title: Toward a molecular pathogenic pathway for Yersinia pestis YopM.
abstract: YopM is one of the six "effector Yops" of the human-pathogenic Yersinia, but its mechanism has not been defined. After delivery to J774A.1 monocyte-like cells, YopM can rapidly bind and activate the serine/threonine kinases RSK1 and PRK2. However, in infected mice, effects of Y. pestis YopM have been seen only after 24-48 h post-infection (p.i.). To identify potential direct effects of YopM in-vivo we tested for effects of YopM at 1 h and 16-18 h p.i. in mice infected systemically with 10(6) bacteria. At 16 h p.i., there was a robust host response to both parent and ΔyopM-1 Y. pestis KIM5. Compared to cells from non-infected mice, CD11b(+) cells from spleens of infected mice produced more than 100-fold greater IFNγ. In the corresponding sera there were more than 100-fold greater amounts of IFNγ, G-CSF, and CXCL9, as well as more than 10-fold greater amounts of IL-6, CXCL10, and CXCL1. The only YopM-related differences were slightly lower CXCL10 and IL-6 in sera from mice infected 16 h with parent compared to ΔyopM-1 Y. pestis. Microarray analysis of the CD11b(+) cells did not identify consistent transcriptional differences of ≥4-fold at 18 h p.i. However, at 1 h p.i. mRNA for early growth response transcription factor 1 (Egr1) was decreased when YopM was present. Bone marrow-derived macrophages infected for 1 h also expressed lower Egr1 message when YopM was present. Infected J774A.1 cells showed greater expression of Egr1 at 1 h p.i. when YopM was present, but this pattern reversed at 3 h. At 6 h p.i., Cxcl10 mRNA was lower in parent-strain infected cells. We conclude that decreased Egr1 expression is a very early transcriptional effect of YopM and speculate that a pathway may exist from RSK1 through Egr1. These studies revealed novel early transcriptional effects of YopM but point to a time after 18 h of infection when critical transitional events lead to later major effects on cytokine gene transcription.
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky Lexington, KY, USA.
authors.forename: Annette M
authors.initials: AM
authors.lastname: Uittenbogaard
authors.forename: R Lakshman
authors.initials: RL
authors.lastname: Chelvarajan
authors.forename: Tanya
authors.initials: T
authors.lastname: Myers-Morales
authors.forename: Amanda A
authors.initials: AA
authors.lastname: Gorman
authors.forename: W June
authors.initials: WJ
authors.lastname: Brickey
authors.forename: Zhan
authors.initials: Z
authors.lastname: Ye
authors.forename: Alan M
authors.initials: AM
authors.lastname: Kaplan
authors.forename: Donald A
authors.initials: DA
authors.lastname: Cohen
authors.forename: Jenny P-Y
authors.initials: JP
authors.lastname: Ting
authors.forename: Susan C
authors.initials: SC
authors.lastname: Straley
mesh_terms: D000818:Animals; D001425:Bacterial Outer Membrane Proteins / Q000378:metabolism*; D001853:Bone Marrow / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D004195:Disease Models, Animal; D051766:Early Growth Response Protein 1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D005260:Female; D020869:Gene Expression Profiling; D007963:Leukocytes, Mononuclear / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D046228:Microarray Analysis; D010930:Plague / Q000382:microbiology / Q000473:pathology*; D013154:Spleen / Q000276:immunology; D013997:Time Factors; D037521:Virulence Factors / Q000378:metabolism*; D015010:Yersinia pestis / Q000472:pathogenicity*
chemical_list: D001425:Bacterial Outer Membrane Proteins; D016207:Cytokines; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D037521:Virulence Factors; C060772:yopM protein, Yersinia