Shift from primary pneumonic to secondary septicemic plague by decreasing the volume of intranasal challenge with Yersinia pestis in the murine model

Yersinia pestis is the causative agent of pneumonic plague, a disease involving uncontrolled bacterial growth and host immunopathology. Secondary septicemic plague commonly occurs as a consequence of the host inflammatory response that causes vasodilation and vascular leakage, which facilitates systemic spread of the bacteria and the colonization of secondary tissues. The mortality rates of pneumonic and septicemic plague are high even when antibiotics are administered. In this work, we show that primary pneumonic or secondary septicemic plague can be preferentially modeled in mice by varying the volume used for intranasal delivery of Y. pestis. Low volume intranasal challenge (10μL) of wild type Y. pestis resulted in a high frequency of lethal secondary septicemic plague, with a low degree of primary lung infection and rapid development of sepsis. In contrast, high volume intranasal challenge (30μL) yielded uniform early lung infection and primary disease and a significant increase in lethality. In a commonly used BSL2 model, high volume challenge with Y. pestis lacking the pigmentation locus (pgm-) gave 10(5)-fold greater deposition compared to low volume challenge, yet moribund mice did not develop severe lung disease and there was no detectable difference in lethality. These data indicate the primary cause of death of mice in the BSL2 model is sepsis regardless of intranasal dosing method. Overall, these findings allow for the preferential modeling of pneumonic or septicemic plague by intranasal dosing of mice with Y. pestis.