Hyperosmotic niche adaptation and tissue polyamines underlie MRSA persistence in the kidney.

Authors

Nobuhiro Kanazawa, Caroline P Martens, Shinichi Makino, Segewkal Hawaze Heruye, Amy Zollman, Jered Myslinski, Annabelle White, Chetan Poudel, Jodi Yanagida, Farooq Syed, Bernhard Maier, Yinghua Cheng, Bill Bowen, Tarek M El-Achkar, Patrick C McGuire, Fang Fang, Yunlong Liu, Kyle McCrocklin, Juexin Wang, Kazuya Hirakochi, Tomohiko Ai, Taeok Bae, Kimberly Martinod, Paul D Fey, Pierre C Dagher, Takashi Hato

Published in

Science translational medicine. Volume 18. Issue 869. Pages eaed4200. Sep 30, 2026. Epub Sep 30, 2026.

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia causes substantial morbidity, but tissue reservoirs that permit bacterial persistence remain poorly defined. Using intravenous USA300 MRSA infection in mice, multiplexed imaging, dual-species transcriptomics, host and bacterial genetics, and cell-based assays, we uncovered the renal inner medulla, the site of urine concentration, as an MRSA reservoir. In this hyperosmotic niche, MRSA evaded immune detection and co-opted tissue polyamines to sustain growth, enabling subsequent spread toward the renal cortex. Neutrophil recruitment to the inner medulla was profoundly delayed owing to osmotic inhibition of immune cell migration. Disruption of medullary osmolality with the loop diuretic furosemide accelerated neutrophil infiltration, limited bacterial spread, and improved renal outcomes. Mechanistically, polyamines promoted MRSA persistence through both extracellular and intracellular actions that depended on local osmolality and pH. In the medullary milieu, polyamines primarily associated with the bacterial surface and stabilized membranes against osmotic stress. Intracellular polyamines enhanced translation of guaB (inosine monophosphate dehydrogenase), the rate-limiting enzyme in bacterial de novo purine biosynthesis. The polyamine-catabolizing gene speG (spermidine acetyltransferase), uniquely present in epidemic USA300 MRSA strains, mitigated polyamine toxicity and conferred a selective advantage in the polyamine-rich kidney. These findings revealed the inner medulla as a physiologically immune-restricted MRSA reservoir and supported modulation of medullary osmolality and bacterial polyamine metabolism as candidate adjunctive strategies for limiting renal persistence and dissemination during MRSA bacteremia.

PMID:
42814799
Bibliographic data and abstract were imported from PubMed on 01 Oct 2026.

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