Emergence and Pathogenicity of Highly Virulent Cryptococcus gattii Genotypes in the Northwest United States

Edmond J Byrnes,Kerstin Voelz,Ping Ren,Yonathan Lewit,Robin C May,Hansong Ma,Joseph Heitman,Dee A Carter,Wenjun Li,Robert J Bildfell,Vishnu Chaturvedi

doi:10.1371/journal.ppat.1000850

Abstract

Cryptococcus gattii causes life-threatening disease in otherwise healthy hosts and to a lesser extent in immunocompromised hosts. The highest incidence for this disease is on Vancouver Island, Canada, where an outbreak is expanding into neighboring regions including mainland British Columbia and the United States. This outbreak is caused predominantly by C. gattii molecular type VGII, specifically VGIIa/major. In addition, a novel genotype, VGIIc, has emerged in Oregon and is now a major source of illness in the region. Through molecular epidemiology and population analysis of MLST and VNTR markers, we show that the VGIIc group is clonal and hypothesize it arose recently. The VGIIa/IIc outbreak lineages are sexually fertile and studies support ongoing recombination in the global VGII population. This illustrates two hallmarks of emerging outbreaks: high clonality and the emergence of novel genotypes via recombination. In macrophage and murine infections, the novel VGIIc genotype and VGIIa/major isolates from the United States are highly virulent compared to similar non-outbreak VGIIa/major-related isolates. Combined MLST-VNTR analysis distinguishes clonal expansion of the VGIIa/major outbreak genotype from related but distinguishable less-virulent genotypes isolated from other geographic regions. Our evidence documents emerging hypervirulent genotypes in the United States that may expand further and provides insight into the possible molecular and geographic origins of the outbreak.

Highlights

Emerging and reemerging diseases have become a major focus of infectious disease research in the 21st century
We examine the expansion on an outbreak of a fungus, Cryptococcus gattii, in the Pacific Northwest of the United States
We expand on the discovery of a new pathogenic strain recently identified only in Oregon and show that it is highly virulent in immune cell and whole animal virulence experiments

Summary

Introduction

Emerging and reemerging diseases have become a major focus of infectious disease research in the 21st century. An additional factor contributing to increases in morbidity and mortality for many infectious diseases involves genetic recombination events or gene/pathogenicity island acquisitions. These events can occur via either horizontal gene transfer or conjugation/introgression, leading to novel pathogenic genotypes. This form of virulence evolution has been well characterized in bacterial, viral, fungal, and parasitic human diseases [4,5,6,7,8,9]. The ability to cause damage to mammalian hosts is a common theme among all microbial pathogens, making it a key aspect of host-pathogen studies [10]

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