Inflammatory and cardiac response to end-stage pneumonic plague

Abstract

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Yersinia pestis is the etiologic agent of pneumonic plague, a devastating disease in humans characterized by acute bronchopneumonia that is frequently accompanied by bacteremia and sepsis. In 2001, the Amerithrax attacks occurred resulting in an increased awareness for better understanding of threat agents which can be weaponized and the need for therapeutic development. Within, we report on studies on the role of Y. pestis virulence factors on the host response as well on evaluation of therapeutics. As such, we refined a Brown Norway rat animal model with the goal of studying the pathophysiological and therapeutic response to pneumonic plague. We defined the natural history of pneumonic plague in this model. Interestingly, development of cardiac arrhythmias during the end-stage of the infection was discovered. In addition, the host response to the virulence factor YopJ was characterized in an in vivo pneumonic plague infection. Although bacteremia was present in WT and yopJ-infected animals during late stage disease, there was a delay in sepsis in the absence of YopJ. Electrophysiology of the cardiac system was analyzed to elucidate the cause of the arrhythmia development as a disease progression. Findings included elevation of the STE interval in the heart indicating potential disruption of electrical ion channels. Significant differences in the STE were found between WT and mutant yopJ-infected animals. Overall, the discovery of the STE interval could potentially be a finding used for prognostic development for biomarker. Lastly, doxycycline and meropenem were evaluated as a therapeutic for post-exposure prophylaxis (PEP). We report within this dissertation critical threshold PEP treatment windows for both antibiotics.