Yersinia pestis, the causative agent of plague, is typically transmitted by the bite of an in-
fected flea. Many aspects of mammalian innate immune response early after Y. pestis infec-
tion remain poorly understood. A previous study by our lab showed that neutrophils are the
most prominent cell type recruited to the injection site after intradermal needle inoculation of
Y. pestis, suggesting that neutrophil interactions with Y. pestis may be important in bubonic
plague pathogenesis. In the present study, we developed new tools allowing for intravital
microscopy of Y. pestis in the dermis of an infected mouse after transmission by its natural
route of infection, the bite of an infected flea. We found that uninfected flea bites typically in-
duced minimal neutrophil recruitment. The magnitude of neutrophil response to flea-
transmitted Y. pestis varied considerably and appeared to correspond to the number of bac-
teria deposited at the bite site. Macrophages migrated towards flea bite sites and interacted
with small numbers of flea-transmitted bacteria. Consistent with a previous study, we ob-
served minimal interaction between Y. pestis and dendritic cells; however, dendritic cells
did consistently migrate towards flea bite sites containing Y. pestis. Interestingly, we often
recovered viable Y. pestis from the draining lymph node (dLN) 1 h after flea feeding, indicat-
ing that the migration of bacteria from the dermis to the dLN may be more rapid than previ-
ously reported. Overall, the innate cellular host responses to flea-transmitted Y. pestis
differed from and were more variable than responses to needle-inoculated bacteria. This
work highlights the importance of studying the interactions between fleas, Y. pestis and the
mammalian host to gain a better understanding of the early events in plague pathogenesis.