MRSA Exploits Kidney’s Inner Environment to Persist and Spread

Methicillin-­resistant Staphylococcus aureus (MRSA) has rapidly risen to become one of the gravest threats to global health, with deaths from Staphylococcus aureus (S. aureus) having doubled worldwide since 1990. In severe cases, the bacteria invade the bloodstream in life-threatening systemic infections, which have a high risk of kidney injury and failure.

S. aureus is one of the most concerning bacterial pathogens, given that MRSA accounts for the largest increase in the global antimicrobial resistance burden. In addition, deaths attributable to S. aureus infections have doubled since 1990, making it a leading cause of bacterial mortality worldwide. Despite the continued focus on research, tissue reservoirs that permit bacterial persistence remain poorly defined.

Now, a new study reveals how MRSA exploits the osmotic environment of the inner kidneys to establish a bacterial reservoir and hide from the immune system. This work suggests that MRSA can establish niches in the kidneys and the findings provide a mechanistic explanation for a longstanding question in the field of MRSA biology, and could inform future strategies aimed at limiting kidney damage from infections.

This work is published in Science Translational Medicine in the paper, “Hyperosmotic niche adaptation and tissue polyamines underlie MRSA persistence in the kidney.”

Nobuhiro Kanazawa, PhD, and colleagues used intravenous MRSA infection in mice and combined with multi-plexed imaging, dual-species transcriptomics, host and bacterial genetics, and cell-­based assays, to understand the mechanisms of MRSA persistence in the kidney in a mouse model of systemic infection. The findings reveal the renal inner medulla, the site of urine concentration, as an MRSA reservoir. Here, in this hyperosmotic niche, MRSA evaded immune detection and co-opted tissue polyamines to grow and spread toward the renal cortex.

MRSA spread to other kidney tissues and grew by co-opting polyamines, which buttressed the bacterial membrane against osmotic stress and boosted the translation of a growth-fueling bacterial enzyme.

The extreme osmotic environment also shielded MRSA from immune detection and slowed the migration of neutrophils toward the infection site. More specifically, neutrophil recruitment to the inner medulla was delayed.

The team went on to find that the approved drug furosemide restored neutrophil infiltration and contained MRSA’s spread in the kidneys of mice, hinting that similar “washout” therapies might prove useful. The authors write, “disruption of medullary osmolality with the loop diuretic furosemide accelerated neutrophil infiltration, limited bacterial spread, and improved renal outcomes.”

The findings, the authors note, 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.”

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