In vivo RNA sequencing reveals a crucial role of Fus3-Kss1 MAPK pathway in Candida glabrata pathogenicity.

IF 3.7 2区 生物学 Q2 MICROBIOLOGY mSphere Pub Date : 2024-10-30 DOI:10.1128/msphere.00715-24
Xinreng Mo, Xiangtai Yu, Hao Cui, Kang Xiong, Shan Yang, Chang Su, Yang Lu
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Abstract

Candida glabrata is an important and increasingly common pathogen of humans, particularly in immunocompromised hosts. Despite this, little is known about how this fungus causes disease. Here, we applied RNA sequencing and an in vivo invasive infection model to identify the attributes that allow this organism to infect hosts. Fungal transcriptomes show a dramatic increase in the expression of Fus3 and Kss1, two mitogen-activated protein kinases (MAPKs), during invasive infection. We further demonstrate that they are both highly induced under a combination of serum and high CO2 conditions. Deletion of both FUS3 and KSS1, but neither gene alone, results in a reduced fungal burden in organs, as well as in the gastrointestinal tract in the DSS (Dextran Sulfate Sodium)-induced colitis model. Similarly, the defect in persistence in macrophages and attenuated adhesion to epithelial cells are observed when FUS3 and KSS1 are both disrupted. The fus3 kss1 double mutant also displays defects in the induction of virulence attributes such as genes required for iron acquisition and adhesion and in the anti-fungal drug tolerance. The putative downstream transcription factors Ste12 (1), Ste12 (2), Tec1, and Tec2 are found to be involved in the regulation of these virulence attributes. Collectively, our study indicates that an evolutionary conserved MAPK pathway, which regulates mating and filamentous growth in Saccharomyces cerevisiae, is critical for C. glabrata pathogenicity.

Importance: The MAPK signaling pathway, mediated by closely related kinases Fus3 and Kss1, is crucial for controlling mating and filamentous growth in Saccharomyces cerevisiae, but this pathway does not significantly impact hyphal development and pathogenicity in Candida albicans, a commensal-pathogenic fungus of humans. Furthermore, deletion of Cpk1, the ortholog of Fus3 in pathogenic fungus Cryptococcus neoformans, has no effect on virulence. Here, we demonstrate that the MAPK pathway is crucial for the pathogenicity of Candida glabrata, a fungus that causes approximately one-third of cases of hematogenously disseminated candidiasis in the United States. This pathway regulates multiple virulence attributes including the induction of iron acquisition genes and adhesins, as well as persistence in macrophages and organs. Our work provides insights into C. glabrata pathogenesis and highlights an example in which regulatory rewiring of a conserved pathway confers a virulent phenotype in a pathogen.

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体内 RNA 测序揭示了 Fus3-Kss1 MAPK 通路在念珠菌致病性中的关键作用。
光滑念珠菌是一种重要的人类病原体,而且越来越常见,尤其是在免疫力低下的宿主中。尽管如此,人们对这种真菌如何致病却知之甚少。在这里,我们应用 RNA 测序和体内侵袭感染模型来确定这种真菌感染宿主的属性。真菌转录组显示,在入侵感染过程中,两种丝裂原活化蛋白激酶(MAPK)Fus3 和 Kss1 的表达量急剧增加。我们进一步证明,在血清和高二氧化碳条件下,这两种酶都会被高度诱导。在右旋糖酐硫酸钠(DSS)诱导的结肠炎模型中,同时缺失 FUS3 和 KSS1(而非单独缺失这两个基因)会导致器官以及胃肠道中的真菌负担减轻。同样,当 FUS3 和 KSS1 同时被破坏时,巨噬细胞中的持久性缺陷和对上皮细胞的粘附力也会减弱。fus3 kss1 双突变体在诱导毒力属性(如铁获取和粘附所需的基因)和抗真菌药物耐受性方面也表现出缺陷。推测的下游转录因子 Ste12 (1)、Ste12 (2)、Tec1 和 Tec2 参与了这些毒力属性的调控。总之,我们的研究表明,进化保守的 MAPK 通路(调节酿酒酵母的交配和丝状生长)对 C. glabrata 的致病性至关重要:由密切相关的激酶 Fus3 和 Kss1 介导的 MAPK 信号通路对控制酿酒酵母的交配和丝状生长至关重要,但这一通路对白色念珠菌(一种人类共生致病真菌)的菌丝发育和致病性并无显著影响。此外,致病真菌新生隐球菌中 Fus3 的直向同源物 Cpk1 的缺失对致病性也没有影响。在这里,我们证明了 MAPK 通路对于光滑念珠菌的致病性至关重要,这种真菌导致了美国约三分之一的血源性播散念珠菌病病例。该途径调节多种致病性属性,包括诱导铁获取基因和粘附蛋白,以及在巨噬细胞和器官中的持久性。我们的研究深入了解了玻璃样念珠菌的致病机理,并突出展示了一个实例,即保守通路的调控重构赋予病原体一种毒性表型。
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来源期刊
mSphere
mSphere Immunology and Microbiology-Microbiology
CiteScore
8.50
自引率
2.10%
发文量
192
审稿时长
11 weeks
期刊介绍: mSphere™ is a multi-disciplinary open-access journal that will focus on rapid publication of fundamental contributions to our understanding of microbiology. Its scope will reflect the immense range of fields within the microbial sciences, creating new opportunities for researchers to share findings that are transforming our understanding of human health and disease, ecosystems, neuroscience, agriculture, energy production, climate change, evolution, biogeochemical cycling, and food and drug production. Submissions will be encouraged of all high-quality work that makes fundamental contributions to our understanding of microbiology. mSphere™ will provide streamlined decisions, while carrying on ASM''s tradition for rigorous peer review.
期刊最新文献
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