / Q000453:epidemiology; D014774:Virulence