Yersiniabactin contributes to overcoming zinc restriction during Yersinia pestis infection of mammalian and insect hosts

Abstract

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.

Diisonitrile Lipopeptides Mediate Resistance to Copper Starvation in Pathogenic Mycobacteria

“…There is emerging evidence that pathogens use Zn acquisition systems during infection, through either-the elaboration of Zn-scavenging molecules, transport systems for Zn ( 8 ), or import of host-derived Zn containing molecules ( 9 – 11 ). It was recently shown that yersiniabactin, previously characterized as an iron siderophore, also binds Cu ( 12 , 13 ) and Zn ( 14 ) and that the yersiniabactin system is active during infections ( 12 , 14 – 17 ).…”

Nutritional immunity: the battle for nutrient metals at the host–pathogen interface

“…Bacterial Fe-chelating siderophores are well described, yet the specificity of siderophores to differing metals has not been studied in detail, leaving open the possibility that siderophores may function more broadly in scavenging trace metals. Specifically, siderophores including pyridine-2,6-bis(thiocarboxylic acid) (PDTC), pyochelin, micacocidin and yersiniabactin bind Zn with high affinity 114 – 120 . In fact, scavenging of Zn by yersiniabactin promotes Enterobactericae colonization in the inflamed gut, illustrating the importance of siderophore-mediated Zn acquisition in host colonization 121 .…”

Why is manganese so valuable to bacterial pathogens?

“…However, two recent reports have shown that yersiniabactin, traditionally considered a siderophore, also binds zinc in vivo, helping Y. pestis and E. coli Nissle 1917 to overcome zinc sequestration by CP. In the case of Y. pestis, yersiniabactin contributes to establish the disease, but the same activity of yersiniabactin in probiotic E. coli Nissle 1917 serves the bacterium to outcompete pathogens such as S. Typhimurium (Behnsen et al, 2021;Price et al, 2021).…”