Abstract
Many pathogens (virus, bacteria, fungi, or parasites) have developed a wide variety of mechanisms to evade their host immune system. The budding yeast Saccharomyces cerevisiae has successfully been used to decipher some of these immune evasion strategies. This includes the cis-acting mechanism that limits the expression of the oncogenic Epstein–Barr virus (EBV)-encoded EBNA1 and thus of antigenic peptides derived from this essential but highly antigenic viral protein. Studies based on budding yeast have also revealed the molecular bases of epigenetic switching or recombination underlying the silencing of all except one members of extended families of genes that encode closely related and highly antigenic surface proteins. This mechanism is exploited by several parasites (that include pathogens such as Plasmodium, Trypanosoma, Candida, or Pneumocystis) to alternate their surface antigens, thereby evading the immune system. Yeast can itself be a pathogen, and pathogenic fungi such as Candida albicans, which is phylogenetically very close to S. cerevisiae, have developed stealthiness strategies that include changes in their cell wall composition, or epitope-masking, to control production or exposure of highly antigenic but essential polysaccharides in their cell wall. Finally, due to the high antigenicity of its cell wall, yeast has been opportunistically exploited to create adjuvants and vectors for vaccination.
Highlights
Gaëlle Angrand 1, Alicia Quillévéré 1, Nadège Loaëc 1, Chrysoula Daskalogianni 2, Anton Granzhan 3, Marie-Paule Teulade-Fichou 3, Robin Fahraeus 2, Rodrigo Prado Martins 2,4, * and Marc Blondel 1, *
The fungal cell wall, which plays an essential role in fungal morphogenesis and resistance to osmotic shock, represents around 30% of the yeast cell dry weight, up to 50% of the cell volume and polysaccharides represent over 90% of its components
Another use of yeast as a biotechnological tool is the production of recombinant Epstein–Barr virus (EBV) protein for use as an EBV vaccine
Summary
Yeast has been a popular and powerful model to study basic cell biology mechanisms that include DNA replication [1] and transcription [2], cell cycle regulation [3], vesicular transport [4], autophagy [5], and cell death [6]. This way, nucleolin (Nsr1p in yeast, NCL in humans) was identified (Figure 2C, bottom) as the first host cell factor critically involved in EBNA1/EBV immune evasion In both the yeast model and human cells, overexpression of nucleolin exacerbated the inhibitory effect of GAr on translation whereas its down-regulation led to alleviation of this effect and of GAr-based limitation of antigen presentation by the MHC class I. The cellular NCL protein binds to G-quadruplex (G4) that form in the GAr-encoding sequence of the viral EBNA1 mRNA, thereby leading to inhibition of the translation of the latter, leading to a limited production of EBNA1-derived antigenic peptides and this way to immune evasion of EBV-infected cells. S. cerevisiae provided a model mechanism for the role of DNA recombination which seems especially important for the epigenetic switching within MSG genes in Pneumocystis in which the expression site determines the expressed variant [71,72]
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