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

Abstract

Ehrlichia chaffeensis is an obligatory intracellular bacterium which resides in an early endosome in monocytes. E. chaffeensis infection 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 of Ehrlichia. First, E. chaffeensis avoided 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 make Ehrlichia a stealth organism for the macrophage. Second, E. chaffeensis up-regulated NF-B and apoptosis inhibitors and differentially regulated cell cyclins and CDK expression, which may enhance host cell survival. Third, E. chaffeensis also 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 with E. 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 intracellular Ehrlichia, whose survival depends entirely on a long evolutionary process of outmaneuvering macrophages.

Inhibition of Apoptosis byEscherichia coliK1 Is Accompanied by Increased Expression of BclXLand Blockade of Mitochondrial CytochromecRelease in Macrophages

“…However, a variety of bacteria and viruses that survive inside host cells have developed strategies to interfere with the host cell apoptotic process (6,28,31,41). Here we show that E. coli K1 interferes with cytochrome c release from the mitochondria and subsequent down-regulation of caspase activity by inducing the expression of Bcl XL as an antiapoptotic mechanism in macrophages.…”

Infection with Anaplasma phagocytophilum Activates the Phosphatidylinositol 3-Kinase/Akt and NF-κB Survival Pathways in Neutrophil Granulocytes

“…NF-B activation leads to enhanced expression of prosurvival genes in several infection models (7,51,52). In human neutrophils, NF-B activation regulates spontaneous apoptosis as well as the antiapoptotic effect of TNF-␣, a cytokine that exerts both pro-and antiapoptotic effects upon these cells (26).…”

Expression of Members of the 28-Kilodalton Major Outer Membrane Protein Family of Ehrlichia chaffeensis during Persistent Infection

“…Our results suggest that E. chaffeensis may utilize other mechanisms to evade the host immune response. Downregulation or avoidance of stimulation of production of cytokines such as interleukin-12, interleukin-15, and interleukin-18, that are critical for innate immune and adaptive immune response, by E. chaffeensis suggests that persistent E. chaffeensis infection may be caused by modulation of cytokine production (37).…”