RNA sequencing reveals a crucial role of Fus3-Kss1 MAPK pathway in pathogenicity.

mSphere

Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, China.

Published: November 2024

AI Article Synopsis

  • The study focuses on a pathogenic fungus that poses significant risks to immunocompromised individuals, aiming to understand how it causes disease by examining fungal gene expression during infection.* -
  • Researchers found that the expression of two specific MAPK proteins, Fus3 and Kss1, greatly increases during infection, and deleting both genes simultaneously reduces fungal presence in the host's organs and gut.* -
  • The findings suggest that this MAPK signaling pathway is essential for the fungus's ability to persist and exhibit virulence, highlighting its importance in the organism's pathogenic capabilities.*

Article Abstract

Unlabelled: 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 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 CO conditions. Deletion of both and , 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 and are both disrupted. The 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 , is critical for pathogenicity.

Importance: The MAPK signaling pathway, mediated by closely related kinases Fus3 and Kss1, is crucial for controlling mating and filamentous growth in , but this pathway does not significantly impact hyphal development and pathogenicity in , a commensal-pathogenic fungus of humans. Furthermore, deletion of Cpk1, the ortholog of Fus3 in pathogenic fungus , has no effect on virulence. Here, we demonstrate that the MAPK pathway is crucial for the pathogenicity of , 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 pathogenesis and highlights an example in which regulatory rewiring of a conserved pathway confers a virulent phenotype in a pathogen.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11580445PMC
http://dx.doi.org/10.1128/msphere.00715-24DOI Listing

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