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Subtractive proteomics assisted therapeutic targets mining and designing ensemble vaccine against Candida auris for immune response induction.

ABSTRACT: The emergence of variants and the reports of co-infection caused by Candida auris in COVID-19 patients adds a further complication to the global pandemic situation. To date, no effective therapy is available for C. auris infections. Thus, characterization of therapeutic targets and designing effective vaccine candidates using subtractive proteomics and immune-informatics approaches is useful tool in controlling the emerging infections associated with SARS-CoV-2. In the current study, subtractive proteomics-assisted annotation of the vaccine targets was performed, which revealed seven vaccine targets. An immunoinformatic-driven approach was then employed to map protein-specific and proteome-wide immunogenic peptides (CTL, B cell, and HTL) for the design of multi-epitope vaccine candidates (MEVCs). The results demonstrated that the vaccine candidates possess strong antigenic features (>0.4 threshold score) and are classified as non-allergenic. Validation of the designed MEVCs through molecular docking, in-silico cloning, and immune simulation further demonstrated the efficacy of the vaccines by producing immune factor titers (ranging from 2500 to 16000 au/mL) i.e., IgM, IgG, IL-6, and Interferon-α. In conclusion, the current study provides a strong impetus in designing anti-fungal strategies against Candida auris.

SUBMITTER: Khan T

PROVIDER: S-EPMC8971067 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Subtractive proteomics assisted therapeutic targets mining and designing ensemble vaccine against Candida auris for immune response induction.

Khan Taimoor T Suleman Muhammad M Ali Syed Shujait SS Sarwar Muhammad Farhan MF Ali Imtiaz I Ali Liaqat L Khan Abbas A Rokhan Bakht B Wang Yanjing Y Zhao Ruili R Wei Dong-Qing DQ

Computers in biology and medicine 20220401

The emergence of variants and the reports of co-infection caused by Candida auris in COVID-19 patients adds a further complication to the global pandemic situation. To date, no effective therapy is available for C. auris infections. Thus, characterization of therapeutic targets and designing effective vaccine candidates using subtractive proteomics and immune-informatics approaches is useful tool in controlling the emerging infections associated with SARS-CoV-2. In the current study, subtractive ...[more]

PMID: 35427985

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Project description:Candida auris is a serious health concern of the current world that possesses a serious global health threat and is emerging at a high rate. Available antifungal drugs are failing to combat this pathogen as they are growing resistant to those drugs and some strains have already shown resistance to all three available antifungal drugs in the market. Hence, finding alternative therapies is essential for saving lives from this enemy. To make the development of new treatments easier, we conducted some in silico study of this pathogen to discover possible targets for drug design and also recommended some possible metabolites to test in vivo circumstances. The complete proteome of the representative strain was retrieved, and the duplicate, non-essential, human homologous, non-metabolic, and druggable proteins were then eliminated. As a result, out of a total of 5441 C. auris proteins, we were able to isolate three proteins (XP 028890156.1, XP 028891672.1, and XP 028891858.1) that are crucial for the pathogen's survival as well as host-non-homolog, metabolic, and unrelated proteins to the human microbiome. Their subcellular locations and interactions with a large number of proteins (10 proteins) further point to them being good candidates for therapeutic targets. Following in silico docking of 29 putative antifungals of plant origin against the three proteins we chose, Caledonixanthone E, Viniferin, Glaucine, and Jatrorrhizine were discovered to be the most effective means of inhibiting those proteins since they displayed higher binding affinities (ranging from -28.97 kcal/mol to -51.99 kcal/mol) than the control fluconazole (which ranged between -28.84 kcal/mol and -41.15 kcal/mol). According to the results of MD simulations and MM-PBSA calculations, Viniferin and Caledonixanthone E are the most effective ligands for the proteins XP 028890156.1, XP 028891672.1, and XP 028891858.1. Furthermore, they were predicted to be safe and also showed proper ADME properties.

Project description:Vaccines have always been one of the promising therapeutic sources against many pathogens including infectious fungi. Candida lusitaniae is also one of those fungi which is responsible for different infections in human beings including vaginitis, endocarditis, endophthalmitis and blood stream infections. There is thus, a need to adopt effective therapeutic strategies to tackle such infections. Vaccine is one of those efficient therapeutic agents which stimulates immune response and prevents a certain infection to get hazardous. Keeping in view this very important concept, we have designed in-silico vaccine against C. lusitaniae by following the subtractive proteomics approach. Initially, the screening of therapeutic targets was performed to identify potent vaccine candidates from the whole proteome of C. lusitaniae. Several significant factors were taken into account in this context, such as stability index, IFN status, allergenicity, and antigenicity. As a result, four distinct proteins that were both antigenic and non-allergenic, were selected from the whole proteome. Furthermore, physiochemical investigation revealed that these vaccine candidates were stable and that their IFN status was positive. Notably, each of these proteins was non-homologous to human beings. This particular attribute of the selected proteins i.e., to be non-homologous, was made in order to possess the ability to trigger an immunological response in host (humans). Furthermore, the whole proteome (WP) vaccine was constructed accordingly. The structural modelling of all the selected vaccine candidates was then performed to proceed them further for docking with the human toll-like receptor 2 (TLR2). Afterwards, the codon optimization was executed, followed by in-silico cloning of the final vaccine construct. The pet28A plasmid was incorporated for this purpose while, the SnapGene tool was utilized for this particular analysis. Ultimately, the immune simulations were executed to assess the immune response of the designed vaccine (WP). Upon final results, it was found that highest count of IgG and IgM was achieved i.e., up to 700000 between the days 8 to 13 and then slowly neutralized till the day 30. These results signified that the designed vaccine possessed the potential to stimulate the required immune response.

Project description:Fungal infections are a global threat, but treatments are limited due to a paucity in antifungal drug targets and the emergence of drug-resistant fungi such as Candida auris. Metabolic adaptations enable microbial growth in nutrient-scarce host niches, and they further control immune responses to pathogens, thereby offering opportunities for therapeutic targeting. Because it is a relatively new pathogen, little is known about the metabolic requirements for C. auris growth and its adaptations to counter host defenses. Here, we establish that triggering metabolic dysfunction is a promising strategy against C. auris. Treatment with pyrvinium pamoate (PP) induced metabolic reprogramming and mitochondrial dysfunction evident in disrupted mitochondrial morphology and reduced tricarboxylic acid (TCA) cycle enzyme activity. PP also induced changes consistent with disrupted iron homeostasis. Nutrient supplementation experiments support the proposition that PP-induced metabolic dysfunction is driven by disrupted iron homeostasis, which compromises carbon and lipid metabolism and mitochondria. PP inhibited C. auris replication in macrophages, which is a relevant host niche for this yeast pathogen. We propose that PP causes a multipronged metabolic hit to C. auris: it restricts the micronutrient iron to potentiate nutritional immunity imposed by immune cells, and it further causes metabolic dysfunction that compromises the utilization of macronutrients, thereby curbing the metabolic plasticity needed for growth in host environments. Our study offers a new avenue for therapeutic development against drug-resistant C. auris, shows how complex metabolic dysfunction can be caused by a single compound triggering antifungal inhibition, and provides insights into the metabolic needs of C. auris in immune cell environments. IMPORTANCE Over the last decade, Candida auris has emerged as a human pathogen around the world causing life-threatening infections with wide-spread antifungal drug resistance, including pandrug resistance in some cases. In this study, we addressed the mechanism of action of the antiparasitic drug pyrvinium pamoate against C. auris and show how metabolism could be inhibited to curb C. auris proliferation. We show that pyrvinium pamoate triggers sweeping metabolic and mitochondrial changes and disrupts iron homeostasis. PP-induced metabolic dysfunction compromises the utilization of both micro- and macronutrients by C. auris and reduces its growth in vitro and in immune phagocytes. Our findings provide insights into the metabolic requirements for C. auris growth and define the mechanisms of action of pyrvinium pamoate against C. auris, demonstrating how this compound works by inhibiting the metabolic flexibility of the pathogen. As such, our study characterizes credible avenues for new antifungal approaches against C. auris.

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Subtractive proteomics assisted therapeutic targets mining and designing ensemble vaccine against Candida auris for immune response induction.

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Subtractive proteomics assisted therapeutic targets mining and designing ensemble vaccine against Candida auris for immune response induction.

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