Japanese encephalitis is a neuropathological disorder caused by Japanese encephalitis virus (JEV), which is characterized by severe pathological neuroinflammation and damage to the blood–brain barrier (BBB). Inflammatory cytokines/chemokines can regulate the expression of tight junction (TJ) proteins and are believed to be a leading cause of BBB disruption, but the specific mechanisms remain unclear. IP-10 is the most abundant chemokine produced in the early stage of JEV infection, but its role in BBB disruption is unknown. The administration of IP-10-neutralizing antibody ameliorated the decrease in TJ proteins and restored BBB integrity in JEV-infected mice. In vitro study showed IP-10 and JEV treatment did not directly alter the permeability of the monolayers of endothelial cells. However, IP-10 treatment promoted tumor necrosis factor alpha (TNF-α) production and IP-10-neutralizing antibody significantly reduced the production of TNF-α. Thus, TNF-α could be a downstream cytokine of IP-10, which decreased TJ proteins and damaged BBB integrity. Further study indicated that JEV infection can stimulate upregulation of the IP-10 receptor CXCR3 on astrocytes, resulting in TNF-α production through the JNK-c-Jun signaling pathway. Consequently, TNF-α affected the expression and cellular distribution of TJs in brain microvascular endothelial cells and led to BBB damage during JEV infection. Regarding regulation of the BBB, the IP-10/TNF-α cytokine axis could be considered a potential target for the development of novel therapeutics in BBB-related neurological diseases.

Animal and human pathogens of the genus Bordetella are not commonly considered to be intracellular pathogens, although members of the closely related classical bordetellae are known to enter and persist within macrophages in vitro and have anecdotally been reported to be intracellular in clinical samples. B. bronchiseptica, the species closest to the ancestral lineage of the classical bordetellae, infects a wide range of mammals but is known to have an alternate life cycle, persisting, replicating and disseminating with amoeba. These observations give rise to the hypothesis that the ability for intracellular survival has an ancestral origin and is common among animalpathogenic and environmental Bordetella species. Here we analyzed the survival of B. bronchiseptica and defined its transcriptional response to internalization by murine macrophage-like cell line RAW 264.7. Although the majority of the bacteria were killed and digested by the macrophages, a consistent fraction survived and persisted inside the phagocytes. Internalization prompted the activation of a prominent stress response characterized by upregulation of genes involved in DNA repair, oxidative stress response, pH homeostasis, chaperone functions, and activation of specific metabolic pathways. Cross species genome comparisons revealed that most of these upregulated genes are highly conserved among both the classical and non-classical Bordetella species. The diverse Bordetella species also shared the ability to survive inside RAW 264.7 cells, with the single exception being the bird pathogen B. avium, which has lost several of those genes. Knockout mutations in genes expressed intracellularly resulted in decreased persistence inside the phagocytic cells, emphasizing the importance of these genes in this environment. These data show that the ability to persist inside macrophage-like RAW 264.7 cells is shared among nearly all Bordetella species, suggesting that resisting phagocytes may be an ancient mechanism that precedes speciation in the genus and may have facilitated the adaptation of Bordetella species from environmental bacteria to mammalian respiratory pathogens.

The health effects of bisphenol A (BPA) have become a great concern in recent years. In this study, the reproductive toxicity of BPA was investigated. Male CD-1 mice were orally administrated with BPA (0, 100, 300 and 600 mg kg body weight) for 56 consecutive days. Results showed that relative testis weight to total body weight was significantly lower in the high-dose group ( p < 0.01, p < 0.05). Microscopic examination under light and transmission electron microscopes showed disorders of spermatogenesis after BPA exposure, including rough basal lamina of seminiferous tubules and damage of tight junctions between Sertoli cells. Further study by terminal-deoxynucleoitidyl transferase-mediated nick end labelling assay showed a significant induction of apoptosis in the testis tissue of the BPA groups ( p < 0.01). Immunohistochemical study found that the expression of androgen-binding protein (ABP) was significantly decreased in BPA-treated mice ( p < 0.01). Our results indicated that impairment of the basal lamina of seminiferous tubules and tight junctions may contribute to BPA-induced cell injury. A decrease in the level of ABP could be the possible mechanism for the reproductive toxicity of BPA. These findings provided direct evidence and novel insight into the reproductive toxicity of BPA and may have implications for understanding the toxicity of other endocrine disruptors.

Purpose of review: To relate genomic changes to phenotypic adaptation and evolution from environmental bacteria to obligate human pathogens, focusing on the examples within Bordetella species. Recent findings:Recent studies showed that animal-pathogenic and human-pathogenic Bordetella species evolved from environmental ancestors in soil. The animal-pathogenic B. bronchiseptica can hijack the life cycle of the soil-living amoeba Dictyostelium discoideum, surviving inside single-celled trophozoites, translocating to the fruiting bodies and disseminating along with amoeba spores. The association with amoeba may have been a 'training ground' for bacteria during the evolution to pathogens. Adaptation to an animal-associated life style was characterized by decreasing metabolic versatility and genome size and by acquisition of 'virulence factors' mediating the interaction with the new animal hosts. Subsequent emergence of humanspecific pathogens such as B. pertussis from zoonoses of broader host range progenitors was accompanied by a dramatic reduction in genome size, marked by the loss of hundreds of genes. Summary:The evolution of Bordetella from environmental microbes to animal-adapted and obligate human pathogens was accompanied by significant genome reduction with large scale gene loss during divergence.

Rabbit hepatitis E virus (HEV) is a novel genotype of HEV, and is considered to pose a risk of zoonotic transmission. Research into the systemic distribution of rabbit HEV in rabbits during different periods of infection has rarely been reported. To better understand this virus, we infected rabbits with second-passage rabbit HEV via an intraperitoneal route. After inoculation, the infection showed two types, temporary and constant infection. The detection of HEV RNA in the feces varied with time, and serum antigen correlated with fecal HEV RNA. Viremia only appeared 72 days after inoculation. The rabbits remained antibody negative throughout the experimental period. When HEV was localized, several organs besides the liver were HEV RNA positive. Tissue antigen was observed immunohistochemically in the different cells of various organs, especially in parts of the small intestine and the characteristic rabbit gut-associated lymphoid tissue. These data provide valuable information for future research into the pathogenesis of HEV.

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Systemic Lupus Erythematosus is a complex autoimmune disease and its etiology remains unknown. Increased gut permeability has been reported in lupus patients, yet whether it promotes or results from lupus progression is unclear. Recent studies indicate that an impaired intestinal barrier allows the translocation of bacteria and bacterial components into systemic organs, increasing immune cell activation and autoantibody generation. Indeed, induced gut leakage in a mouse model of lupus enhanced disease characteristics, including the production of anti-dsDNA antibody, serum IL-6 as well as cell apoptosis. Gut microbiota dysbiosis has been suggested to be one of the factors that decreases gut barrier integrity by outgrowing harmful bacteria and their products, or by perturbation of gut immune homeostasis, which in turn affects gut barrier integrity. The restoration of microbial balance eliminates gut leakage in mice, further confirming the role of microbiota in maintaining gut barrier integrity. In this review, we discuss recent advances on the association between microbiota dysbiosis and leaky gut, as well as their influences on the progression of lupus. The modifications on host microbiota and gut integrity may offer insights into the development of new lupus treatment.

B ordetella pertussis, the causative agent of pertussis (whooping cough), continues to reemerge in countries that have high vaccine coverage, such as the United States, and has accelerated since the switch during the mid-1990s from whole-cell pertussis (wP) formulations comprising many partially characterized bacterial proteins to the less reactogenic 1-5 component acellular pertussis (aP) vaccines (1,2). These aP vaccines, including DTaP (diphtheria, tetanus, and aP for children) and Tdap (tetanus, diphtheria, and aP for adolescents and adults), protect against disease, but this protection wanes rapidly and does not prevent colonization or transmission of the pathogen (3-5). In this background of suboptimally performing aP vaccines, many countries have noted the emergence and expansion of strains specifi cally lacking pertactin (PRN), a membrane bound autotransporter, and 1 of up to 5 B. pertussis protein antigens included in the vaccines (6-11).