DNA mutations mediate microevolution between host-adapted forms of the pathogenic fungus Cryptococcus neoformans.
DNA mutations mediate microevolution between host-adapted forms of the pathogenic fungus Cryptococcus neoformans.
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DOI：
10.1371/journal.ppat.1002936
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发表时间：
2012
期刊：
影响因子：
6.7
通讯作者：
Idnurm A
中科院分区：
文献类型：
--
作者：
Magditch DA;Liu TB;Xue C;Idnurm A
隐球菌病是由新型隐球菌真菌引起的，是直接从环境暴露中获得的，而不是人与人之间传播的。对该物种致病性的一种解释是，与环境捕食者的相互作用选择了毒性。然而，C.具有变形虫的新生酵母菌可以引起从正常酵母形态到假菌丝形式的“转换”，使得真菌能够在暴露于变形虫的情况下存活，但相反地降低了隐球菌病的哺乳动物模型中的毒力。与其他人类致病真菌一样，C.新生儿能够发生微进化变化，影响生物体的生物学和宿主-病原体相互作用的结果。酵母-假菌丝表型转换也发生在体外条件下。在这里，我们表明，这种形态开关，而不是在表观遗传控制下，是由DNA突变控制的，因为所有的假菌丝菌株携带突变的RAM途径的基因编码组件内。假菌丝菌株的高分离率可以通过RAM途径基因的物理大小和表型转换研究中使用的菌株的超变表型来解释。在体外或在哺乳动物宿主内回复到野生型酵母形态可以通过不同的机制发生，其中一种是反作用突变。用RAM突变体感染小鼠揭示了几种结果：感染的清除，菌株的无症状维持，或回复到野生型形式和疾病进展。这些发现证明了突变事件在微进化中调节真菌病原体引起疾病的能力的关键作用。许多疾病是从环境而不是从病人那里感染的。目前还不清楚为什么这些物种能够引起疾病，因为环境中的选择压力被认为与宿主体内的选择压力非常不同。新型隐球菌是一种真菌，每年约有100万人患上危及生命的肺部和中枢神经系统疾病。真菌是从环境中吸入的。一个假设来解释C。新形虫的毒力在于变形虫是这种真菌的捕食者，并且存活的菌株被预先选择为在人类宿主中是有毒的。另一方面，实验发现变形虫吃C。新人类一种假菌丝细胞类型可以存活，并且在保护免受变形虫的同时，这些细胞不能在小鼠模型中引起疾病。我们预测，假菌丝形态反映了一个途径的基因的功能的变化，并发现所有的假菌丝分离物包含该途径的基因内的突变。假菌丝性状是不稳定的，通过反作用突变恢复正常酵母生长。这些突变可以在哺乳动物感染过程中发生。我们的研究结果表明，突变事件占目前描述为表型转换的微进化系统，突变，至少在实验条件下，可以调节病原体的适应和影响其宿主范围。
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. 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.
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影响因子：
9.2
作者：
Alvarez, Mauricio;Casadevall, Arturo
通讯作者：
Casadevall, Arturo
影响因子：
8
作者：
Goldman, DL;Khine, H;Casadevall, A
通讯作者：
Casadevall, A
DOI：
10.1073/pnas.95.25.14967
发表时间：
1998-12-08
影响因子：
11.1
作者：
Goldman, DL;Fries, BC;Casadevall, A
通讯作者：
Casadevall, A
影响因子：
3.1
作者：
Cox, GM;Mukherjee, J;Perfect, JR
通讯作者：
Perfect, JR
影响因子：
3
作者：
da Silva, EG;Baroni, FD;Paula, CR
通讯作者：
Paula, CR