ABSTRACT: Infection of humans with Ehrlichia chaffeensis, the etiologic agent of human monocytic ehrlichiosis, can cause hepatitis of varying severity. When the three human isolates of E. chaffeensis, each belongs to different geno-groups, are inoculated into severe combined immunodeficiency mice, the severity of clinical signs and bacterial burden detected in the liver are strain Wakulla>Liberty>Arkansas. Disseminated and granulomatous inflammation is evident in the liver of mice infected with strains Wakulla and Arkansas, respectively, but not in mice infected with strain Liberty. In this paper, we used microarray analysis to define transcriptional profiles characteristic to the histopathological features in the mouse liver. Cytokine and chemokine profiles were strikingly different among three strains of E. chaffeensis: IFN-γ, CCL5, CXCL1, CXCL2, CXCL7 and CXCL9 were highly up-regulated with strain Arkansas, TNF-α, CCL2, CCL3, CCL5, CCL6, CCL12, CCL20, CXCL2, CXCL7, CXCL9 and CXCL13 were highly up-regulated with strain Wakulla. With strain Liberty, only CXCL13 was highly up-regulated. In the livers infected with the Arkansas strain, monocytes/macrophages and NK cells were enriched in the granulomas and increase of NK cell-marker mRNAs was detected. Livers infected with the Wakulla strain displayed infiltration of significantly more neutrophils and increase of neutrophil-marker mRNAs. Genes up-regulated commonly in the liver infected with the three stains are other host innate immune and inflammatory response genes including several acute phase proteins. Genes down-regulated commonly are related to host physiologic functions. The results suggest that marked modulation of host cytokine and chemokine profiles by E. chaffeensis strains underlie the distinct host liver disease. Experiment Overall Design: E. chaffeensis strains Arkansas, Wakulla and Liberty were propagated in DH82 cells. Three to four week-old male ICR-scid mice were infected intraperitoneally with 10^6 E. chaffeensis-infected DH82 cells (typically >95% infected) containing approximately the same number of bacteria. At day 15 post infection (PI) mice were euthanized and livers were harvested. Experiment Overall Design: Total RNAs were extracted from E. chaffeensis-infected or mock-infected (uninfected) mouse liver. About 8 ug of each RNA sample was applied to double-strand cDNA preparation. The labeled cRNA was hybridized to GeneChip Mouse Genome 430 2.0 Array (Affymetrix). After washing and staining with streptoavidin phycoerythrin, the array was scanned. Experiment Overall Design: Three mice were examined for each of the 4 groups.
