Yersinia pestis evades TLR4-dependent induction of IL-12(p40)2 by dendritic cells and subsequent cell migration.
At the temperature of its flea vector (approximately 20-30 degrees C), the causative agent of plague, Yersinia pestis, expresses a profile of genes distinct from those expressed in a mammalian host (37 degrees C). When dendritic cells (DC) are exposed to Y. pestis grown at 26 degrees C (Y. pestis-26 degrees), they secrete copious amounts of IL-12p40 homodimer (IL-12(p40)(2)). In contrast, when DCs are exposed to Y. pestis grown at 37 degrees C (Y. pestis-37 degrees), they transcribe very little IL-12p40, which is secreted as IL-12p40 monomer (IL-12p40). Y. pestis-26 degrees also induces migration of DCs to the homeostatic chemokine CCL19, whereas Y. pestis-37 degrees 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 degrees results in the production of a hexa-acylated lipid A, also seen in Y. pestis-26 degrees, rather than tetra-acylated lipid A normally seen in Y. pestis-37 degrees. The LpxL-expressing Y. pestis-37 degrees 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 degrees. 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.
Robinson
Richard T
RT
Trudeau Institute, Saranac Lake, NY 12983, USA.
Khader
Shabaana A
SA
Locksley
Richard M
RM
Lien
Egil
E
Smiley
Stephen T
ST
Cooper
Andrea M
AM
D000107:Acetylation; D000217:Acyltransferases / Q000235:genetics / Q000276:immunology; D000818:Animals; D002465:Cell Movement / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D054415:Chemokine CCL19 / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000382:microbiology; D019281:Dimerization; D004926:Escherichia coli / Q000235:genetics / Q000276:immunology; D029968:Escherichia coli Proteins / Q000235:genetics / Q000276:immunology; D015964:Gene Expression Regulation, Bacterial / Q000235:genetics / Q000276:immunology*; D006358:Hot Temperature; D006801:Humans; D007303:Insect Vectors / Q000382:microbiology; D053762:Interleukin-12 Subunit p40 / Q000235:genetics / Q000276:immunology*; D008050:Lipid A / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D010930:Plague / Q000235:genetics / Q000276:immunology*; D005423:Siphonaptera / Q000382:microbiology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology*; D015010:Yersinia pestis / Q000235:genetics / Q000276:immunology*
C515461:Ccl19 protein, mouse; D054415:Chemokine CCL19; D029968:Escherichia coli Proteins; D053762:Interleukin-12 Subunit p40; D008050:Lipid A; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D000217:Acyltransferases; C492237:LpxL protein, E coli