Integrated genomics of Mucorales reveals novel therapeutic targets

Authors: CHIBUCOS, MARCUS - University Of Maryland; SOLIMAN, SAMEH - Harbor-Ucla Medical Center; GHEBREMARIMAM, TECLEGIORGIS - Harbor-Ucla Medical Center; LEE, HONGKYU - Harbor-Ucla Medical Center; DAUGHERTY, SEAN - University Of Maryland; ORVIS, JOSHUA - University Of Maryland; SHETTY, AMOL - University Of Maryland; CRABTREE, JONATHAN - University Of Maryland; HAZEN, TRACY - University Of Maryland; ETIENNE, KIZEE - Centers For Disease Control And Prevention (CDC) - United States; KUMAN, PRITI - University Of Maryland; O'CONNOR, TIMOTHY - University Of Maryland; RASKO, DAVID - University Of Maryland; FILLER, SCOTT - Harbor-Ucla Medical Center; FRAZER, CLAIRE - University Of Maryland; LOCKHART, SHAWN - Centers For Disease Control And Prevention (CDC) - United States; Skory, Christopher - Chris; IBRAHIM, ASHRAF - Harbor-Ucla Medical Center; BRUNO, VINCENT - University Of Maryland

Submitted to: Nature Magazine
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/9/2016
Publication Date: 7/22/2016
Citation: Chibucos, M.C., Soliman, S., Gebremariam, T., Lee, H., Daugherty, S., Orvis, J., Shetty, A.C., Crabtree, J., Hazen, T.H., Etienne, K.A., Kumari, P., O'Connor, T.D., Rasko, D.A., Filler, S.G., Frazer, C.M., Lockhart, S.R., Skory, C.D., Ibrahim, A.S., Bruno, V.M. 2016. An integrated genomic and transcriptomic survey of mucormycosis-causing fungi. Nature Communications. 7:12218. doi: 10.1038/ncomms12218.

Interpretive Summary: Mucorales fungi are an important group of ubiquitous organisms used in a variety of food and industrial applications. However, they are also the cause of infections, called mucormycoses, which more commonly occur in individuals with weakened immune systems, uncontrolled diabetes, trauma and burns, and those receiving hemodialysis. Depending on the fungal strain, infections may result in mortalities greater than 50%. The current standard of care involves the use of aggressive antifungal medications, which have significant side effects, and, in some instances, the surgical removal of the infected tissue. Therefore, it is imperative to better understand the genetic differences between these strains and use this information to identify novel therapeutic targets. In this study, we sequenced thirty fungal genomes and discovered a number of molecular pathways that appear to be important in the infection process. This work provides new knowledge about these medically and economically important fungi and identifies several targets that medical researchers can exploit in the development of innovative treatment methods.

Technical Abstract: Mucormycosis is a life-threatening infection caused by Mucorales fungi. We sequenced 30 fungal genomes and performed transcriptomics with three representative Rhizopus and Mucor strains 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 specifically revealed platelet-derived growth factor receptor B (PDGFRB) signaling as part of a core response to divergent pathogenic fungi and inhibition of PDGFRB reduced Mucorales-induced damage to host cells. The unique presence of the CotH invasins in all invasive Mucorales and the correlation between copy number and clinical prevalence reflects an important role for these proteins in mucormycosis pathogenesis. Our work provides a new framework for understanding the evolution of this medically and economically important group of fungi and identifies a number of molecular pathways that can be exploited to develop novel therapies to treat these invasive fungal infections.