Mucoricin is a ricin-like toxin that is critical for the pathogenesis of mucormycosis
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...
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| Published in | Nature microbiology Vol. 6; no. 3; pp. 313 - 326 |
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| Main Authors | , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
London
Nature Publishing Group UK
01.03.2021
Nature Publishing Group |
| Subjects | |
| Online Access | Get full text |
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| Summary: | 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. |
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| Bibliography: | Equal contribution Author contributions S.S.M.S. conceived, designed and performed studies to purify and identify the toxin, and screen its activity in vitro and in vivo and wrote the manuscript. C.B. generated mucoricin mutants and characterized their virulence in vitro and in vivo and conducted the antibody efficacy studies. Y.G. helped in animal studies, conducted confocal microscopy, cross reactivity studies, and RIP activity studies. S.S. designed and performed homology modeling, cross reactivity studies, and toxin secretion studies. T.G. helped in the animal studies. M.S. performed the necrosis/apoptosis assay and the mouse immunohistochemistry studies. A.A. performed permeability studies, E.G.Y. performed sequence alignment and gene ontology studies. S.A. purified recombinant toxin and polyclonal antibodies. A.P. and G.C. provided and performed the human immunohistochemistry studies. C.P. and V.V. performed and interpreted the mouse histology studies. AR carried out studies on cross-reactivity of mucoricin and ricin. V.M.B. and J.D.H. performed phylogenetic studies and blast search of mucoricin in Mucorales. N.J.M. generated and characterized the 8A1 monoclonal antibody. J.E.E. and S.G.F. provided intellectual advice, designed studies, and edited the manuscript. E.S.V. conceived, designed and carried out studies of cross reactivity, provided reagents and expertise on ricin and helped write the manuscript. A.S.I. conceived, designed, coordinated and supervised the studies, performed experiments, analyzed data, and wrote the manuscript along with comments from co-authors. |
| ISSN: | 2058-5276 2058-5276 |
| DOI: | 10.1038/s41564-020-00837-0 |