&lt;em&gt;&lt;/em&gt;&lt;em&gt;Candida albicans &lt;/em&gt;Morphology Dependent Host FGF-2 Response as a Potential Therapeutic Target

Vellanki, Sandeep; Huh, Eun Young; Saville, Stephen P.; Lee, Soo Chan

doi:10.20944/preprints201902.0025.v1

Cited by 4 publications

References 48 publications

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A novel resistance pathway for calcineurin inhibitors in the human pathogenic MucoralesMucor circinelloides

Vellanki

Billmyre

Lorenzen

et al. 2019

Preprint

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24Mucormycosis is an emerging lethal fungal infection in immunocompromised 25 patients. Mucor circinelloides (Mucor) is a causal agent of mucormycosis and serves as 26 a model system to understand genetics in Mucorales. Calcineurin is a conserved 27 virulence factor in many pathogenic fungi and calcineurin inhibition or deletion of the 28 calcineurin regulatory subunit (CnbR) in Mucor results in a shift from hyphal to yeast 29 growth. We analyzed thirty-six calcineurin inhibitor resistant or bypass mutants that 30 exhibited hyphal growth in the presence of calcineurin inhibitors or in the yeast-locked 31 cnbR mutant background without carrying any mutations in known calcineurin 32 components. We found that a majority of the mutants had altered sequence in a gene, 33 named here bycA (bypass of calcineurin A). bycA encodes an amino acid permease. 34 We verified that both bycA, and the bycA cnbR double mutant are resistant to the 35 calcineurin inhibitor FK506, thereby demonstrating a novel resistance mechanism 36 against calcineurin inhibitors. We also found that the expression of bycA was 37 significantly higher in the wild type with FK506 and in the cnbR mutants, but 38 significantly lower in the wild type without FK506. These findings suggest that bycA is a 39 negative regulator of hyphal growth and/or a positive regulator of yeast growth in Mucor 40 and calcineurin suppresses the bycA gene at the mRNA level to promote hyphal growth. 41BycA is involved in the Mucor hyphal-yeast transition as our data demonstrates a 42 positive correlation between bycA expression, protein kinase A activity, and Mucor 43 yeast-growth. Also, calcineurin activity rather than hyphal morphology primarily 44 contributes to virulence traits including phagosome maturation blockade, host cell 45 damages, and pro-angiogenic growth factor induction during interactions with hosts. 46 3 Importance 47 Mucor is intrinsically resistant to most known antifungals, which makes 48 mucormycosis treatment challenging. Calcineurin is a serine/threonine phosphatase 49 widely conserved across eukaryotes. When calcineurin function is inhibited in Mucor, 50 growth shifts to a less-virulent yeast growth form which makes calcineurin an attractive 51 target for development of new antifungal drugs. Previously we identified two distinct 52 mechanisms through which Mucor can become resistant to calcineurin inhibitors 53 involving Mendelian mutations in the gene for FKBP12, calcineurin A or B subunits and 54 epimutations silencing the FKBP12 gene. Here, we identified a third novel mechanism 55 where loss of function mutations in the amino acid permease encoding the bycA gene 56 contribute to resistance against calcineurin inhibitors. When calcineurin activity is 57 absent, BycA can activate PKA to promote yeast growth via a cAMP-independent 58 pathway. Our data also shows that calcineurin activity, not morphology, primarily 59 contributes to host -pathogen interactions in the pathogenesis of Mucor. 60 61 62

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A novel resistance pathway for calcineurin inhibitors in the human pathogenic MucoralesMucor circinelloides

Vellanki

Billmyre

Lorenzen

et al. 2019

Preprint

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The Mycobiome: Cancer Pathogenesis, Diagnosis, and Therapy

Gamal

Elshaer

Alabdely

et al. 2022

Cancers

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Cancer is among the leading causes of death globally. Despite advances in cancer research, a full understanding of the exact cause has not been established. Recent data have shown that the microbiome has an important relationship with cancer on various levels, including cancer pathogenesis, diagnosis and prognosis, and treatment. Since most studies have focused only on the role of bacteria in this process, in this article we review the role of fungi—another important group of the microbiome, the totality of which is referred to as the “mycobiome”—in the development of cancer and how it can impact responses to anticancer medications. Furthermore, we provide recent evidence that shows how the different microbial communities interact and affect each other at gastrointestinal and non-gastrointestinal sites, including the skin, thereby emphasizing the importance of investigating the microbiome beyond bacteria.

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Transcriptomic Analysis of Long Non-Coding RNA during Candida albicans Infection

Gonçalves

Poloni

Dorn

2023

Genes

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Candida albicans is one of the most commonly found species in fungal infections. Due to its clinical importance, molecular aspects of the host immune defense against the fungus are of interest to biomedical sciences. Long non-coding RNAs (lncRNAs) have been investigated in different pathologies and gained widespread attention regarding their role as gene regulators. However, the biological processes in which most lncRNAs perform their function are still unclear. This study investigates the association between lncRNAs with host response to C. albicans using a public RNA-Seq dataset from lung samples of female C57BL/6J wild-type Mus musculus with induced C. albicans infection. The animals were exposed to the fungus for 24 h before sample collection. We selected lncRNAs and protein-coding genes related to the host immune response by combining the results from different computational approaches used for gene selection: differential expression gene analysis, co-expression genes network analysis, and machine learning-based gene selection. Using a guilt by association strategy, we inferred connections between 41 lncRNAs and 25 biological processes. Our results indicated that nine up-regulated lncRNAs were associated with biological processes derived from the response to wounding: 1200007C13Rik, 4833418N02Rik, Gm12840, Gm15832, Gm20186, Gm38037, Gm45774, Gm4610, Mir22hg, and Mirt1. Additionally, 29 lncRNAs were related to genes involved in immune response, while 22 lncRNAs were associated with processes related to reactive species production. These results support the participation of lncRNAs during C. albicans infection, and may contribute to new studies investigating lncRNA functions in the immune response.

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<em></em><em>Candida albicans </em>Morphology Dependent Host FGF-2 Response as a Potential Therapeutic Target

Cited by 4 publications

References 48 publications

A novel resistance pathway for calcineurin inhibitors in the human pathogenic MucoralesMucor circinelloides

A novel resistance pathway for calcineurin inhibitors in the human pathogenic MucoralesMucor circinelloides

The Mycobiome: Cancer Pathogenesis, Diagnosis, and Therapy

Transcriptomic Analysis of Long Non-Coding RNA during Candida albicans Infection

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