Anaplasma (formerly Ehrlichia) phagocytophilum, Ehrlichia chaffeensis, and Neorickettsia (formerly Ehrlichia) sennetsu are intracellular vector-borne pathogens that cause human ehrlichiosis, an emerging infectious disease. We present the complete genome sequences of these organisms along with comparisons to other organisms in the Rickettsiales order. Ehrlichia spp. and Anaplasma spp. display a unique large expansion of immunodominant outer membrane proteins facilitating antigenic variation. All Rickettsiales have a diminished ability to synthesize amino acids compared to their closest free-living relatives. Unlike members of the Rickettsiaceae family, these pathogenic Anaplasmataceae are capable of making all major vitamins, cofactors, and nucleotides, which could confer a beneficial role in the invertebrate vector or the vertebrate host. Further analysis identified proteins potentially involved in vacuole confinement of the Anaplasmataceae, a life cycle involving a hematophagous vector, vertebrate pathogenesis, human pathogenesis, and lack of transovarial transmission. These discoveries provide significant insights into the biology of these obligate intracellular pathogens.

CREBH is a liver-specific transcription factor that is localized in the endoplasmic reticulum (ER) membrane. Our previous work demonstrated that CREBH is activated by ER stress or inflammatory stimuli to induce an acute-phase hepatic inflammation. Here we demonstrate that CREBH is a key metabolic regulator of hepatic lipogenesis, fatty acid (FA) oxidation, and lipolysis under metabolic stress. Saturated FA, insulin signals, or an atherogenic high-fat diet can induce CREBH activation in the liver. Under the normal chow diet, CrebH knockout mice display a modest decrease in hepatic lipid contents but an increase in plasma triglycerides (TG). After feeding an atherogenic high-fat diet, massive accumulation of hepatic lipid metabolites and significant increase in plasma TG levels were observed in the CrebH knockout mice. Along with the hypertriglyceridemia phenotype, the CrebH null mice displayed significantly reduced body weight gain, diminished abdominal fat, and increased non-alcoholic steatohepatitis (NASH) activities under the atherogenic high-fat diet. Gene expression analysis and chromatin-immunoprecipitation (ChIP) assay indicated that CREBH is required to activate expression of the genes encoding functions involved in de novo lipogenesis, TG and cholesterol biosynthesis, FA elongation and oxidation, lipolysis, and lipid transport. Supporting the role of CREBH in lipogenesis and lipolysis, forced expression of an activated form of CREBH protein in the liver significantly increases accumulation of hepatic lipids but reduces plasma TG levels in mice. All together our study shows that CREBH plays a key role in maintaining lipid homeostasis by regulating expression of the genes involved in hepatic lipogenesis, FA oxidation, and lipolysis under metabolic stress. The identification of CREBH as a stress-inducible metabolic regulator has important implications in the understanding and treatment of metabolic disease.

A novel bacterium that infects laboratory rats was isolated from wild Rattus norvegicus rats in Japan. Transmission electron microscopy of the spleen tissue revealed small cocci surrounded by an inner membrane and a thin, rippled outer membrane in a membrane-bound inclusion within the cytoplasm of endothelial cells. Phylogenetic analysis of the 16S rRNA gene sequence of the bacterium found in R. norvegicus rats and Ixodes ovatus ticks in Japan revealed that the organism represents a novel clade in the family Anaplasmataceae, which includes the Schotti variant found in Ixodes ricinus ticks in the Netherlands and the Ehrlichia-like Rattus strain found in R. norvegicus rats from China. The novel clade was confirmed by phylogenetic analysis of groESL sequences found in R. norvegicus rats and Ixodes ovatus ticks in Japan. No serological cross-reactivity was detected between this bacterium and members of the genera Anaplasma, Ehrlichia or Neorickettsia in the family Anaplasmataceae. It is proposed that this new cluster of bacteria should be designated 'Candidatus Neoehrlichia mikurensis'.The family Anaplasmataceae currently includes five genera: Ehrlichia, Anaplasma, Neorickettsia, Aegyptianella and Wolbachia (Dumler et al., 2001;Rikihisa et al., 2003). These are all obligately intracellular bacteria that are capable of infecting invertebrates and/or vertebrates. Species of the genera Ehrlichia and Anaplasma include the emerging tick-borne human pathogens, such as Ehrlichia chaffeensis and Anaplasma phagocytophilum. As it is difficult to isolate and culture this group of bacteria, the ultrastructure and sequences of conserved genes, such as 16S rRNA, groEL and gltA (citrate synthase gene), are primarily used to identify and classify this group of bacteria. The present study describes a novel bacterium in the family Anaplasmataceae that was isolated from wild Rattus norvegicus rats by using laboratory rats. The bacteria were found in R. norvegicus rats and Ixodes ovatus ticks in Japan and represent a novel genetic cluster, based on phylogenetic analysis of 16S rRNA gene sequences that included the bacteria found in R. norvegicus rats in China (Pan et al., 2003) and in Ixodes ricinus ticks in the Netherlands (Schouls et al., 1999). Of note, infection of I. ricinus ticks with similar bacteria in Baltic regions of Russia was reported by Alekseev et al. (2001). A similar 16S

Background Air pollution is a global challenge to public health. Epidemiological studies have linked exposure to ambient particulate matter with aerodynamic diameters < 2.5 μm (PM2.5) to the development of metabolic diseases. In this study, we investigated the effect of PM2.5 exposure on liver pathogenesis and the mechanism by which ambient PM2.5 modulates hepatic pathways and glucose homeostasis. Methods Using “Ohio’s Air Pollution Exposure System for the Interrogation of Systemic Effects (OASIS)-1”, we performed whole-body exposure of mice to concentrated ambient PM2.5 for 3 or 10 weeks. Histological analyses, metabolic studies, as well as gene expression and molecular signal transduction analyses were performed to determine the effects and mechanisms by which PM2.5 exposure promotes liver pathogenesis. Results Mice exposed to PM2.5 for 10 weeks developed a non-alcoholic steatohepatitis (NASH)-like phenotype, characterized by hepatic steatosis, inflammation, and fibrosis. Mice after PM2.5 exposure displayed impaired hepatic glycogen storage, glucose intolerance, and insulin resistance. Further investigation revealed that exposure to PM2.5 led to activation of inflammatory response pathways mediated through c-Jun N-terminal kinase (JNK), nuclear factor kappa B (NF-κB), and Toll-like receptor 4 (TLR4) but suppression of the insulin receptor substrate 1 (IRS1)-mediated signaling. Moreover, PM2.5 exposure repressed expression of the peroxisome proliferator-activated receptor (PPAR) γ and PPARα in the liver. Conclusions Our study suggests that PM2.5 exposure represents a significant “hit” that triggers a NASH-like phenotype and impairs hepatic glucose metabolism. The information from this work has important implications in our understanding of air pollution-associated metabolic disorders.

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