Fungal biotin homeostasis is essential for immune evasion after macrophage phagocytosis and virulence

Abstract

Biotin is an important cofactor for multiple enzymes in central metabolic processes.While many bacteria and most fungi are able to synthesise biotin de novo, Candida spp. are auxotrophic for this vitamin and thus require efficient uptake systems to facilitate biotin acquisition during infection. Here we show that Candida glabrata and Candida albicans use a largely conserved system for biotin uptake and regulation, consisting of the high-affinity biotin transporter Vht1 and the transcription factor Vhr1. Both species induce expression of biotin-metabolic genes upon in vitro biotin depletion and following phagocytosis by macrophages, indicating low biotin levels in the Candida-containing phagosome. In line with this, we observed reduced intracellular proliferation of both Candida cells pre-starved of biotin and deletion mutants lacking VHR1 or VHT1 genes. VHT1 was essential for the full virulence of C. albicans during systemic mouse infections, and the lack of VHT1 led to reduced fungal burden in C. glabrata-infected brains and C. albicans-infected brains and kidneys. Together, our data suggest a critical role of Vht1-mediated biotin acquisition for C. glabrata and C. albicans during intracellular growth in macrophages and systemic infections. K E Y W O R D S biotin, Candida albicans, Candida glabrata, macrophage, metabolism, virulence

Identification of Essential Genes and Fluconazole Susceptibility Genes inCandida glabrataby ProfilingHermesTransposon Insertions

“…In the four species with duplicates, the ancestral CAGL0K04565g orthologs evolved more than twice as fast as the duplicated CAGL0K04609g orthologs (Supplemental Figure 2), suggesting that the duplicates are more likely to retain the essential function in biotin transport. Recently, individual knockouts of the CAGL0K04565g and CAGL0K04609g genes in C. glabrata showed that only the latter was essential for growth in these conditions (Sprenger et al 2020), thus validating our assessments with transposon mutagenesis.…”

Identification of essential genes and fluconazole resistance genes inCandida glabrataby profiling ofHermestransposon insertions

“…In the four species with duplicates, the ancestral CAGL0K04565g orthologs evolved more than twice as fast as the duplicated CAGL0K04609g orthologs (Supplemental Figure 2), suggesting that the duplicates are more likely to retain the essential function in biotin transport. Recently, individual knockouts of the CAGL0K04565g and CAGL0K04609g genes in C. glabrata showed that only the latter was essential for growth in these conditions (32), thus validating our assessments with transposon mutagenesis.…”

Corrigendum

“…In “Fungal biotin homeostasis is essential for immune evasion after macrophage phagocytosis and virulence”, which was published in Volume 22, Issue 7 July 2020 e13197 (Sprenger et al ., 2020), the authors would like to note that Figure 6a was incorrectly labelled.…”