Abstract
ABSTRACTUrinary tract infection (UTI) is one of the most common infectious conditions affecting people in the United States and around the world. Our knowledge of the host-pathogen interaction during UTI caused by Gram-positive bacterial uropathogens is limited compared to that for Gram-negative pathogens. Here, we investigated whether copper and the primary copper-containing protein, ceruloplasmin, are mobilized to urine during naturally occurring UTI caused by Gram-positive uropathogens in patients. Next, we probed the role of copper resistance in the fitness of methicillin-resistant Staphylococcus aureus (MRSA) during experimental UTI in a murine model. Our findings demonstrate that urinary copper and ceruloplasmin content are elevated during UTI caused by Enterococcus faecalis, S. aureus, S. epidermidis, and S. saprophyticus. MRSA strains successfully colonize the urinary tract of female CBA mice with selective induction of inflammation in the kidneys but not the bladder. MRSA mutants lacking CopL, a copper-binding cell surface lipoprotein, and the ACME genomic region containing copL, exhibit decreased fitness in the mouse urinary tract compared to parental strains. Copper sensitivity assays, cell-associated copper and iron content, and bioavailability of iron during copper stress demonstrate that homeostasis of copper and iron is interlinked in S. aureus. Importantly, relative fitness of the MRSA mutant lacking the ACME region is further decreased in mice that receive supplemental copper compared to the parental strain. In summary, copper is mobilized to the urinary tract during UTI caused by Gram-positive pathogens, and copper resistance is a fitness factor for MRSA during UTI.
Highlights
Urinary tract infection (UTI) is one of the most common infectious conditions affecting people in the United States and around the world
Our findings paint a portrait in which copper is mobilized to urine during UTI, and copper resistance conferred by ACME and copper-binding lipoprotein (CopL) contributes to optimal fitness of S. aureus in a murine model of UTI
Since copper is involved in protection from multiple bacterial pathogens [24], including Uropathogenic Escherichia coli (UPEC) [32,33,34], we investigated whether urinary copper levels change during UTI caused by Gram-positive pathogens
Summary
Urinary tract infection (UTI) is one of the most common infectious conditions affecting people in the United States and around the world. Copper is mobilized to the urinary tract during UTI caused by Gram-positive pathogens, and copper resistance is a fitness factor for MRSA during UTI. Our findings from the murine model of UTI demonstrate that copper resistance is involved in the fitness of methicillin-resistant S. aureus (MRSA) during interaction with the host. We present findings from our investigation using human clinical samples, in vitro assays, and a mouse model of UTI on the role of copper at the host-pathogen interface during UTI caused by S. aureus. Copper resistance phenotypes of mutants lacking ACME, CopL, and CopX were validated in vitro, and their role in fitness of S. aureus was interrogated in a murine model of UTI. Our findings paint a portrait in which copper is mobilized to urine during UTI, and copper resistance conferred by ACME and CopL contributes to optimal fitness of S. aureus in a murine model of UTI
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