Survival Strategy of Obligately IntracellularEhrlichia chaffeensis: Novel Modulation of Immune Response andHost CellCycles

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Abstract
Ehrlichia chaffeensisis an obligatory intracellular bacterium which resides in an early endosome in monocytes.E. chaffeensisinfection in a human monocyte cell line (THP1) significantly altered the transcriptional levels of 4.5% of host genes, including those coding for apoptosis inhibitors, proteins regulating cell differentiation, signal transduction, proinflammatory cytokines, biosynthetic and metabolic proteins, and membrane trafficking proteins. The transcriptional profile of the host cell revealed key themes in the pathogenesis ofEhrlichia. First,E. chaffeensisavoided stimulation of or repressed the transcription of cytokines involved in the early innate immune response and cell-mediated immune response to intracellular microbes, such as the interleukin-12 (IL-12), IL-15, and IL-18 genes, which might makeEhrlichiaa stealth organism for the macrophage. Second,E. chaffeensisup-regulated NF-κB and apoptosis inhibitors and differentially regulated cell cyclins and CDK expression, which may enhance host cell survival. Third,E. chaffeensisalso inhibited the gene transcription of RAB5A, SNAP23, and STX16, which are involved in membrane trafficking. By comparing the transcriptional response of macrophages infected with other bacteria and that of macrophages infected withE. chaffeensis, we have identified few genes that are commonly induced and no commonly repressed genes. These results illustrate the stereotyped macrophage response to other pathogens, in contrast with the novel host response to obligate intracellularEhrlichia, whose survival depends entirely on a long evolutionary process of outmaneuvering macrophages.