Abstract

Yersinia pestis is the causative agent of plague, which can manifest as either bubonic or pneumonic plague. Kinetics of infection were investigated using a murine model of primary pneumonic plague. Both a delay in the appearance of pro-inflammatory molecules and in the recruitment of immune cells to the lungs were observed. In vitro studies determined that the delay in the appearance of pro-inflammatory molecules was dependent on a component(s) of the pCD1 virulence plasmid. These data indicate that Y. pestis is actively causing a delay in the "normal" innate response to the presence of a Gram-negative bacterium.

The role of YopH, a tyrosine phosphatase, was investigated. CO92Δ yoph was created and used for in vivo studies. Mice infected intranasally with this mutant demonstrate a robust and early pro-inflammatory response and are able to survive an infectious dose of up to ∼1×10 ⁷ CFU/mouse (highest dose tested). Additionally, this mutant makes an excellent live-attenuated vaccine against wild-type Y. pestis CO92. The studies with CO92ΔyopH demonstrate that YopH is playing an important role in the immunomodulation of the host response to infection by blocking early pro-inflammatory responses. We speculate that this early response is key to initiating an appropriate immune response to Y. pestis.

A mMIP-2 expressing replication-deficient adenovirus was created. Mice were infected with mMIP-2 expressing adenovirus and subsequently infected with Y. pestis CO92 at the onset of mMIP-2 expression and neutrophil recruitment to the lungs. A significant increase in the percentage of survival or time to death post-CO92 infection was not observed. Due to the complexity of this type of experiment, it can not be conclusively stated that future experiments based on this concept would yield negative results, however, the initial experimental results indicated that the presence of neutrophils in the lungs at the time of infection did not provide significant protection.