The role of morphogenesis in the pathogenesis of systemic candidiasis
Final Report Abstract
The ability of C. albicans to switch between the oval yeast form and filamentous growth is thought to be essential for full virulence, as mutants with filamentation defects commonly show reduced capacity to damage host cells in vitro and have been reported to be less virulent in systemically infected mice. However, there are some notable exceptions, for example deletion of EED1, resulting in severely impaired in filamentation maintenance, significantly less epithelial cell damage in vitro, and attenuation in a murine intraperitoneal infection model, whereas virulence upon systemic (i.v.) infection in mice is not impaired. This raised the question why mice infected with an EED1 mutant die and if pathogenesis differs from systemic candidiasis in wild type infected animals. Using both deletion mutants and mutants in which expression of the gene of interest is under control of a tetracycline-regulable promoter system, we could demonstrate that the effects of filamentation depend on the target gene: While morphological flexibility driven by NRG1 significantly affects virulence, this is not the case for EED1. Retained virulence in the absence of filamentation driven by EED1 coincides with (i) the absence of any defects in stress responses in vitro, (ii) increased fungal proliferation in vivo, and (iii) initially reduced immune responses that increase at later time points likely due to higher fungal numbers. Our data furthermore indicate that renal damage does not depend on filamentation and that fungal proliferation (in combination with immune cell infiltration) is sufficient to damage renal tissue and lead to renal failure, thus leading to pathology indistinguishable from that caused by filamentous isogenic strains. These findings provide an explanation why non-filamentous yeast species can cause lethal infections in some patients: It appears that the ability of the host to control fungal proliferation is critical, and as in murine models even immunocompromised animals eventually clear infections with non-filamentous species such as C. glabrata, this might explain while these yeast due not cause mortality in animal models. The molecular mechanisms facilitating enhanced growth of EED1 deficient strains in vivo could not be fully clarified, but the better growth of EED1 deficient strains on carbon sources relevant in vivo, such as lactate, citrate, and amino acids, suggest metabolic adaptation as one important factor. Furthermore, farnesol production might play a role: Unexpectedly, we discovered a link between Eed1 and farnesol, as EED1 deficient strains are both hypersensitive to the filamentinhibiting effects of farnesol and produce larger amounts of this Quorum sensing molecule. Genetic approaches revealed that farnesol hypersensitivity in eed1Δ is independent of the known pathways mediating farnesol effects, thereby raising new questions about farnesol signaling in this yeast. Farnesol could influence virulence by both its filament-inhibitory function and its impact on host cells; to decipher the exact role of farnesol for virulence and its contribution to the in vivo phenotype of EED1 deficient strains thus requires further experimental approaches.
Publications
- (2017) A Flow-assay for Farnesol Removal from Adherent Candida albicans Cultures. Bio-protocol 7(19), e2562
Polke M, Jacobsen I
(See online at https://doi.org/10.21769/BioProtoc.2562) - (2017) A functional link between hyphal maintenance and quorum sensing in Candida albicans. Mol Microbiol 103(4), 595-617
Polke M, Sprenger M, Scherlach K, Albán-Proaño MC, Martin R, Hertweck C, Hube B, Jacobsen ID
(See online at https://doi.org/10.1111/mmi.13526) - (2017) Farnesol signalling in Candida albicans - more than just communication. Crit Rev Microbiol 44(2), 230-243
Polke M, Leonhardt I, Kurzai O, Jacobsen ID
(See online at https://doi.org/10.1080/1040841X.2017.1337711) - (2017) Quorum sensing by farnesol revisited. Curr Genet 63(5), 791-797
Polke M, Jacobsen ID
(See online at https://doi.org/10.1007/s00294-017-0683-x)
