Mucormycosis is a fungal infection of the sinuses, brain, or lungs that causes a mortality rate of at least 50% despite first-line therapy. Because angioinvasion is a hallmark of mucormycosis infections, we sought to define the endothelial cell receptor(s) for fungi of the order Mucorales (the fungi that cause mucormycosis). Furthermore, since patients with elevated available serum iron, including those with diabetic ketoacidosis (DKA), are uniquely susceptible to mucormycosis, we sought to define the role of iron and glucose in regulating the expression of such a receptor. Here, we have identified glucose-regulated protein 78 (GRP78) as what we believe to be a novel host receptor that mediates invasion and damage of human endothelial cells by Rhizopus oryzae, the most common etiologic species of Mucorales, but not Candida albicans or Aspergillus fumigatus. Elevated concentrations of glucose and iron, consistent with those seen during DKA, enhanced GRP78 expression and the resulting R. oryzae invasion and damage of endothelial cells in a receptor-dependent manner. Mice with DKA, which have enhanced susceptibility to mucormycosis, exhibited increased expression of GRP78 in sinus, lungs, and brain compared with normal mice. Finally, GRP78-specific immune serum protected mice with DKA from mucormycosis. These results suggest a unique susceptibility of patients with DKA to mucormycosis and provide a foundation for the development of new therapeutic interventions for these deadly infections.
Mingfu Liu, Brad Spellberg, Quynh T. Phan, Yue Fu, Yong Fu, Amy S. Lee, John E. Edwards Jr., Scott G. Filler, Ashraf S. Ibrahim
Title and authors | Publication | Year |
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Genes, Pathways, and Mechanisms Involved in the Virulence of Mucorales
C Lax, C Pérez-Arques, MI Navarro-Mendoza, JT Cánovas-Márquez, G Tahiri, JA Pérez-Ruiz, M Osorio-Concepción, L Murcia-Flores, E Navarro, V Garre, FE Nicolás |
Genes & development | 2020 |
GRP78 and Integrins Play Different Roles in Host Cell Invasion during Mucormycosis
A Alqarihi, T Gebremariam, Y Gu, M Swidergall, S Alkhazraji, SS Soliman, VM Bruno, JE Edwards, SG Filler, P Uppuluri, AS Ibrahim, JA Alspaugh |
mBio | 2020 |
Iron Assimilation during Emerging Infections Caused by Opportunistic Fungi with emphasis on Mucorales and the Development of Antifungal Resistance
FA Stanford, K Voigt |
Genes & development | 2020 |
It’s all in your head: antifungal immunity in the brain
BD Snarr, RA Drummond, MS Lionakis |
Current Opinion in Microbiology | 2020 |
GRP78 targeting: Hitting two birds with a stone
AA Elfiky, AM Baghdady, SA Ali, MI Ahmed |
Life Sciences | 2020 |
A case of invasive pulmonary mucormycosis resulting from short courses of corticosteroids in a well-controlled diabetic patient
K Hoang, T Abdo, JM Reinersman, R Lu, NI Higuita |
Medical Mycology Case Reports | 2020 |
Mucorales Species and Macrophages.
Nicolás FE, Murcia L, Navarro E, Navarro-Mendoza MI, Pérez-Arques C, Garre V |
2020 | |
Alteration of Fermentative Metabolism Enhances Mucor circinelloides Virulence.
Díaz-Pérez SP, Patiño-Medina JA, Valle-Maldonado MI, López-Torres A, Jácome-Galarza IE, Anaya-Martínez V, Gómez-Ruiz V, Campos-García J, Nuñez-Anita RE, Ortiz-Alvarado R, Ramírez-Díaz MI, Gutiérrez-Corona JF, Meza-Carmen V |
Infection and immunity | 2020 |
Isolated Cerebral Mucormycosis in Immunocompetent Adults who Inject Drugs: Case Reports and Systematic Review of the Literature
Meyerowitz EA, Sanchez S, Mansour MK, Triant VA, Goldberg MB |
Open Forum Infectious Diseases | 2020 |
Comparative host transcriptome in response to pathogenic fungi identifies common and species-specific transcriptional antifungal host response pathways
Bruno M, Dewi IM, Matzaraki V, ter Horst R, Pekmezovic M, Rösler B, Groh L, Röring RJ, Kumar V, Li Y, Carvalho A, Netea MG, Latgé JP, Gresnigt MS, van de Veerdonk FL |
Computational and Structural Biotechnology Journal | 2020 |