Inflammation and the Treatment of Primary 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. Even in the event of appropriate antibiotic therapy, as evidenced in recent outbreaks mortality can still approach 50%. The rapid progression of pneumonic plague and its difficulty to treat highlight a need for improved therapeutic options and a more complete understanding of the host factors driving disease progression. The work proposed here seeks to evaluate the suppression of damaging host immune responses coupled with antibiotic therapy to treat late-stage pneumonic plague. Further, host responses and physiological parameters in the lung are monitored during disease and treatment to understand those conditions that correlate with survival, and those that accompany lethality. The ultimate goals of the proposal are to identify conditions for treatment of late-stage pneumonic plague that favor survivability. This work may have lasting impact on pneumonic plague treatment, as well as severe pneumonia caused by a number of pathogens. The specific aims of the proposal are as follows: Aim 1. Co-treatment with antibiotics and corticosteroids for late-stage pneumonic plague. Preliminary data indicates that pretreating mice with the corticosteroid fluticasone propionate dramatically increases survival after antibiotic treatment of pneumonic plague. Aim 1 seeks to test co-administration of different classes of antibiotics and corticosteroids to treat late-stage pneumonic plague, which is difficult to treat and is highly fatal. This is the first study of its kind that focuses on treatment of disease after symptoms arise. The goal of Aim 1 is to develop an optimal treatment regime for severe and lethal pneumonic plague. Aim 2. Evaluate pulmonary function and innate immune responses during treatment of pneumonic plague. The finding that limiting pulmonary inflammation increases survival in mice offers the opportunity to evaluate host responses under conditions associated with both survivability and lethality. Aim 2 seeks to evaluate host inflammatory responses, immune cell repertoire, and physiological conditions in the lung during disease and treatment of pneumonic plague to identify those conditions that lead to lethality. Further, identifying pulmonary conditions conducive to survival may help to define key metrics and goals for the development of effective therapeutics.