Engineered Control of Cell Morphology In Vivo Reveals Distinct Roles for Yeast and Filamentous Forms of Candida albicans during Infection

By S. Saville, A. Lazzell, C. Monteagudo, J. López-Ribot. Eukaryotic Cell, 2003

702 citations recorded by the source corpus.

ABSTRACT It is widely assumed that the ability of Candida albicans to switch between different morphologies is required for pathogenesis. However, most virulence studies have used mutants that are permanently locked into either the yeast or filamentous forms which are avirulent but unsuitable for discerning the role of morphogenetic conversions at the various stages of the infectious process. We have constructed a strain in which this developmental transition can be externally modulated both in vitro and in vivo. This was achieved by placing one copy of the NRG1 gene (a negative regulator of filamentation) under the control of a tetracycline-regulatable promoter. This modified strain was then tested in an animal model of hematogenously disseminated candidiasis. Mice injected with this strain under conditions permitting hyphal development succumbed to the infection, whereas all of the animals injected under conditions that inhibited this transition survived. Importantly, fungal burdens were almost identical in both sets of animals, indicating that, whereas filament formation appears to be required for the mortality resulting from a deep-seated infection, yeast cells play an important role early in the infectious process by extravasating and disseminating to the target organs. Moreover, these infecting Candida yeast cells still retained their pathogenic potential, as demonstrated by allowing this developmental transition to occur at various time points postinfection. We demonstrate here the importance of morphogenetic conversions in C. albicans pathogenesis. This engineered strain should provide a useful tool in unraveling the individual contributions of the yeast and filamentous forms at various stages of the infectious process.

Subfields: Epidemiology, Food Science, Infectious Diseases

View Paper: https://www.semanticscholar.org/paper/c4bd936468ce46477c7d3e5ebd71f90f3f04963f

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In Epidemiology

1. K. Young
2. A. Ibrahim
3. Duncan W. Wilson
4. François L. Mayer
5. Bernhard Hube

In Food Science

1. Duncan W. Wilson
2. François L. Mayer
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In Infectious Diseases

1. K. Young
2. Duncan W. Wilson
3. François L. Mayer
4. Bernhard Hube

Citations in the corpus

• Als3 Is a Candida albicans Invasin That Binds to Cadherins and Induces Endocytosis by Host Cells (2007, background): “The ability to reversibly change between blastospores and hyphae is a key virulence factor for this fungus, and mutants that are unable to form hyphae have greatly attenuated virulence [12,13].”
• The Selective Value of Bacterial Shape (2006, background): “However, the mice survived if they were infected with the yeast form but without subsequent filamentation, even though the livers of these mice were just as packed with fungal cells as were the livers of those mice that died while harboring the hyphal form (286).”
• Candida albicans pathogenicity mechanisms (2013, background): “On the other hand the smaller yeast form is believed to represent the form primarily involved in dissemination.(27) Mutants that are unable to form hyphae under in vitro conditions are generally attenuated in virulence.”
• Dectin‐1 mediates macrophage recognition of Candida albicans yeast but not filaments (2005, background): “…to rapidly and reversibly switch between yeast and filamentous morphologies is cru- cial to pathogenicity, and it is thought that the filamentous morphology provides some advantage during interaction with the mammalian immune system (Lo et al, 1997; Calderone and Fonzi, 2001; Saville et al, 2003).”