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Urinary Tract Infection Vaccines—Putting Metal to the Pedal

Metals such as iron and copper are necessary co-factors in many microbial molecular pathways. Thus, during an infection, host organisms will try to limit access to these essential nutrients to help quash microbial growth, and microbes will try to acquire them to thrive and survive. Microbial acquisition of metals is usually accomplished by small metal-binding molecules, such as siderophores, which are small, high-affinity compounds that bind iron. In one recent report, investigators describe new evidence suggesting that UPEC use a siderophore called yersiniabactin (Ybt) more broadly to also modulate uptake of copper, preserving its availability while minimizing its toxicity to the bacteria. This multi-metal tasking aspect of Ybt adds to its importance to UPEC.

In a second study, researchers focused on using Ybt and another UPEC siderophore, aerobactin (Aer) as vaccination agents in mice, with the goal of raising host immune responses to UTI-causing bacteria. The mice were then challenged with exposure to a UPEC strain known to encode Ybt and Aer, which are not normally detected by host immune responses, and enterobactin (Ent), a siderophore that is targeted by innate immune host defenses, thus making Ybt and Aer essential to iron acquisition by this strain. The results showed that vaccination with Ybt or Aer reduced acute bacterial burden in the bladder by 12- and 19-fold, respectively. The mouse model they used is one that experiences “ascending” UTIs—i.e., infections that move into the kidneys—and the researchers observed that the siderophore vaccines also significantly reduced bacterial burden in the kidneys. Unlike innate immune responses, which act quickly, inducing adaptive immune responses—such as the formation of antibodies in response to a vaccine agent—takes time. Thus, although the researchers did not have the means to confirm that anti-siderophore antibodies were being generated, an additional experiment showed that their vaccination approach was not effective if the mice were exposed to bacteria only 1 week after administration, providing indirect evidence that the siderophore vaccines are inducing an adaptive immune response. These encouraging results point toward an additional pool of candidate targets for vaccines to prevent UTIs.

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