Candida albicans Cannot Acquire Sufficient Ethanolamine from the Host To Support Virulence in the Absence of <i>De Novo</i> Phosphatidylethanolamine Synthesis

Abstract

<i>Candida albicans</i> mutants for phosphatidylserine (PS) synthase (<i>cho1</i>ΔΔ) and PS decarboxylase (<i>psd1</i>ΔΔ <i>psd2</i>ΔΔ) are compromised for virulence in mouse models of systemic infection and oropharyngeal candidiasis (OPC). Both of these enzymes are necessary to synthesize phosphatidylethanolamine (PE) by the <i>de novo</i> pathway, but these mutants are still capable of growth in culture media, as they can import ethanolamine from media to synthesize PE through the Kennedy pathway. Given that the host has ethanolamine in its serum, the exact mechanism by which virulence is lost in these mutants is not clear. There are two competing hypotheses to explain their loss of virulence. (i) PE from the Kennedy pathway cannot substitute for <i>de novo</i>-synthesized PE. (ii) The mutants cannot acquire sufficient ethanolamine from the host to support adequate PE synthesis. These hypotheses can be simultaneously tested if ethanolamine availability is increased for <i>Candida</i> while it is inside the host. We accomplish this by transcomplementation of <i>C. albicans</i> with the <i>Arabidopsis thaliana</i> serine decarboxylase gene (<i>AtSDC</i>), which converts cytoplasmic serine to ethanolamine. Expression of <i>AtSDC</i> in either mutant restores PE synthesis, even in the absence of exogenous ethanolamine. <i>AtSDC</i> also restores virulence to <i>cho1</i>ΔΔ and <i>psd1</i>ΔΔ <i>psd2</i>ΔΔ strains in systemic and OPC infections. Thus, in the absence of <i>de novo</i> PE synthesis, <i>C. albicans</i> cannot acquire sufficient ethanolamine from the host to support virulence. In addition, expression of <i>AtSDC</i> restores PS synthesis in the <i>cho1</i>ΔΔ mutant, which may be due to causing PS decarboxylase to run backwards and convert PE to PS.