Vascular-associated bacterial burden and neuroinflammatory transcriptional responses observed in models of pneumonic...

Yersinia pestis is the etiologic agent of plague, and the disease is categorized into several forms, including bubonic, septicemic, and pneumonic. Plague meningitis is a rare but severe complication and estimated to occur in 6-11% of documented cases. It is most frequently observed in bubonic plague patients under 15 years old that receive inadequate or no antibiotic treatment. To date, there are no reports describing plague meningitis in laboratory animal models of pneumonic plague.

Therefore, we sought to use the BALB/c mouse pneumonic plague model to investigate central nervous system (CNS) involvement after exposure to aerosolized Y. pestis. We used a multifaceted approach analyzing bacterial burden, histopathological analyses, transcriptomic data, and cytokine expression in mice exposed to aerosolized Y. pestis CO92 collected at intervals post-exposure for 3 days.

Y. pestis was detected in brain homogenates as early as 2 days post challenge. CNS involvement is further supported by increased pro-inflammatory cytokine expression in the brain homogenates including IL-6. Histopathological analyses conducted in mice and confirmed in non-human primate tissue sections did not demonstrate meningitis but rather indicated that the bacteria remain within the blood vessels of the cerebellum, cerebrum, and nasal turbinates. However, transcriptomic data targeting mouse neuroinflammatory responses indicated alterations in several transcriptional signatures of gene sets, including those that regulate astrocyte, oligodendrocyte, and microglial cell functions.

While Y. pestis does not appear to breach the blood vessels resulting in meningitis in our acute models of pneumonic plague, we found evidence of a neuroinflammatory response within the brain homogenates of infected mice. We also compared this mouse model of pneumonic plague to a mouse model of inhalational melioidosis, a known neuroinvasive disease caused by Burkholderia pseudomallei. The establishment of a murine model of plague-induced neuroinflammation described herein will contribute to the refinement of animal models, development of medical countermeasures for neurological infections or neurological impacts associated with systemic infection, and improvement of diagnostic strategies for Y. pestis.