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

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.

Authors

Institutions

Publication Details

Journal
Science Translational Medicine
Published
2026-09-30
DOI
https://doi.org/10.1126/scitranslmed.aed4200
Primary Topic
Polyamine Metabolism and Applications
Type
article
Field-Weighted Citation Impact
0.00
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
article

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

William S. Bowen, Paul D. Fey, Taeok Bae, Shin‐ichi Makino et al.
Science Translational Medicine
Polyamine Metabolism and Applications
article

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

William S. Bowen, Paul D. Fey, Taeok Bae, Shin‐ichi Makino, Jered Myslinski, Takashi Hato, Bernhard Maier, Farooq Syed, Patrick C. McGuire, Tomohiko Ai, Ying‐Hua Cheng, Segewkal Heruye, Caroline P. Martens, Nobuhiro Kanazawa, Juexin Wang, Pierre C. Dagher, Kimberly Martinod, Chetan Poudel, Tarek M. El‐Achkar, Yunlong Liu, Fang Fang, Amy Zollman, Kyle McCrocklin, Kazuya Hirakochi, Annabelle White, Jodi Yanagida
article en

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.

Science Translational MedicineVol. 18(869)
Rochester Institute of Technology (US), Juntendo University (JP), Northwest University (US), Indiana University Northwest (US), Richard L. Roudebush VA Medical Center (US), City of Hope (US), Indiana University School of Medicine, University of Rochester (US), Indiana University – Purdue University Indianapolis (US), University of Nebraska Medical Center (US), Indiana University (US), KU Leuven (BE)
Life in Land
Openalex Percentile: Top 20%
Polyamine Metabolism and Applications
DOISourceOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.