Clostridioides difficile ferrosome organelles combat nutritional immunity

Hualiang Pi, Rong Sun, James R. McBride, Angela R. S. Kruse, Katherine N. Gibson-Corley, Evan S. Krystofiak, Maribeth R. Nicholson, Jeffrey M. Spraggins, Qiangjun Zhou () and Eric P. Skaar ()
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Hualiang Pi: Vanderbilt University
Rong Sun: Vanderbilt University
James R. McBride: Vanderbilt University
Angela R. S. Kruse: Vanderbilt University Medical Center
Katherine N. Gibson-Corley: Vanderbilt University Medical Center
Evan S. Krystofiak: Vanderbilt University
Maribeth R. Nicholson: Vanderbilt University Medical Center
Jeffrey M. Spraggins: Vanderbilt University
Qiangjun Zhou: Vanderbilt University
Eric P. Skaar: Vanderbilt University

Nature, 2023, vol. 623, issue 7989, 1009-1016

Abstract: Abstract Iron is indispensable for almost all forms of life but toxic at elevated levels1–4. To survive within their hosts, bacterial pathogens have evolved iron uptake, storage and detoxification strategies to maintain iron homeostasis1,5,6. Recent studies showed that three Gram-negative environmental anaerobes produce iron-containing ferrosome granules7,8. However, it remains unclear whether ferrosomes are generated exclusively by Gram-negative bacteria. The Gram-positive bacterium Clostridioides difficile is the leading cause of nosocomial and antibiotic-associated infections in the USA9. Here we report that C. difficile undergoes an intracellular iron biomineralization process and stores iron in membrane-bound ferrosome organelles containing non-crystalline iron phosphate biominerals. We found that a membrane protein (FezA) and a P1B6-ATPase transporter (FezB), repressed by both iron and the ferric uptake regulator Fur, are required for ferrosome formation and play an important role in iron homeostasis during transition from iron deficiency to excess. Additionally, ferrosomes are often localized adjacent to cellular membranes as shown by cryo-electron tomography. Furthermore, using two mouse models of C. difficile infection, we demonstrated that the ferrosome system is activated in the inflamed gut to combat calprotectin-mediated iron sequestration and is important for bacterial colonization and survival during C. difficile infection.

Date: 2023
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DOI: 10.1038/s41586-023-06719-9

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