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An integrated genomic and transcriptomic survey of mucormycosis-causing fungi.

ABSTRACT: Mucormycosis is a life-threatening infection caused by Mucorales fungi. Here we sequence 30 fungal genomes, and perform transcriptomics with three representative Rhizopus and Mucor strains and with human airway epithelial cells during fungal invasion, to reveal key host and fungal determinants contributing to pathogenesis. Analysis of the host transcriptional response to Mucorales reveals platelet-derived growth factor receptor B (PDGFRB) signaling as part of a core response to divergent pathogenic fungi; inhibition of PDGFRB reduces Mucorales-induced damage to host cells. The unique presence of CotH invasins in all invasive Mucorales, and the correlation between CotH gene copy number and clinical prevalence, are consistent with an important role for these proteins in mucormycosis pathogenesis. Our work provides insight into the evolution of this medically and economically important group of fungi, and identifies several molecular pathways that might be exploited as potential therapeutic targets.

SUBMITTER: Chibucos MC

PROVIDER: S-EPMC4961843 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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An integrated genomic and transcriptomic survey of mucormycosis-causing fungi.

Chibucos Marcus C MC Soliman Sameh S Gebremariam Teclegiorgis T Lee Hongkyu H Daugherty Sean S Orvis Joshua J Shetty Amol C AC Crabtree Jonathan J Hazen Tracy H TH Etienne Kizee A KA Kumari Priti P O'Connor Timothy D TD Rasko David A DA Filler Scott G SG Fraser Claire M CM Lockhart Shawn R SR Skory Christopher D CD Ibrahim Ashraf S AS Bruno Vincent M VM

Nature communications 20160722

Mucormycosis is a life-threatening infection caused by Mucorales fungi. Here we sequence 30 fungal genomes, and perform transcriptomics with three representative Rhizopus and Mucor strains and with human airway epithelial cells during fungal invasion, to reveal key host and fungal determinants contributing to pathogenesis. Analysis of the host transcriptional response to Mucorales reveals platelet-derived growth factor receptor B (PDGFRB) signaling as part of a core response to divergent pathoge ...[more]

PMID: 27447865

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Project description:The Covid-19 associated mucormycosis (CAM) is an emerging disease affecting immunocompromised patients. Prevention of such infections using probiotics and their metabolites persist as effective therapeutic agents. Therefore, the present study emphasizes on assessment of their efficacy and safety. Samples from different sources like human milk, honey bee intestine, toddy, and dairy milk were collected, screened and characterized for potential probiotic lactic acid bacteria (LAB) and their metabolites to be used as effective antimicrobial agents to curtail CAM. Three isolates were selected based on probiotic properties and characterized as Lactobacillus pentosus BMOBR013, Lactobacillus pentosus BMOBR061 and Pediococcus acidilactici BMOBR041 by 16S rRNA sequencing and MALDI TOF-MS. The antimicrobial activity against standard bacterial pathogens showed ˃9 mm zone of inhibition. Furthermore, the antifungal activity of three isolates was tested against Aspergillus flavus MTCC 2788, Fusarium oxysporum, Candida albicans and Candida tropicalis where the results showed significant inhibition of each fungal strain. Further studies were carried out on lethal fungal pathogens like Rhizopus sp. and two Mucor sp. which are associated with post Covid-19 infection in immunosuppressed diabetic patients. Our studies on CAM inhibitory effect of LAB revealed the efficient inhibition against Rhizopus sp. and two Mucor sp. The cell free supernatants of three LAB showed varied inhibitory activity against these fungi. Following the antimicrobial activity, the antagonistic metabolite 3-Phenyllactic acid (PLA) in culture supernatant was quantified and characterized by HPLC and LC-MS using standard PLA (Sigma Aldrich). The isolate L. pentosus BMOBR013 produced highest PLA (0.441 g/L), followed by P. acidilactici BMOBR041 (0.294 g/L) and L. pentosus BMOBR061 (0.165 g/L). The minimum inhibitory concentration of HPLC eluted PLA on the Rhizopus sp. and two Mucor sp. was found to be 180 mg/ml which was further confirmed by inhibition of total mycelia under live cell imaging microscope.

Project description:Mucormycosis is an increasingly common, life-threatening fungal infection caused by fungi belonging to the subphylum Mucormycotina, order Mucorales. The major risk factors for mucormycosis include uncontrolled diabetes mellitus, treatment with corticosteroids, organ or bone marrow transplantation, neutropenia, trauma and burns, malignant hematological disorders, and deferoxamine-therapy in patients receiving hemodialysis. Amphotericin B (AmB) remains the only antifungal agent approved for the treatment of invasive mucormycosis. Because fungi belonging to the mucorales order are relatively resistant to AmB, high doses are required, which frequently causes nephrotoxicity and other adverse effects. In the absence of surgical removal of the infected focus (such as excision of the eye in patients with rhinocerebral mucormycosis), antifungal therapy alone is rarely curative. Even when surgical debridement is combined with high-dose AmB, the mortality associated with mucor¬mycosis is >50%. In patients with prolonged neutropenia or disseminated disease, mortality is 90-100%. Rhizopus oryzae is by far the most common organism isolated from patients with mucormycosis, and is responsible for approximately 70% of all cases of mucormycosis. Recent epidemiological data collected from transplant centers have demonstrated a striking increase in the number of reported cases of mucormycosis. Furthermore, mucormycosis outbreaks are also known to follow natural disasters as was the case following the tsunami that devastated Indonesia in 2004 and the tornadoes that destroyed Joplin, Missouri in June 2011. Hence, there exists a large impetus to identify particular virulence factors and biomarkers associated with mucormycosis, which would lead to a rational approach to develop new antifungals and vaccines to prevent deaths specifically due to mucormycosis. In order to better understand the complex nature of the host pathogen interaction during mucormycosis, we performed dual species RNA-seq on 5 different Mucorales strains during in vitro infection of endothelial or epithelial cells.

Dataset Information

An integrated genomic and transcriptomic survey of mucormycosis-causing fungi.

Publications

An integrated genomic and transcriptomic survey of mucormycosis-causing fungi.

Similar Datasets

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