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* Trudeau Institute, Saranac Lake, NY 12983;
Howard Hughes Medical Institute, Department of Medicine and Microbiology and Immunology, University of California, San Francisco, CA 94143; and
Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655
At the temperature of its flea vector (
20–30°C), the causative agent of plague, Yersinia pestis, expresses a profile of genes distinct from those expressed in a mammalian host (37°C). When dendritic cells (DC) are exposed to Y. pestis grown at 26°C (Y. pestis-26°), they secrete copious amounts of IL-12p40 homodimer (IL-12(p40)2). In contrast, when DCs are exposed to Y. pestis grown at 37°C (Y. pestis-37°), they transcribe very little IL-12p40, which is secreted as IL-12p40 monomer (IL-12p40). Y. pestis-26° also induces migration of DCs to the homeostatic chemokine CCL19, whereas Y. pestis-37° does not; migratory DCs are positive for IL-12p40 transcription and secrete mostly IL-12(p40)2; DCs lacking IL-12p40 do not migrate. Expression of acyltransferase LpxL from Escherichia coli in Y. pestis-37° results in the production of a hexa-acylated lipid A, also seen in Y. pestis-26°, rather than tetra-acylated lipid A normally seen in Y. pestis-37°. The LpxL-expressing Y. pestis-37° promotes DC IL-12(p40)2 production and induction of DC migration. In addition, absence of TLR4 ablates production of IL-12(p40)2 in DC exposed to Y. pestis-26°. The data demonstrate the molecular pathway by which Y. pestis evades induction of early DC activation as measured by migration and IL-12(p40)2 production.
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1 This work was supported by Trudeau Institute Training Fellowship T32 AI49823 (to R.T.R.) as well as National Institutes of Health Grants R01-AI67723 (to A.M.C.), R01-A1057588 (to E.L.), R01-AI61577 (to S.T.S.), R01-AI26918 (to R.M.L.), and U54-AI057158-Lipkin, a New York Community Trust-Heiser Fund Fellowship and Career Development Award AI057158 (North East Biodefense Center-Lipkin) (to S.A.K.).
2 Current address: Division of Medicine, Allergy and Immunology, Children’s Hospital of Pittsburgh, Pittsburgh, PA 15213.
3 Address correspondence and reprint requests to Dr. Andrea M. Cooper, Trudeau Institute, 154 Algonquin Avenue, Saranac Lake, NY 12983. E-mail address: acooper{at}trudeauinstitute.org
4 Abbreviations used in this paper: DC, dendritic cell; IL-12(p40)2, IL-12p40 homodimer; Y. pestis-26°, Y. pestis grown at 26°C; Y. pestis-37°, Y. pestis grown at 37°C; YFP, yellow-fluorescent protein; Yet40 mice, IL-12p40-IRES-YFP reporter mice; BMDC, bone marrow-derived DC; MOI, multiplicity of infection.
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