Journal Article

Mucoricin is a ricin-like toxin that is critical for the pathogenesis of mucormycosis

Soliman, Sameh S. M., Hotopp, Julie Dunning, Youssef, Eman G., Gu, Yiyou, Alkhazraji, Sondus, Chamilos, Georgios, Perske, Christina, Swidergall, Marc, Filler, Scott G., Ibrahim, Ashraf S., Edwards, John E., Venkataramani, Vivek, Baldin, Clara, Gebremariam, Teclegiorgis, Alqarihi, Abdullah, Rich, Abigail, Pikoulas, Antonis, Singh, Shakti, Vitetta, Ellen S., Mantis, Nicolas J., Bruno, Vincent M.

2021

Overview

Fungi of the order Mucorales cause mucormycosis, a lethal infection with an incompletely understood pathogenesis. We demonstrate that Mucorales fungi produce a toxin, which plays a central role in virulence. Polyclonal antibodies against this toxin inhibit its ability to damage human cells in vitro and prevent hypovolemic shock, organ necrosis and death in mice with mucormycosis. Inhibition of the toxin in Rhizopus delemar through RNA interference compromises the ability of the fungus to damage host cells and attenuates virulence in mice. This 17 kDa toxin has structural and functional features of the plant toxin ricin, including the ability to inhibit protein synthesis through its N -glycosylase activity, the existence of a motif that mediates vascular leak and a lectin sequence. Antibodies against the toxin inhibit R. delemar- or toxin-mediated vascular permeability in vitro and cross react with ricin. A monoclonal anti-ricin B chain antibody binds to the toxin and also inhibits its ability to cause vascular permeability. Therefore, we propose the name ‘mucoricin’ for this toxin. Not only is mucoricin important in the pathogenesis of mucormycosis but our data suggest that a ricin-like toxin is produced by organisms beyond the plant and bacterial kingdoms. Importantly, mucoricin should be a promising therapeutic target. Mucorales fungi produce a ricin-like toxin, mucoricin, which is required for fungal pathogenesis and represents a potential therapeutic target.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/326/193/2542 / 692/420/254 / Animals / Antitoxins - immunology / Antitoxins - pharmacology / Antitoxins - therapeutic use / Apoptosis / Biomedical and Life Sciences / Capillary Permeability / Cells, Cultured / Cross Reactions / Fungi / Humans / Hyphae - chemistry / Hyphae - pathogenicity / Infectious Diseases / Lectins - metabolism / Life Sciences / Medical Microbiology / Mice / Microbiology / Mucorales / Mucorales - chemistry / Mucorales - classification / Mucorales - genetics / Mucorales - pathogenicity / Mucormycosis / Mucormycosis - microbiology / Mucormycosis - pathology / Mucormycosis - prevention & control / Mycotoxins - chemistry / Mycotoxins - genetics / Mycotoxins - immunology / Mycotoxins - metabolism / N-Glycosylase / Necrosis / Parasitology / Pathogenesis / Permeability / Polyclonal antibodies / Protein biosynthesis / Rhizopus - chemistry / Rhizopus - genetics / Rhizopus - pathogenicity / Ribosome Inactivating Proteins - metabolism / Ricin / Ricin - chemistry / Ricin - immunology / Ricin - metabolism / RNA Interference / RNA-mediated interference / Structure-function relationships / Therapeutic applications / Therapeutic targets / Virology / Virulence / Virulence - drug effects / Virulence - genetics