Natural History of Yersinia pestis Pneumonia in Aerosol-Challenged BALB/c Mice

Abstract

b After a relatively short untreated interval, pneumonic plague has a mortality approaching 100%. We employed a murine model of aerosol challenge with Yersinia pestis to investigate the early course of pneumonic plague in the lung, blood, and spleen. We fit a mathematical model to all data simultaneously. The model fit to the data was acceptable. The number of organisms in the lung at baseline was estimated to be 135 (median) or 1,184 (mean) CFU/g. The doubling time was estimated as 1.5 to 1.7 h. Between 1 and 12 h postexposure, counts declined, but they then increased by 24 h, a finding hypothesized to be due to innate immunity. The model predicted that innate immunity declined with a half-time of 3 to 3.8 h. The threshold for bacteremia was 6.4 ؋ 10 4 to 1.52 ؋ 10 6 CFU/g. By 42 to 48 h, stationary phase was obtained. Lung bacterial burdens exceeded 10 log CFU/g. Obviating early defenses allows for rapid amplification of Y. pestis in bacteremia, making the rapid course with high mortality understandable.

Evaluation of Imipenem for Prophylaxis and Therapy of Yersinia pestis Delivered by Aerosol in a Mouse Model of Pneumonic Plague

“…In our present experiments, imipenem produced good survivorship when the delay between exposure and intervention was short (PEP scenario) and when the bacterial burden would be smaller. However, when the delay in treatment was increased to 42 h (treatment scenario), when the bacterial burden would be larger (6,19), there was a decrease in survivorship. However, in the two different imipenem regimens, five or six deaths occurred at the same time as in the untreated controls, with the two treatment groups having one or two extra deaths after therapy ended at day 5, leaving 30% survivorship overall for the two imipenem treatment regimens.…”

“…It should be noted that the mean times to death were similar in both of these studies. In addition, a natural history study using the whole-body exposure indicates that the differences in the two exposures may not be that great, as the initial lung load was observed to be between 2 and 3 logs (19).…”

Natural History of Francisella tularensis in Aerosol-Challenged BALB/c Mice

“…The natural history of F. tularensis differs substantially from the model for Yersinia pestis that we described earlier (11). The first and most straightforward difference is in replication rate in the lung, where the doubling time was approximately 4-fold higher with F. tularensis than with Y. pestis.…”

“…In contrast to Y. pestis, F. tularensis has initial involvement in macrophage penetration as part of the process (11,18). This likely explains the differences in the infection courses, with breakthrough bacteremia occurring at approximately the same time point for the two pathogens; however, overwhelming burdens of bacteria in the blood lead to very early death in cases of Y. pestis infection, whereas lower burdens of bacteremia, probably resulting from a greater affinity for macrophage infection for F. tularensis, result in a more tissue-focused profile of infection.…”

Remote monitoring of the progression of primary pneumonic plague in Brown Norway rats in high-capacity, high-containment housing

“…Primary pneumonic plague begins after inhalation of Y. pestis aerosol and, shortly after infection, the bacteria establish an anti-inflammatory environment that permits colonization of the alveoli (Price , et al , 2012). Once this replicative niche is established, Y. pestis growth combined with a mounting inflammatory response leads to dissemination through the vasculature to seed distal organs such as the liver (Heine , et al , 2013). The resulting bacteremia is believed to cause a fever response, and in humans, this is often the first indication of infection (Pollitzer, 1954).…”