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Genetically Compromising Phospholipid Metabolism Limits Candida albicans’ Virulence

  • Dorothy Wong
  • James Plumb
  • Hosamiddine Talab
  • Mouhamad Kurdi
  • Keshav Pokhrel
  • Peter OelkersEmail author
Original Paper
  • 59 Downloads

Abstract

Perturbing ergosterol synthesis has been previously shown to reduce the virulence of Candida albicans. We tested the hypothesis that further altering cell membrane composition by limiting phospholipid synthesis or remodeling will have the same effect. To model partial inhibition, C. albicans strains independently harboring heterozygous deletion of four genes that encode for enzymes that mediate phospholipid synthesis or modification were generated. Quantitative PCR determined that heterozygous deletion routinely caused a nearly 50% reduction in the respective gene’s transcript abundance. Compensatory increased transcript abundance was only found with the deletion of LRO1, a homolog of phospholipid diacylglycerol acyltransferases. Virulence of the mutants was assayed in a Caenorhabditis elegans host model. Even modestly reduced expression of LRO1, phosphatidylserine synthase (CHO1), and lysophospholipid acyltransferase (LPT1) significantly reduced virulence by 23–38%. Reintroducing a second functional allele, respectively, to all three mutants restored virulence. Heterozygous deletion of SLC1, a homolog of 1-acylglycerol-3-phosphate O-acyltransferases, did not significantly reduce virulence. Electrospray ionization tandem mass spectrometry analysis of phospholipid composition followed by principal component analysis identified comprehensive changes in the LRO1 and CHO1 deletion heterozygotes. Strikingly (p < 0.001), univariate comparisons found that both deletion heterozygotes had 20% more phosphatidylinositol, 75% less lysophosphatidylcholine, and 35% less lysophosphatidylethanolamine compared to wild type. Heterozygous deletion of LPT1 also significantly increased phosphatidylinositol abundance. No growth phenotype, including filamentation, was affected by any mutation. Together, these data predict that even partial pharmacological inhibition of Lro1p, Cho1p, and Lpt1p will limit C. albicans virulence through altering phospholipid composition.

Keywords

Membranes Acyltransferases Phosphatidylserine synthase Heterozygous deletion Electrospray ionization tandem mass spectrometry Caenorhabditis elegans 

Notes

Acknowledgements

D.W. was supported by an Undergraduate Fellowship sponsored by the University of Michigan, Dearborn Office of Research and Sponsored Programs. P.O. received a seed grant from the same office. We thank Ruth Welti and Mary Roth for the mass spectrometry analysis performed at the Kansas Lipidomics Research Center (KLRC). Instrument acquisition and method development at the KLRC were supported by National Science Foundation (NSF) Grants MCB 0455318, MCB 0920663, DBI 0521587, DBI 1228622, Kansas IN BRE (National Institutes of Health Grant P20 RR16475 from the IN BRE program of the National Center for Research Resources), NSF EPS CoR Grant EPS-0236913, Kansas Technology Enterprise Corporation, and Kansas State University.

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

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Supplementary material 3 (PDF 121732 kb)
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Supplementary material 4 (PDF 729 kb)

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© Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.Department of Natural SciencesUniversity of Michigan-DearbornDearbornUSA
  2. 2.Department of Mathematics and StatisticsUniversity of Michigan-DearbornDearbornUSA

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