bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2024.02.27.582329

The amino acid permease Byc1 is involved in calcineurin-dependent thermos-tolerance in Cryptococcus neoformans

Lee, K.-T.·Giner, M.·Bahn, D.·Cornitius, C. P.·Lee, S. C.
View original source ↗Export metadata ↓

Abstract

Cryptococcosis is one of the most serious infectious fungal diseases. It is known to infect the human respiratory tract and central nervous system and cause meningitis and encephalitis, especially in patients with AIDS. In the sub-Saharan area, cryptococcosis causes more mortality than tuberculosis. Cryptococcus neoformans is the etiological agent. There has been a growing number of reports of antifungal resistance in C. neoformans, and this fungus is also primarily resistant to the newest antifungal drug class, the echinocandins. Despite advances in modern medicine, the morbidity and mortality of C. neoformans infections remain unacceptably high. In C. neoformans, calcineurin, a serine/threonine phosphatase, is required for growth at the human host temperature, and calcineurin mutants are not virulent in murine models of cryptococcal meningitis. Therefore, calcineurin has long been considered an antifungal target. However, calcineurin is highly conserved in fungi and humans, and thus direct pharmacological inhibition of calcineurin can risk lowering host immunity as the human calcineurin is required for T-cell responses. A previous study demonstrated that there is a link between calcineurin, an amino acid permease, and protein kinase As in Mucorales. In this study, we further reveal the existence of a novel link between calcineurin and an amino acid permease, Byc1, for a thermo-tolerance phenotype in this fungus. We found that calcineurin negatively regulates the expression of the BYC1 gene and that byc1{Delta} mutants are partially resistant to FK506. Moreover, we revealed that overexpression of the BYC1 gene recapitulates the calcineurin mutants thermos-sensitive phenotypes, including FK506 sensitivity and lowered virulence in a murine infection model. We also found that protein kinase A (Pka1) mutants are also partially resistant to FK506. These results support the link between calcineurin, Byc1, and Pka1 in C. neoformans and will serve as a platform for developing novel antifungal drugs against the calcineurin pathway without directly targeting the phosphatase.

Explore related subjects

microbiologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Lee, K.-T., Giner, M., Bahn, D., Cornitius, C. P., Lee, S. C.. 2024-02-28. The amino acid permease Byc1 is involved in calcineurin-dependent thermos-tolerance in Cryptococcus neoformans. https://doi.org/10.1101/2024.02.27.582329

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

A population-scale landscape of the subgingival microbiome reveals divergent routes to periodontal dysbiosis

Periodontitis is an archetypical mucosal inflammatory disease in which microbiome dysbiosis at the tooth-epithelial interface interacts with host genetic and behavioral risk factors to drive immune-mediated tissue destruction. Although subgingival microbiome compositional shifts are thought to parallel disease severity, microbiome variation at the population-level and its relationship to periodontal clinical phenotypes and disease-modifying factors remain poorly defined. Here, we use unsupervised manifold learning to map the compositional landscape of the subgingival microbiome in 1,355 adults spanning periodontal health to severe periodontitis. We identified eight latent microbiome states organized along a branching continuum from eubiosis to dysbiosis. An intermediate microbial configuration marked ecological destabilization and bifurcation into two distinct periodontitis-associated dysbiotic trajectories, distinguished by links to gingival inflammation and smoking. Although the microbiome trajectories broadly tracked periodontal destruction, a minority of individuals showed discordant microbiome-clinical phenotypes, with some individuals with periodontitis retaining otherwise eubiotic microbiomes enriched for low-abundance pathobionts, while some cases of health or mild disease had highly dysbiotic communities, suggesting distinct host susceptibility. Together, these findings define a population-scale ecological landscape of the subgingival microbiome, reveal divergent trajectories to periodontal dysbiosis, and highlight heterogeneity in the relationship between microbial community structure and clinical disease expression.

microbiology↗
bioRxiv2026

The iron-binding siderophore enterobactin is required for the response of multi-drug resistant Klebsiella pneumoniae to zinc limitation

To persist during infection Klebsiella pneumoniae must overcome nutrient iron and zinc limitation imposed by the host immune system through a process called nutritional immunity. Secreted small molecule siderophores are a major virulence determinant of Klebsiella pneumoniae pathogenesis and are presumed to overcome nutritional immunity by binding iron for bacterial acquisition. In this work, we set out to identify how a multi-drug resistant K. pneumoniae grows in zinc limited environments. Using unbiased transcriptomics, proteomics, and an arrayed transposon screen, we identified that synthesis and uptake of the siderophore enterobactin is required to allow for growth in low zinc conditions. Iron-specific chelators did not replicate this phenotype and addition of supplemental iron through heme in growth media could not complement severe growth defects of enterobactin mutant K. pneumoniae experiencing zinc limitation. Finally, zinc starvation induced enterobactin production independent of the canonical zinc uptake regulator (Zur) transcription factor suggesting an unidentified regulatory mechanism by which Gram-negative pathogens may respond to zinc stress. Together, these studies expand the role of enterobactin beyond iron regulation and highlight a previously unreported link between iron and zinc homeostasis in Klebsiella pneumoniae.

microbiology↗
bioRxiv2026

A microbiota-derived protease links phage susceptibility to host epithelial responses

Bacteriophages are major ecological drivers of gut microbial ecology, yet whether bacterial mechanisms that determine phage susceptibility have consequences for the mammalian host remains poorly understood. Here, we identify dipeptidyl peptidase 11 (Dpp11a), the predominant active serine protease of the prevalent gut commensal Phocaeicola vulgatus, as an unexpected bacterial defence factor. Dpp11a protects against environmental proteases and confers resistance to bacteriophage infection. Metatranscriptomic analyses further reveal increased expression of both dpp11a and P. vulgatus-associated phage transcripts in ulcerative colitis stool samples, indicating that both components of this interaction are transcriptionally active in disease-associated human microbiomes. Using the microfluidic gut-on-a-chip co-culture model HuMiX, we show that the absence of Dpp11 is accompanied by altered epithelial tight-junction remodelling during phage-bacterial infection. Together, our findings reveal that the consequences of bacterial phage defence can extend beyond phage-bacterium interactions to the mammalian epithelium.

microbiology↗