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DNA mutations mediate microevolution between host-adapted forms of the pathogenic fungus Cryptococcus neoformans
- Source :
- PLoS Pathogens, PLoS Pathogens, Vol 8, Iss 10, p e1002936 (2012)
- Publication Year :
- 2012
-
Abstract
- The disease cryptococcosis, caused by the fungus Cryptococcus neoformans, is acquired directly from environmental exposure rather than transmitted person-to-person. One explanation for the pathogenicity of this species is that interactions with environmental predators select for virulence. However, co-incubation of C. neoformans with amoeba can cause a “switch” from the normal yeast morphology to a pseudohyphal form, enabling fungi to survive exposure to amoeba, yet conversely reducing virulence in mammalian models of cryptococcosis. Like other human pathogenic fungi, C. neoformans is capable of microevolutionary changes that influence the biology of the organism and outcome of the host-pathogen interaction. A yeast-pseudohyphal phenotypic switch also happens under in vitro conditions. Here, we demonstrate that this morphological switch, rather than being under epigenetic control, is controlled by DNA mutation since all pseudohyphal strains bear mutations within genes encoding components of the RAM pathway. High rates of isolation of pseudohyphal strains can be explained by the physical size of RAM pathway genes and a hypermutator phenotype of the strain used in phenotypic switching studies. Reversion to wild type yeast morphology in vitro or within a mammalian host can occur through different mechanisms, with one being counter-acting mutations. Infection of mice with RAM mutants reveals several outcomes: clearance of the infection, asymptomatic maintenance of the strains, or reversion to wild type forms and progression of disease. These findings demonstrate a key role of mutation events in microevolution to modulate the ability of a fungal pathogen to cause disease.<br />Author Summary Many diseases are contracted from the environment, rather than from sick people. It is unclear why those species are able to cause disease, since the selective pressures in the environment are presumed to be very different from those found within the host. Cryptococcus neoformans is a fungus that causes life-threatening lung and central nervous system disease in approximately one million people each year. The fungus is inhaled from environmental sources. One hypothesis to account for C. neoformans virulence is that amoeba are predators for this fungus, and surviving strains are pre-selected to be virulent in the human host. On the other hand, experiments have found that amoeba eat C. neoformans. A pseudohyphal cell type can survive, and while protecting against amoeba these cells are unable to cause disease in mouse models. We predicted that the pseudohyphal morphology reflected a change in function of a pathway of genes, and found that all pseudohyphal isolates contain mutations within genes for this pathway. The pseudohyphal trait is unstable, with reversion to normal yeast growth by counter-acting mutations. These mutations can occur during the course of mammalian infection. Our results show that mutation events account for a microevolution system currently described as phenotypic switching, and that mutations, at least under experimental conditions, can regulate pathogen adaptation and influence its host range.
- Subjects :
- Mutant
Phenotypic switching
Gene Identification and Analysis
Pathogenesis
Mice
Molecular Cell Biology
Natural Selection
Fungal Evolution
Amoeba
DNA, Fungal
lcsh:QH301-705.5
Genetics
0303 health sciences
Fungal protein
biology
Microbial Mutation
Fungal genetics
Environmental exposure
Cryptococcosis
3. Good health
Host-Pathogen Interaction
Phenotype
Medical Microbiology
Host-Pathogen Interactions
Research Article
lcsh:Immunologic diseases. Allergy
Saccharomyces cerevisiae Proteins
Evolutionary Processes
Immunology
Genes, Fungal
Molecular Sequence Data
Hyphae
Virulence
Mycology
Microbiology
Cell Growth
Evolution, Molecular
Fungal Proteins
Molecular Genetics
03 medical and health sciences
Genetic Mutation
Virology
medicine
Animals
Selection, Genetic
Adaptation
Molecular Biology
Biology
030304 developmental biology
Adaptor Proteins, Signal Transducing
Cryptococcus neoformans
Evolutionary Biology
030306 microbiology
Mutation Types
biology.organism_classification
medicine.disease
lcsh:Biology (General)
Mutation
Microbial Evolution
Parasitology
Gene Function
lcsh:RC581-607
Subjects
Details
- ISSN :
- 15537374
- Volume :
- 8
- Issue :
- 10
- Database :
- OpenAIRE
- Journal :
- PLoS pathogens
- Accession number :
- edsair.doi.dedup.....67e999bbec1cee75321b36215d40ed1f