Yersinia pestis causes human
plague and colonizes both a mammalian host and a flea vector during its transmission cycle. A key barrier to
bacterial infection is the host's ability to actively sequester key
biometals (e.g.,
iron,
zinc, and
manganese) required for bacterial growth. This is referred to as nutritional immunity. Mechanisms to overcome nutritional immunity are essential
virulence factors for bacterial pathogens. Y. pestis produces an
iron-scavenging
siderophore called
yersiniabactin (Ybt) that is required to overcome
iron-mediated nutritional immunity and cause lethal
infection. Recently, Ybt has been shown to bind to
zinc, and in the absence of the
zinc transporter ZnuABC, Ybt improves Y. pestis growth in
zinc-limited medium. These data suggest that, in addition to
iron acquisition, Ybt may also contribute to overcoming
zinc-mediated nutritional immunity. To test this hypothesis, we used a mouse model defective in
iron-mediated nutritional immunity to demonstrate that Ybt contributes to virulence in an
iron-independent manner. Furthermore, using a combination of bacterial mutants and mice defective in
zinc-mediated nutritional immunity, we identified
calprotectin as the primary barrier for Y. pestis to acquire
zinc during
infection and that Y. pestis uses Ybt to compete with
calprotectin for
zinc. Finally, we discovered that Y. pestis encounters
zinc limitation within the flea midgut, and Ybt contributes to overcoming this limitation. Together, these results demonstrate that Ybt is a bona fide
zinc acquisition mechanism used by Y. pestis to surmount
zinc limitation during the
infection of both the mammalian and insect hosts.