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Involvement of Toll-like receptor 2 in the cerebral immune response and behavioral changes caused by latent Toxoplasma infection in mice
Get PDFapplication/pdfSubacute and chronic infections with the intracellular protozoan parasite Toxoplasma gondii are associated with an increased risk of psychiatric diseases like schizophrenia. However, little is known about the mechanisms involved in T. gondii-induced neuronal disorders. Recently, we reported that Toll-like receptor 2 (TLR2) was required to initiate the innate immune response in cultured mouse brain cells. However, how TLR2 contributes to latent infection with T. gondii remains unclear. Therefore, we examined the role of TLR2 in brain pathology and behavior using wild-type (TLR2+/+) and TLR2-deficient (TLR2-/-) mice. The behavioral analyses showed that TLR2 deficiency increased the anxiety state of the uninfected and infected animals alike, and TLR2 deficiency showed no relationship with the infection. In the contextual and cued fear-conditioning tests, T. gondii infection decreased the mouse freezing reaction while TLR2 deficiency increased it, but there was no interaction between the two factors. Our histopathological analysis showed that the TLR2+/+ and TLR2-/- mice had similar brain lesions at 30 days post infection (dpi) with T. gondii. Higher numbers of parasites were detected in the brains of the TLR2-/- mice than in those from the TLR2+/+ mice at 30 dpi, but not at 7 and 14 dpi. No significant differences were observed in the proinflammatory gene expression levels in the TLR2+/+ and TLR2-/- mice. Therefore, it appears that TLR2 signaling in the brain might contribute to the control of parasite growth, but not to brain pathology or the impaired fear memory response induced by infection with T. gondii.journal articl
Serotonin 5-HT4 receptor agonists improve facilitation of contextual fear extinction in an MPTP-induced mouse model of parkinson’s disease
Get PDFapplication/pdfPreviously, we found that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson’s disease (PD) model mice (PD mice) showed facilitation of hippocampal memory extinction via reduced cyclic adenosine monophosphate (cAMP)/cAMP-dependent response element-binding protein (CREB) signaling, which may cause cognitive impairment in PD. Serotonergic neurons in the median raphe nucleus (MnRN) project to the hippocampus, and functional abnormalities have been reported. In the present study, we investigated the effects of the serotonin 5-HT4 receptor (5-HT4R) agonists prucalopride and velusetrag on the facilitation of memory extinction observed in PD mice. Both 5-HT4R agonists restored facilitation of contextual fear extinction in PD mice by stimulating the cAMP/CREB pathway in the dentate gyrus of the hippocampus. A retrograde fluorogold-tracer study showed that γ-aminobutyric acid-ergic (GABAergic) neurons in the reticular part of the substantia nigra (SNr), but not dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNpc), projected to serotonergic neurons in the MnRN, which are known to project their nerve terminals to the hippocampus. It is possible that the degeneration of the SNpc DAergic neurons in PD mice affects the SNr GABAergic neurons, and thereafter, the serotonergic neurons in the MnRN, resulting in hippocampal dysfunction. These findings suggest that 5HT4R agonists could be potentially useful as therapeutic drugs for treating cognitive deficits in PD.journal articl
Causal phenotypic networks for egg traits in an F2 chicken population
Get PDFapplication/pdfTraditional single-trait genetic analyses, such as quantitative trait locus (QTL) and genome-wide association studies (GWAS), have been used to understand genotype–phenotype relationships for egg traits in chickens. Even though these techniques can detect potential genes of major effect, they cannot reveal cryptic causal relationships among QTLs and phenotypes. Thus, to better understand the relationships involving multiple genes and phenotypes of interest, other data analysis techniques must be used. Here, we utilized a QTL-directed dependency graph (QDG) mapping approach for a joint analysis of chicken egg traits, so that functional relationships and potential causal effects between them could be investigated. The QDG mapping identified a total of 17 QTLs affecting 24 egg traits that formed three independent networks of phenotypic trait groups (eggshell color, egg production, and size and weight of egg components), clearly distinguishing direct and indirect effects of QTLs towards correlated traits. For example, the network of size and weight of egg components contained 13 QTLs and 18 traits that are densely connected to each other. This indicates complex relationships between genotype and phenotype involving both direct and indirect effects of QTLs on the studied traits. Most of the QTLs were commonly identified by both the traditional (single-trait) mapping and the QDG approach. The network analysis, however, offers additional insight regarding the source and characterization of pleiotropy affecting egg traits. As such, the QDG analysis provides a substantial step forward, revealing cryptic relationships among QTLs and phenotypes, especially regarding direct and indirect QTL effects as well as potential causal relationships between traits, which can be used, for example, to optimize management practices and breeding strategies for the improvement of the traits.journal articl
Anti-piroplasmic potential of the methanolic Peganum harmala seeds and ethanolic Artemisia absinthium leaf extracts
Get PDFapplication/pdfThe available drugs against piroplasmosis are insufficient and faced with several challenges, such as drug-resistant parasites and toxicity to treated animals. Therefore, the discovery of new drug compounds is necessary for the effective control of babesiosis and theileriosis. Methanolic Peganum harmala seed extract (MPHSE) and ethanolic Artemisia absinthium leaf extract(EAALE) have several medicinal properties. In the present study, the growth-inhibition effects of MPHSE and EAALE were evaluated in vitro and in vivo. The half-maximal inhibitory concentration (IC50) values for MPHSE against Babesia bovis, B. bigemina, B. divergens, B. caballi, and Theileria equi were 24.9 ± 1.2, 77.1 ± 2.3, 61.1 ± 2.9, 80.8 ± 4.1, and 11.3 ± 2.1 μg/mL,respectively. EAALE exhibited IC50 values of 43.3 ± 3.1, 39.2 ± 2.7, 38.5 ±3.7, 50.3 ± 2.1, and 28.2 ± 2.1 μg/mL against B. bovis, B. bigemina, B. divergens, B.caballi, and T. equi, respectively. The toxicity assay on Madin–Darby bovine kidney (MDBK), mouse embryonic fibroblast(NIH/3T3), and human foreskin fibroblast (HFF) cell lines showed that MPHSE affected the viability of MDBK, NIH/3T3, and HFF cell lines with half maximum effective concentration(EC50) values of 611.7± 10.9, 870 ± 22, and ˃1500 μg/mL, respectively, while EAALE exhibited EC50 values of 340.7 ± 8.5, 736.7 ± 9.3, and 1371.5 ± 17.3 μg/mL against MDBK, NIH/3T3, and HFF cell lines, respectively. In the in vivo experiment, MPHSE and EAALE oral treatments at 150mg/kg inhibited the growth of Babesia microti in mice by 60% and 55.1%, respectively. These findings suggest that MPHSE and EAALE have the potential to be alternative remedies for treating piroplasmosis.journal articl
Outbreak of toxoplasmosis in four squirrel monkeys (Saimiri sciureus) in Japan
Get PDFapplication/pdfToxoplasma gondii is a protozoan parasite that causes fatal disease in New World monkeys. Several reports have described outbreaks of toxoplasmosis in squirrel monkeys. Here, we report the death of four squirrel monkeys in a captive colony from acute toxoplasmosis, one of which developed toxoplasmosis about 1 year after the initial outbreak. Serum anti–T. gondii antibody was detected by a latex agglutination test in the animals, and one presented seropositive before clinical signs were observed. Macroscopically, the lungs were severely affected and three animals showed pulmonary edema. Microscopically, interstitial pneumonia was observed in all animals. In the liver and heart, multifocal mononuclear cell infiltration with necrosis was detected. Parasite loading tended to be higher in the lungs, liver and heart than in the spleen, kidney and brain. The parasite was isolated from the brain of one animal and this isolate showed type II restriction patterns in the SAG1, SAG2, SAG3, BTUB, GRA6, c22-8, c29-2 and PK1 genes of T. gondii and type I restriction patterns in the L358 and Apico genes by PCR-Restriction Fragment Length Polymorphism analysis. The clinical signs were reduced in mice infected with this isolate compared with those infected with reference type II strain PLK in a bioassay. To our knowledge, this is the first report of isolation of the parasite from squirrel monkeys in Japan and offers the opportunity for genomic and pathogenic analyses to aid our understanding of acute toxoplasmosis. © 2018 Elsevier B.V.journal articl
Critical role of TLR2 in triggering protective immunity with cyclophilin entrapped in oligomannose-coated liposomes against Neospora caninum infection in mice
Get PDFapplication/pdfNeospora caninum is an intracellular protozoan parasite closely related to Toxoplasma gondii. N. caninum is thought to be a major cause of abortion in cattle worldwide. Given the current situation of drastic economic losses and a lack of efficient control strategies against such parasites, the challenge to develop potent vaccine candidates and technologies remains. We investigated the immune stimulating activity of N. caninum cyclophilin (NcCyp) with and without a formulation with oligomannose-coated-liposomes (OML) as the potential adjuvant. NcCyp-OML activated NF-κB in RAW 264.7 cells and triggered interleukin (IL)-12p40 production from murine peritoneal macrophages. In BALB/c mice, immunization with NcCyp-OML was associated with the production of specific antibodies (IgG1 and IgG2a). The specific antibody (IgG1) against naked NcCyp was also observed after the challenge infection, but it was significantly lower than those of NcCyp-OML. Moreover, significant cellular immune responses were induced, including spleen cell proliferation and interferon-gamma production. The immunization of mice with NcCyp-OML, and to lesser extent with naked NcCyp, induced significant protection against challenge with a lethal dose of N. caninum compared with the PBS control group. This protection was associated with a higher survival rate, slight changes in body weight, and lower clinical score of mice. In addition, the significant protective efficacy of NcCyp-OML was confirmed in another mouse strain, male C57BL/6 mice. The current study revealed the marked contribution of Toll-like receptor 2 (TLR2) to the protective immunity triggered by NcCyp-OML because higher numbers of TLR2−/− mice succumbed to a lethal dose of N. caninum compared with C57BL/6 mice. Moreover, prominent spleen cell proliferation and IFN-γ production was induced in NcCyp-OML-immunized mice by a TLR2-dependent mechanism. © 2019 Elsevier Ltdjournal articl
Understanding the hidden relations between pro- and anti-inflammatory cytokine genes in bovine oviduct epithelium using a multilayer response surface method
Get PDFapplication/pdfAn understanding gene-gene interaction helps users to design the next experiments efficiently and (if applicable) to make a better decision of drugs application based on the different biological conditions of the patients. This study aimed to identify changes in the hidden relationships between pro- and anti-inflammatory cytokine genes in the bovine oviduct epithelial cells (BOECs) under various experimental conditions using a multilayer response surface method. It was noted that under physiological conditions (BOECs with sperm or sex hormones, such as ovarian sex steroids and LH), the mRNA expressions of IL10, IL1B, TNFA, TLR4, and TNFA were associated with IL1B, TNFA, TLR4, IL4, and IL10, respectively. Under pathophysiological + physiological conditions (BOECs with lipopolysaccharide + hormones, alpha-1-acid glycoprotein + hormones, zearalenone + hormones, or urea + hormones), the relationship among genes was changed. For example, the expression of IL10 and TNFA was associated with (IL1B, TNFA, or IL4) and TLR4 expression, respectively. Furthermore, under physiological conditions, the co-expression of IL10 + TNFA, TLR4 + IL4, TNFA + IL4, TNFA + IL4, or IL10 + IL1B and under pathophysiological + physiological conditions, the co-expression of IL10 + IL4, IL4 + IL10, TNFA + IL10, TNFA + TLR4, or IL10 + IL1B were associated with IL1B, TNFA, TLR4, IL10, or IL4 expression, respectively. Collectively, the relationships between pro- and anti-inflammatory cytokine genes can be changed with respect to the presence/absence of toxins, sex hormones, sperm, and co-expression of other gene pairs in BOECs, suggesting that considerable cautions are needed in interpreting the results obtained from such narrowly focused in vitro studies. © 2019, The Author(s).journal articl
Epidemiological survey of tick-borne encephalitis virus in wild animals and livestock, 1998–2018, Japan
Get PDF帯広畜産大学博士（畜産衛生学）2018application/pdf博士学位論文大学院畜産学研究科畜産衛生学専攻Doctor’s Course of Animal and Food Hygienedoctoral thesi