The plague is caused by the bacteria Yersinia pestis. Infected rats carry the disease and pass it to fleas, the disease vector. The bacteria grow in the fleas’ abdomen and are passed to humans through a flea bite. There are three types of the plague; bubonic, septicemic and pneumonic. The bubonic plague has an early lymphatic stage, where the plague is local, and a later systemic stage, where the plague has fully infiltrated the body. The septicemic plague skips the lymphatic stage in bubonic plague and begins with a systemic infection, likely because the Y. pestis was injected directly into the blood. There are two types of pneumonic plague, secondary pneumonic plague is caused by a progression of bubonic or septicemic plague into the lungs, while primary pneumonic plague is caused by inhaling the respiratory droplets of someone with pneumonic plague.
Studies of metal transporters for Y. pesitis in vitro showed four different iron transport systems. Heme uptake requires the HmuP’RSTUV ABC transporter. HmuR mutant is unable to transport any hemoproteins. Fe3+ uptake is controlled by ferric ABC transporters; YfeABCDE, YfuABC, and YiuABC. YfeA-E is a better transporter than YfuABC, which is a better transporter than YiuABC. Fe²⁺ is transported into the cell through ferrous ABC transporters; Feo, Efe, Yfe and Fet-Flp under microaerobic conditions. The last of the iron transport systems is the siderophore system, which uses the siderophore yersiniabactin (Ybt) which binds iron and transports it into the cell. Uptake of Fe³⁺-Ybt requires outer membrane receptor Psn and two inner membrane ATPases YbtP and YbtQ. Under iron-deficient conditions, psn, ybtP and ybtQ all show reduced iron-deficient growth
In vitro analysis of zinc, manganese and copper, showed two uptake systems for both zinc and manganese, but the uptake system for copper has not been fully identified. ZnuABC is the only zinc importer. Ybt has a high affinity for zinc and serves as a zincophore. YbtX is required for zinc uptake instead of Psn, YbtP and YbtQ as seen in iron uptake. Manganese is imported into the cell through MntH, a widespread manganese transporter in bacteria, and through YfeA-E. Mutations of both MntH and YfeA-E suggest there is a third manganese uptake transporter that has yet to be identified. No copper transport system has been identified, but one has been suggested based on studies on similar bacteria.
In vivo studies in fleas showed that no iron transport systems are highly expressed in the flea midgut. MntH levels were similar in the flea and in the rat, but YfeA-E has higher levels in the rat than the flea. Since they are both regulated by iron and manganese this suggests that there is additional regulation of one or both. In rats infected with bubonic plague, mutations to Ybt made the bacteria avirulent while a single feoB mutant is dully virulent while a single yfeAB mutant is 8-9-fold less virulent and the combination of both mutations is 89-fold less virulent. Also while mntH mutants retain virulence, a yfeAB mntH double mutants have a 133-fold virulence loss. The Ybt-siderophore system is essential for the progression of bubonic plague while feo and yfe play a lesser role. Full virulence in a mouse model of bubonic plague requires Ybt and Yfe or Feo for Fe acquisition and Yfe or MntH for Mn acquisition. In rats infected with septicemic plague, mutations in Yfe and Znu show that Yfe system for Fe and Mn transport as well as Znu and Ybt for Zn transport play an important role. In rats infected with pneumonic plague, the only mutation that resulted in a loss of virulence was in the Ybt-siderophore system, showing that it is required for iron transport in this form of the plague.
In summary, only three iron transporters (Ybt, Yfe and Feo) are important in at least one form of the plague. Ybt is important in the early stages of bubonic plague, irrelevant in septicemic plague, and crucial in pneumonic plague. Two manganese transporters (Yfe and MntH) have been characterized. The Ybt-siderophore is important in Zn acquisition, but it is a completely different system from the Fe-Ybt uptake system. Ybt and ZnuABC play a crucial role Zn acquisition in vivo in mouse models.
Perry, R. D., Brobrov, A. G., & Fetherston, J. D. (2015). The role of transition metal transporters for iron, zinc, manganese and copper in the pathogenesis of Yersinia pestis. Metallomics, 7(6), 965–978. https://doi.org/10.1039/C4MT00332B