Determining how Yersinia pestis YbX and the competition for host zinc impact the progression of pneumonic plague

Project Summary Pneumonic plague is the deadliest form of disease caused by Yersinia pestis. Disease manifests as a rapidly progressing and highly lethal necrotic pneumonia that is typically fatal within seven days. If antibiotic treatment is not administered within 24 hours after the onset of symptoms, pneumonic plague is 100% fatal. The lethality of plague is due to the abrupt onset of a hyper-inflammatory response that compromises pulmonary function. Deletion of the Y. pestis inner membrane protein YbtX results in decreased neutrophil infiltration into the airways and decreased expression of select pro-inflammatory cytokines/chemokines during the later stages of pneumonic plague. YbtX is part of a zinc acquisition system by which the Y. pestis siderophore Yersiniabactin (Ybt) competes with host protein calprotectin to scavenges bioavailable zinc. YbtX acts as an inner membrane transporter that facilitates transport of Ybt-Zn into the bacterial cytosol. Calprotectin is also known to be a driver of host inflammatory responses. We hypothesize that YbtX-mediated zinc import contributes to the onset inflammation in the lung by activating calprotectin-dependent inflammatory responses. To test this, we will characterize how zinc depletion impacts inflammation during infection in the absence of YbtX. Further, we will alter the balance of host zinc/calprotectin in a murine intranasal infection model of pneumonic plague and characterize how this balance affects pulmonary inflammation. This work will determine how zinc and host calprotectin impact host inflammatory responses during pneumonic plague.