Candida albicans Cannot Acquire Sufficient Ethanolamine from the Host To Support Virulence in the Absence of De Novo Phosphatidylethanolamine Synthesis
Candida albicans Cannot Acquire Sufficient Ethanolamine from the Host To Support Virulence in the Absence of De Novo Phosphatidylethanolamine Synthesis
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DOI：
10.1128/iai.00815-17
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发表时间：
2018-08-01
影响因子：
3.1
通讯作者：
Reynolds, Todd B.
中科院分区：
文献类型：
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作者：
Davis, Sarah E.;Tams, Robert N.;Reynolds, Todd B.
白念珠菌磷脂酰丝氨酸（PS）合酶（cho 1 Delta Delta）和PS脱羧酶（psd 1 Delta Delta psd 2 Delta Delta Delta）突变体在全身感染和口咽念珠菌病（OPC）小鼠模型中的毒力受损。这两种酶都是通过从头途径合成磷脂酰乙醇胺（PE）所必需的，但这些突变体仍然能够在培养基中生长，因为它们可以通过肯尼迪途径从培养基中输入乙醇胺合成PE。由于宿主血清中含有乙醇胺，因此这些突变体丧失毒力的确切机制尚不清楚。有两种相互竞争的假设来解释它们的毒性丧失。(i)来自肯尼迪途径的PE不能替代重新合成的PE。(ii)突变体不能从宿主获得足够的乙醇胺以支持足够的PE合成。这些假设可以同时测试，如果乙醇胺的可用性增加念珠菌，而它是在主机内。我们通过C.白念珠菌与拟南芥丝氨酸脱羧酶基因（AtSDC），该基因将细胞质丝氨酸转化为乙醇胺。AtSDC在任一突变体中的表达恢复PE合成，即使在不存在外源乙醇胺的情况下。AtSDC还在系统性和OPC感染中恢复对cho1 Delta Delta和psd 1 Delta Delta psd 2 Delta Delta Delta菌株的毒力。因此，在没有从头合成PE的情况下，C.白色念珠菌不能从宿主获得足够的乙醇胺以支持毒力。此外，AtSDC的表达恢复了cho1 Delta Delta突变体中的PS合成，这可能是由于导致PS脱羧酶向后运行并将PE转化为PS。
Candida albicans mutants for phosphatidylserine (PS) synthase (cho1 Delta Delta) and PS decarboxylase (psd1 Delta Delta psd2 Delta Delta) 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 de novo 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 de novo-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 Candida while it is inside the host. We accomplish this by transcomplementation of C. albicans with the Arabidopsis thaliana serine decarboxylase gene (AtSDC), which converts cytoplasmic serine to ethanolamine. Expression of AtSDC in either mutant restores PE synthesis, even in the absence of exogenous ethanolamine. AtSDC also restores virulence to cho1 Delta Delta and psd1 Delta Delta psd2 Delta Delta strains in systemic and OPC infections. Thus, in the absence of de novo PE synthesis, C. albicans cannot acquire sufficient ethanolamine from the host to support virulence. In addition, expression of AtSDC restores PS synthesis in the cho1 Delta Delta mutant, which may be due to causing PS decarboxylase to run backwards and convert PE to PS.