Cooperative Role of MAPK Pathways in the Interaction of Candida albicans with the Host Epithelium

Abstract

Candida albicans is an important human fungal pathogen responsible for tens of millions of infections as well as hundreds of thousands of severe life-threatening infections each year. MAP kinase (MAPK) signal transduction pathways facilitate the sensing and adaptation to external stimuli and control the expression of key virulence factors such as the yeast-to-hypha transition, the biogenesis of the cell wall, and the interaction with the host. In the present study, we have combined molecular approaches and infection biology to analyse the role of C. albicans MAPK pathways during an epithelial invasion. Hog1 was found to be important for adhesion to abiotic surfaces but was dispensable for damage to epithelial cells. The Mkc1 cell wall integrity (CWI) and Cek1 pathways, on the other hand, were both required for oral epithelial damage. Analysis of the ability to penetrate nutrient-rich semi-solid media revealed a cooperative role for Cek1 and Mkc1 in this process. Finally, cek2Δ (as well as cek1Δ) but not mkc1Δ or hog1Δ mutants, exhibited elevated β-glucan unmasking as revealed by immunofluorescence studies. Therefore, the four MAPK pathways play distinct roles in adhesion, epithelial damage, invasion and cell wall remodelling that may contribute to the pathogenicity of C. albicans.

Characterization of a Candida albicans Mutant Defective in All MAPKs Highlights the Major Role of Hog1 in the MAPK Signaling Network

“…Previous studies by our group and others have revealed the crucial role that efficient MAPK-mediated signaling plays in response to stress. In order to understand and uncover putative crosstalk between MAPKs, we expanded our previously described collection of single- and double-MAPK mutants [ 34 , 37 ] by deleting the remaining MAPKs in order to generate all combinations of triple mutants and a strain defective in all four described MAPKs in this fungus. This strain is viable and does not display evident growth defects under standard laboratory conditions.…”

“…In this work we have generated and characterized strains defective in three or in all four major MAPKs of C. albicans , to further advance our understanding about the complex crosstalk among these pathways [ 33 , 34 , 35 , 55 ]. These mutants allowed us to answer two main questions: Can C. albicans survive without a functional MAPK network?…”

“…Strikingly, cek1 , cek2 and cek1 cek2 double mutants were consistently less susceptible to amphotericin B. Cell wall alterations caused by the deletion of these kinases [ 34 , 37 , 59 ] could alter the accessibility of the antifungal to the membrane. While we cannot discard this, we are more inclined to the hypothesis of a more permeable, loose, and weakened cell wall in cek1/2 mutants.…”

“…Hog1 regulates adaptation to oxidative and osmotic stress [ 15 , 25 , 26 ], Mkc1 is involved in cell wall construction (cell integrity pathway) [ 27 ] and invasion of solid surfaces [ 28 ], Cek1 is implicated in cell wall biogenesis [ 29 , 30 , 31 ], while Cek2 is involved in mating [ 32 ]. However, the interconnections among these pathways are frequent and increase the plasticity and complexity of the response [ 33 , 34 , 35 ]. For example, Mkc1, like Hog1, is also phosphorylated in response to oxidative stress [ 36 ].…”

Candida Albicans Virulence Factors and Its Pathogenicity

“…MAP kinase (MAPK) signal transduction pathways facilitate the sensing and adaptation of C. albicans cells to external stimuli and control the expression of key virulence factors such as the yeast-to-hypha transition, the biogenesis of the cell wall, and the interaction with the host. Correia et al [ 14 ] demonstrated that the four MAPK pathways play distinct roles in adhesion, epithelial damage, invasion, and cell wall remodelling that may contribute to the pathogenicity of C. albicans . The behaviour of C. albicans on simulated human body fluids (artificial saliva and urine) at different values of pH (pH 5.8 and 7) was analysed by Barbosa et al [ 15 ].…”