Vitamin B2 as a virulence factor in Pseudogymnoascus destructans skin infection.
Pathogenic and non-pathogenic related microorganisms differ in secondary metabolite production. Here we show that riboflavin overproduction by a fungal pathogen and its hyperaccumulation in affected host tissue exacerbates a skin infection to necrosis. In white-nose syndrome (WNS) skin lesions caused by Pseudogymnoascus destructans, maximum riboflavin concentrations reached up to 815 μg ml(-1), indicating bioaccumulation and lack of excretion. We found that high riboflavin concentrations are cytotoxic under conditions specific for hibernation, affect bats' primary fibroblasts and induce cell detachment, loss of mitochondrial membrane potential, polymerization of cortical actin, and cell necrosis. Our results explain molecular pathology of WNS, where a skin infection becomes fatal. Hyperaccumulation of vitamin B2 coupled with reduced metabolism and low tissue oxygen saturation during hibernation prevents removal of excess riboflavin in infected bats. Upon reperfusion, oxygen reacts with riboflavin resulting in dramatic pathology after arousal. While multiple molecules enable invasive infection, riboflavin-associated extensive necrosis likely contributes to pathophysiology and altered arousal pattern in infected bats. Bioaccumulation of a vitamin under natural infection represents a novel condition in a complex host-pathogen interplay.
Laboratory of Fungal Genetics and Metabolism, Institute of Microbiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
Miroslav
M
Flieger
Department of Ecology and Diseases of Game, Fish and Bees, University of Veterinary and Pharmaceutical Sciences Brno, Czech Republic.
Hana
H
Bandouchova
Department of Cell Biology, Faculty of Science, Charles University in Prague, Czech Republic.
Jan
J
Cerny
Laboratory of Fungal Genetics and Metabolism, Institute of Microbiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
Milada
M
Chudíčková
Laboratory of Fungal Genetics and Metabolism, Institute of Microbiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
Miroslav
M
Kolarik
Department of Ecology and Diseases of Game, Fish and Bees, University of Veterinary and Pharmaceutical Sciences Brno, Czech Republic.
Veronika
V
Kovacova
Institute of Vertebrate Biology, Academy of Sciences of the Czech Republic, Brno, Czech Republic.
Natália
N
Martínková
Laboratory of Fungal Genetics and Metabolism, Institute of Microbiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
Petr
P
Novák
Department of Cell Biology, Faculty of Science, Charles University in Prague, Czech Republic.
Ondřej
O
Šebesta
Laboratory of Fungal Genetics and Metabolism, Institute of Microbiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
Eva
E
Stodůlková
Department of Ecology and Diseases of Game, Fish and Bees, University of Veterinary and Pharmaceutical Sciences Brno, Czech Republic.
Jiri
J
Pikula
D000818:Animals; D001203:Ascomycota / Q000145:classification / Q000235:genetics / Q000472:pathogenicity*; D002448:Cell Adhesion; D002478:Cells, Cultured; D002685:Chiroptera / Q000382:microbiology*; D003881:Dermatomycoses / Q000382:microbiology*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism / Q000382:microbiology; D054884:Host-Pathogen Interactions; D053078:Membrane Potential, Mitochondrial; D008854:Microscopy, Electron; D010802:Phylogeny; D012256:Riboflavin / Q000378:metabolism*; D037521:Virulence Factors / Q000378:metabolism; D014921:Wings, Animal / Q000166:cytology / Q000382:microbiology* / Q000648:ultrastructure
D037521:Virulence Factors; D012256:Riboflavin