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Infection and Immunity, November 2005, p. 7142-7150, Vol. 73, No. 11
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.11.7142-7150.2005

Pathogenesis of Yersinia pestis Infection in BALB/c Mice: Effects on Host Macrophages and Neutrophils

Roman A. Lukaszewski, Dermot J. Kenny, Rosa Taylor, D. G. Cerys Rees, M. Gill Hartley, and Petra C. F. Oyston*

Department of Biomedical Sciences, Dstl Porton Down, Salisbury, Wiltshire, SP4 0JQ, United Kingdom

Received 22 February 2005/ Returned for modification 13 April 2005/ Accepted 22 June 2005

The pathogenesis of infection with Yersinia pestis, the causative agent of plague, was examined following subcutaneous infection of BALB/c mice with a fully virulent strain expressing green fluorescent protein. Plate culturing, flow cytometry, and laser confocal microscopy of spleen homogenates throughout infection revealed three discernible stages of infection. The early phase was characterized by the presence of a small number of intracellular bacteria mostly within CD11b+ macrophages and Ly-6G+ neutrophils. These bacteria were not viable, as determined by plate culturing of spleen homogenates, until day 2 postinfection. Between days 2 and 4 postinfection, a plateau phase was observed, with bacterial burdens of 103 to 104 CFU per spleen. Flow cytometric analysis revealed that there was even distribution of Y. pestis within both CD11b+ macrophage and Ly-6G+ neutrophil populations on day 2 postinfection. However, from day 3 postinfection onward, intracellular bacteria were observed exclusively within splenic CD11b+ macrophages. The late phase of infection, between days 4 and 5 postinfection, was characterized by a rapid increase in bacterial numbers, as well as escape of bacteria into the extracellular compartment. Annexin V staining of spleens indicated that a large proportion of splenic neutrophils underwent rapid apoptosis on days 1 and 2 postinfection. Fewer macrophages underwent apoptosis during the same period. Our data suggest that during the early stages of Y. pestis infection, splenic neutrophils are responsible for limiting the growth of Y. pestis and that splenic macrophages provide safe intracellular shelters within which Y. pestis is able to grow and escape during the later stages of infection. This macrophage compliance can be overcome in vitro by stimulation with a combination of gamma interferon and tumor necrosis factor alpha.

* Corresponding author. Mailing address: Microbiology, B07A, Biomedical Sciences, Dstl Porton Down, Salisbury, Wiltshire, SP4 0JQ, United Kingdom. Phone: 44 (0)1980 613641. Fax: 44 (0)1980 614370. E-mail: pcoyston{at}dstl.gov.uk.

Editor: D. L. Burns

Infection and Immunity, November 2005, p. 7142-7150, Vol. 73, No. 11
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.11.7142-7150.2005




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