Abstract
Cryptococcal disease is estimated to affect nearly a quarter of a million people annually. Environmental isolates of Cryptococcus deneoformans, which make up 15 to 30% of clinical infections in temperate climates such as Europe, vary in their pathogenicity, ranging from benign to hyper-virulent. Key traits that contribute to virulence, such as the production of the pigment melanin, an extracellular polysaccharide capsule, and the ability to grow at human body temperature have been identified, yet little is known about the genetic basis of variation in such traits. Here we investigate the genetic basis of melanization, capsule size, thermal tolerance, oxidative stress resistance, and antifungal drug sensitivity using quantitative trait locus (QTL) mapping in progeny derived from a cross between two divergent C. deneoformans strains. Using a “function-valued” QTL analysis framework that exploits both time-series information and growth differences across multiple environments, we identified QTL for each of these virulence traits and drug susceptibility. For three QTL we identified the underlying genes and nucleotide differences that govern variation in virulence traits. One of these genes, RIC8, which encodes a regulator of cAMP-PKA signaling, contributes to variation in four virulence traits: melanization, capsule size, thermal tolerance, and resistance to oxidative stress. Two major effect QTL for amphotericin B resistance map to the genes SSK1 and SSK2, which encode key components of the HOG pathway, a fungal-specific signal transduction network that orchestrates cellular responses to osmotic and other stresses. We also discovered complex epistatic interactions within and between genes in the HOG and cAMP-PKA pathways that regulate antifungal drug resistance and resistance to oxidative stress. Our findings advance the understanding of virulence traits among diverse lineages of Cryptococcus, and highlight the role of genetic variation in key stress-responsive signaling pathways as a major contributor to phenotypic variation.
Highlights
Over the last two decades, fungal species have emerged as major threats and pathogens [1, 2], affecting endangered plant and animal species [3,4,5,6,7], reducing crop yields [8, 9], and causing human illness [10,11,12,13]
What makes some strains deadly pathogens, while others are relatively benign? This study describes the characterization of key genetic differences that underlie variation in traits thought to promote virulence in Cryptococcus deneoformans, a wide-spread opportunistic fungal pathogen
Using a combination of quantitative genetic and molecular genetic approaches we dissected the genetic architecture of virulence-related cellular traits, physiological responses to stress, and sensitivity to multiple antifungal drugs
Summary
Over the last two decades, fungal species have emerged as major threats and pathogens [1, 2], affecting endangered plant and animal species [3,4,5,6,7], reducing crop yields [8, 9], and causing human illness [10,11,12,13]. Despite advances in both the molecular genetics of fungal pathogenesis and the genomics of pathogenic species, for most fungal pathogens we have a limited understanding of the genetic changes between isolates that contribute to differences in virulence traits [37, 38]. Neoformans serotype D) is responsible for a significant number of clinical cases in temperate regions of the world, and mixed infections of both C. neoformans and C. deneoformans have been reported [47,48,49,50]. In addition to their clinical relevance, Cryptococcus
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