Secretion of the siderophore rhizoferrin is regulated by the cAMP-PKA pathway and is involved in the virulence of Mucor lusitanicus

• Published in: Scientific reports Vol. 12; no. 1; pp. 10649 - 16
• Main Authors: Alejandre-Castañeda, Viridiana, Patiño-Medina, J. Alberto, Valle-Maldonado, Marco I., Nuñez-Anita, Rosa E., Santoyo, Gustavo, Castro-Cerritos, Karla V., Ortiz-Alvarado, Rafael, Corrales-Escobosa, Alma R., Ramírez-Díaz, Martha I., Gutiérrez-Corona, J. Felix, López-Torres, Adolfo, Garre, Victoriano, Meza-Carmen, Víctor
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23.06.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 631/326; 631/337; Acetylcysteine; Biosynthesis; Cell culture; Cyclic AMP; Diabetes mellitus; Fungal infections; Gene deletion; Glucose metabolism; Humanities and Social Sciences; Hydrogen peroxide; Infections; Macrophages; Metabolism; Mucor; Mucormycosis; multidisciplinary; Oxidative metabolism; Potassium cyanide; Protein kinase A; Science; Science (multidisciplinary); Spores; Toxicity; Virulence factors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-022-14515-0

Mucormycosis is a fungal infection caused by Mucorales, with a high mortality rate. However, only a few virulence factors have been described in these organisms. This study showed that deletion of rfs , which encodes the enzyme for the biosynthesis of rhizoferrin, a siderophore, in Mucor lusitanicus , led to a lower virulence in diabetic mice and nematodes. Upregulation of rfs correlated with the increased toxicity of the cell-free supernatants of the culture broth (SS) obtained under growing conditions that favor oxidative metabolism, such as low glucose levels or the presence of H 2 O 2 in the culture, suggesting that oxidative metabolism enhances virulence through rhizoferrin production. Meanwhile, growing M. lusitanicus in the presence of potassium cyanide, N-acetylcysteine, a higher concentration of glucose, or exogenous cAMP, or the deletion of the gene encoding the regulatory subunit of PKA ( pkaR1 ), correlated with a decrease in the toxicity of SS, downregulation of rfs , and reduction in rhizoferrin production. These observations indicate the involvement of the cAMP-PKA pathway in the regulation of rhizoferrin production and virulence in M. lusitanicus . Moreover, rfs upregulation was observed upon macrophage interaction or during infection with spores in mice, suggesting a pivotal role of rfs in M. lusitanicus infection.