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- Title
Candida albicans' inorganic phosphate transport and evolutionary adaptation to phosphate scarcity.
- Authors
Acosta-Zaldívar, Maikel; Qi, Wanjun; Mishra, Abhishek; Roy, Udita; King, William R.; Li, Yuping; Patton-Vogt, Jana; Anderson, Matthew Z.; Köhler, Julia R.
- Abstract
Phosphorus is essential in all cells' structural, metabolic and regulatory functions. For fungal cells that import inorganic phosphate (Pi) up a steep concentration gradient, surface Pi transporters are critical capacitators of growth. Fungi must deploy Pi transporters that enable optimal Pi uptake in pH and Pi concentration ranges prevalent in their environments. Single, triple and quadruple mutants were used to characterize the four Pi transporters we identified for the human fungal pathogen Candida albicans, which must adapt to alkaline conditions during invasion of the host bloodstream and deep organs. A high-affinity Pi transporter, Pho84, was most efficient across the widest pH range while another, Pho89, showed high-affinity characteristics only within one pH unit of neutral. Two low-affinity Pi transporters, Pho87 and Fgr2, were active only in acidic conditions. Only Pho84 among the Pi transporters was clearly required in previously identified Pi-related functions including Target of Rapamycin Complex 1 signaling, oxidative stress resistance and hyphal growth. We used in vitro evolution and whole genome sequencing as an unbiased forward genetic approach to probe adaptation to prolonged Pi scarcity of two quadruple mutant lineages lacking all 4 Pi transporters. Lineage-specific genomic changes corresponded to divergent success of the two lineages in fitness recovery during Pi limitation. Initial, large-scale genomic alterations like aneuploidies and loss of heterozygosity eventually resolved, as populations gained small-scale mutations. Severity of some phenotypes linked to Pi starvation, like cell wall stress hypersensitivity, decreased in parallel to evolving populations' fitness recovery in Pi scarcity, while severity of others like membrane stress responses diverged from Pi scarcity fitness. Among preliminary candidate genes for contributors to fitness recovery, those with links to TORC1 were overrepresented. Since Pi homeostasis differs substantially between fungi and humans, adaptive processes to Pi deprivation may harbor small-molecule targets that impact fungal growth, stress resistance and virulence. Author summary: Fungi must be able to access enough phosphate in order to invade the human body. Virulence of Candida albicans, the most common invasive human fungal pathogen, is known to decrease when one of the proteins that brings phosphate into the fungal cell, called Pho84, is disabled. We identified three more proteins in C. albicans that transport phosphate into the cell. We found that Pho84 plays the largest role among them across the broadest range of environmental conditions. After eliminating all 4 of these transporters, we let two resulting mutants evolve for two months in limited phosphate and analyzed the growth and stress resistance of the resulting populations. We analyzed genomes of representative populations and found that early adaptations to phosphate scarcity occurred together with major changes to chromosome configurations. In later stages of the adaptation process, these large-scale changes disappeared as populations gained small-scale mutations that increased cells' ability to grow in limited phosphate. Some but not all of these favorable mutations improved resistance of evolving populations to stressors like membrane- and cell wall stress. Pinpointing distinct mutation combinations that affect stress resistance differently in populations adapting to scarce phosphate, may identify useful antifungal drug targets.
- Subjects
WHOLE genome sequencing; CONCENTRATION gradient; CANDIDA albicans; DRUG target; OXIDATIVE stress; FUNGAL growth
- Publication
PLoS Genetics, 2024, Vol 20, Issue 8, p1
- ISSN
1553-7390
- Publication type
Article
- DOI
10.1371/journal.pgen.1011156