■Genetic diversity of feline morbillivirus isolated in Japan 著者最終稿版の公開のみ可能（The final version of Recordは不可）。出版社ウェブサイトへのリンクを以下の通り記載すること「The final version of record is available at http;//jgv.microbiologyresearch.org/」。■In vitro host range of feline morbillivirus 最終版はhttp://jsvetsci.jp/jvms/から入手可能である / 京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19581号 / 医博第4088号 / 新制||医||1013(附属図書館) / 32617 / 京都大学大学院医学研究科医学専攻 / (主査)教授 西渕 光昭, 教授 一山 智, 教授 木原 正博 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Mother-to-child transmission (MTCT) of HIV accounts for more than 90% of pediatric infections worldwide, yet the mechanism of vertical transfer remains unknown. The feline immunodeficiency virus (FIV)-infected cat is a cost-effective, small-animal model of HIV pathogenesis and MTCT, which produces a high rate of reproductive failure and fetal infection in litters delivered at early- and late-term gestation. Our previous data suggest that FIV infection may dysregulate placental cytokines and compromise pregnancy. We hypothesized that FIV-infection may cause dysregulation of placental cytokine expression, and aberrant expression of these cytokines may potentiate inflammation and transplacental infections. The purpose of this project was to evaluate feline placental immunopathology at the whole and cellular levels during early- and late-term gestation to understand how lentiviruses may perturb placental immune parameters. To determine whether placentas were vulnerable to FIV infection, we quantified the expression of the FIV receptors, CD134 and CXCR4, in RNA extracted from late-term placental tissue. We found higher expression of CD134 and CXCR4 in placentas from successful pregnancies. To evaluate relative cytokine expression in randomly-sampled, whole placental specimens, we quantified representative pro- and anti-inflammatory cytokines and a chemokine. IL-6 and IL-12p35 were increased in early-gestation, FIV-infected queens; IL-6 was increased in late-gestation, FIV-infected queens. To evaluate placental immunopathology at the cellular level, we developed a novel immunohistochemistry method to identify trophoblastic cells selectively. Trophoblasts were collected using laser capture microdissection, and RNA was extracted from captured cells. We detected expression of several anti- and pro-inflammatory cytokines and the chemokine receptor CXCR4 (the FIV co-receptor) in trophoblasts at both stages of gestation. However, we failed to detect expression of other cytokines and CD134, the FIV primary receptor. FIV infection slightly lowered expression of all cytokines at both early and late pregnancy, although only the decrease in IL-5, from early pregnancy, and IL-4 and IL-12p35, from late pregnancy, reached significant levels. Fetal non-viability was associated with decreased trophoblast expression of IL-4, IL-6, IL-12p35, and CXCR4 at early gestation and decreased expression of IL-4, IL-12p35, IL-12p40 at late gestation. Collectively, these data indicate that FIV infection negatively impacts pregnancy outcome and alters placental immunomodulation.

We are using the feline immunodeficiency virus (FIV)-infected cat to model HIV mother-to-child-transmission (MTCT). Vertical transmission of either virus may result not only in infected offspring, but also failed pregnancy.In HIV infections, maternal hematological and virological parameters predict MTCT.We hypothesized that such parameters would likewise be predictors of FIV vertical transfer. We inoculated ten cats with FIV-B-2542; 10 cats were uninoculated. Cats were allowed to breed naturally. Fetuses were delivered at approximately week 3 (early) gestation by cesarean section. Fetal and placental tissues were collected.Blood samples were collected from the day of inoculation through delivery. We quantified CD4:CD8 T cell ratios, proviral load, and plasma viremia, and monitored seroreactivity to FIV proteins in longitudinal sera from both groups of cats. We documented clinical and reproductive outcome. The infected group produced reduced litter size and more failed pregnancies; CD4:CD8 ratios were depressed by 3.5 months p.i.Proviral DNA was detected in 14 of 14 (100%) placentas tested and 12 of 14 (86%) fetuses. However, the parameters assessed were not predictive of reproductive outcome and suggested a role for placental immunopathology in compromised pregnancy.Regulatory T cells (Treg) are anti-inflammatory and essential in maintaining pregnancy.Th17 cells are pro-inflammatory and associated with pregnancy failure. The activation of these cell populations is regulated by the cytokines TGF-? and IL-6. We hypothesized that placental immunology may result from altered dynamics of these cell populations.Using immunofluorescence confocal microscopy to measure Treg and Th17 markers FoxP3 and ROR ? , respectively, we quantified these cells in placental specimens from FIV-infected and control cats at early and late (week 8) gestation.Significantly higher levels of ROR ? were measured in FIV-infected placentas at early pregnancy; these cells co-localized at the maternaletal interface. We quantified the expression of Treg immunomodulators by quantitative PCR, noting higher expression of TGF-? in infected queens.A positive correlation of ROR ? with IL-6 occurred in control placentas, as predicted, but not in infected placentas.Collectively, the data suggest that an inflammatory placental microenvironment at early pregnancy in infected queens may result, in part, from dysregulation of the Treg/Th17 balance.

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As alterações inflamatórias que afetam a cavidade oral e a gengiva dos felinos são frequentemente observadas na rotina médica e constituem verdadeiro desafio diagnóstico e terapêutico ao clínico. Denomina-se complexo gengivite-estomatitefaringite felina (CGEF) como sendo uma síndrome onde a apresentação clínica comum é a inflamação grave da gengiva e mucosa oral. A etiopatogênese desta doença não está totalmente elucidada mas acredita-se que seja multifatorial. As viroses têm sido implicadas como agentes etiológicos na patogenia da gengivite-estomatite crônica felina, entretanto, o mecanismo pelo qual as infecções virais participam no desenvolvimento da doença gengival nos animais afetados permanece indeterminado. A hipótese do presente estudo é de que a depleção imunológica induzida pelo lentivírus felino (FIV) aumenta o risco de ocorrência do FCV e do FHV-1 e da estomatite-gengivite em gatos. Para tanto, foram realizados 2 experimentos: o primeiro (A) foi delineado para avaliar a ocorrência do FCV e do FHV-1 na cavidade oral de 58 gatos naturalmente infectados pelo FIV ou não, com e sem gengivite, por meio da reação de polimerização em cadeia (PCR), assim como correlacionar esses achados com as subpopulações de linfócitos T CD4+, CD8+ e da razão CD4+:CD8+ e o segundo (B) foi desenvolvido para avaliar a correlação do FCV e das subpopulações de linfócitos T CD4+ com os diferentes graus de estomatite-gengivite em 35 gatos naturalmente infectados pelo FIV ou não, divididos em 2 grupos. No experimento A, pôde-se determinar que apenas o FCV está relacionado à inflamação gengival, sendo detectado em 88,9% dos gatos com gengivite. Além disso, a infecção pelo FIV promoveu aumento significativo do número de linfócitos T CD8+ (p=0,004) e diminuição da razão CD4+:CD8+ (p<0,001). No experimento B, identificou-se que a infecção pelo FIV está associada à ocorrência da infecção pelo FCV (p=0,011), à presença de gengivite (p=0,022) e ao grau de gengivite (p<0,001), sendo que os gatos infectados pelo FIV foram os que apresentaram graus mais graves de gengivite. Portanto, no grupo dos animais infectados pelo FIV pôde-se observar maior ocorrência do FCV e presença de gengivite. Adicionalmente, o grau de gengivite está diretamente associado à infecção pelo FCV (p<0,001), onde os animais positivos para este vírus apresentaram graus mais graves de gengivite. Pelo presente estudo, pôde-se concluir que a ocorrência da infecção pelo FCV está diretamente associada ao CGEF em felinos e que a ocorrência do FCV foi significativa em animais que apresentaram graus mais graves de gengivite. Além disso, os gatos que apresentaram graus mais graves de gengivite, foram os que apresentaram menores valores de linfócitos T CD4+ e maior ocorrência de infecção pelo FCV. Contudo, não é possível saber se a co-infecção pelo FIV e FCV foi responsável pelo agravamento da gengivite e da condição imunológica dos gatos ou se a disfunção do sistema imune causada pelo FIV predispôs a infecção pelo FCV, levando a piora das lesões orais. / The inflammation that affects the oral cavity and the gingiva of felines are frequently observed in the medical practice and constitute a true diagnosis and therapy challenge to the physician. This condition is referred to as feline gingivitis-stomatitis-pharyngitis complex (FGSC) and it is a syndrome in which the common clinical profile is a severe gingival and oral mucosa inflammation. The etiopathogenesis of this disease is not completely elucidated but it is believed to be multifactorial. The viruses have been involved as etiologic agents in the feline chronic gingivitis-stomatitis pathogeny, however, the mechanism through which the viral infections participate in the development of the gingival disease of the infected animals remains undetermined. The present studys hypothesis is that the immunedepletion induced by the feline lentivirus (FIV) increases the risk of development of FCV and FHV-1, and stomatitis-gingivitis in cats. In order to do so, two experiments were conducted: the first one (A) was designed to evaluate the occurrence of FCV and FHV-1 in the oral cavity of 58 cats naturally infected by FIV or not, with and without gingivitis, through polymerase chain reaction (PCR), and to correlate this findings with the subpopulations of lymphocytes T CD4+, CD8+ and the ratio of CD4+:CD8+; the second one (B) was developed to evaluate the correlation of the FCV and of the subpopulations of lymphocytes T CD4+ with the different degrees of stomatitis-gingivitis in 35 cats naturally infected by the FIV or not, divided into two groups. In the experiment A, it was possible to determine that only the FCV is related to gingivitis, being detected in 88.9% of the cats with gingivitis. Moreover, the FIV infection promoted a significant increase in the number of lymphocytes T CD8+ (p=0.004) and a decrease of the ratio CD4+:CD8+ (p<0.001). In the experiment B, the FIV infection is associated to the occurrence of gingivitis due to the FCV (p=0.011), to the presence of gingivitis (p=0.022), and to the degree of gingivitis (p<0.001), being that the FIV infected cats were the ones that presented the more severe degrees of gingivitis. Therefore, in the group of animals infected by the FIV it was possible to observe a greater occurrence of FCV and the presence of gingivitis. Additionally, the degree of gingivitis is directly related to the FCV infection (p<0.001), where the animals that tested positive for this virus presented more severe degree of gingivitis. From the present study, it was possible to conclude that the occurrence of infection due to the FCV is directly related to FGSC in felines and that the occurrence of FCV was significant in animals that presented more severe degrees of gingivitis. Moreover, the cats that presented more severe degrees of gingivitis were the ones that presented lower values of lymphocytes T CD4+ and greater occurrence of FCV infection. However, it is not possible to know whether the co-infection due to the FIV and the FCV was responsible for the worsening of the gingivitis and of the immune condition of the cats, or if the immune system dysfunction caused by the FIV predisposed the FCV infection, leading to the aggravation of the oral lesions.

As alterações inflamatórias que afetam a cavidade oral e a gengiva dos felinos são frequentemente observadas na rotina médica e constituem verdadeiro desafio diagnóstico e terapêutico ao clínico. Denomina-se complexo gengivite-estomatitefaringite felina (CGEF) como sendo uma síndrome onde a apresentação clínica comum é a inflamação grave da gengiva e mucosa oral. A etiopatogênese desta doença não está totalmente elucidada mas acredita-se que seja multifatorial. As viroses têm sido implicadas como agentes etiológicos na patogenia da gengivite-estomatite crônica felina, entretanto, o mecanismo pelo qual as infecções virais participam no desenvolvimento da doença gengival nos animais afetados permanece indeterminado. A hipótese do presente estudo é de que a depleção imunológica induzida pelo lentivírus felino (FIV) aumenta o risco de ocorrência do FCV e do FHV-1 e da estomatite-gengivite em gatos. Para tanto, foram realizados 2 experimentos: o primeiro (A) foi delineado para avaliar a ocorrência do FCV e do FHV-1 na cavidade oral de 58 gatos naturalmente infectados pelo FIV ou não, com e sem gengivite, por meio da reação de polimerização em cadeia (PCR), assim como correlacionar esses achados com as subpopulações de linfócitos T CD4+, CD8+ e da razão CD4+:CD8+ e o segundo (B) foi desenvolvido para avaliar a correlação do FCV e das subpopulações de linfócitos T CD4+ com os diferentes graus de estomatite-gengivite em 35 gatos naturalmente infectados pelo FIV ou não, divididos em 2 grupos. No experimento A, pôde-se determinar que apenas o FCV está relacionado à inflamação gengival, sendo detectado em 88,9% dos gatos com gengivite. Além disso, a infecção pelo FIV promoveu aumento significativo do número de linfócitos T CD8+ (p=0,004) e diminuição da razão CD4+:CD8+ (p<0,001). No experimento B, identificou-se que a infecção pelo FIV está associada à ocorrência da infecção pelo FCV (p=0,011), à presença de gengivite (p=0,022) e ao grau de gengivite (p<0,001), sendo que os gatos infectados pelo FIV foram os que apresentaram graus mais graves de gengivite. Portanto, no grupo dos animais infectados pelo FIV pôde-se observar maior ocorrência do FCV e presença de gengivite. Adicionalmente, o grau de gengivite está diretamente associado à infecção pelo FCV (p<0,001), onde os animais positivos para este vírus apresentaram graus mais graves de gengivite. Pelo presente estudo, pôde-se concluir que a ocorrência da infecção pelo FCV está diretamente associada ao CGEF em felinos e que a ocorrência do FCV foi significativa em animais que apresentaram graus mais graves de gengivite. Além disso, os gatos que apresentaram graus mais graves de gengivite, foram os que apresentaram menores valores de linfócitos T CD4+ e maior ocorrência de infecção pelo FCV. Contudo, não é possível saber se a co-infecção pelo FIV e FCV foi responsável pelo agravamento da gengivite e da condição imunológica dos gatos ou se a disfunção do sistema imune causada pelo FIV predispôs a infecção pelo FCV, levando a piora das lesões orais. / The inflammation that affects the oral cavity and the gingiva of felines are frequently observed in the medical practice and constitute a true diagnosis and therapy challenge to the physician. This condition is referred to as feline gingivitis-stomatitis-pharyngitis complex (FGSC) and it is a syndrome in which the common clinical profile is a severe gingival and oral mucosa inflammation. The etiopathogenesis of this disease is not completely elucidated but it is believed to be multifactorial. The viruses have been involved as etiologic agents in the feline chronic gingivitis-stomatitis pathogeny, however, the mechanism through which the viral infections participate in the development of the gingival disease of the infected animals remains undetermined. The present studys hypothesis is that the immunedepletion induced by the feline lentivirus (FIV) increases the risk of development of FCV and FHV-1, and stomatitis-gingivitis in cats. In order to do so, two experiments were conducted: the first one (A) was designed to evaluate the occurrence of FCV and FHV-1 in the oral cavity of 58 cats naturally infected by FIV or not, with and without gingivitis, through polymerase chain reaction (PCR), and to correlate this findings with the subpopulations of lymphocytes T CD4+, CD8+ and the ratio of CD4+:CD8+; the second one (B) was developed to evaluate the correlation of the FCV and of the subpopulations of lymphocytes T CD4+ with the different degrees of stomatitis-gingivitis in 35 cats naturally infected by the FIV or not, divided into two groups. In the experiment A, it was possible to determine that only the FCV is related to gingivitis, being detected in 88.9% of the cats with gingivitis. Moreover, the FIV infection promoted a significant increase in the number of lymphocytes T CD8+ (p=0.004) and a decrease of the ratio CD4+:CD8+ (p<0.001). In the experiment B, the FIV infection is associated to the occurrence of gingivitis due to the FCV (p=0.011), to the presence of gingivitis (p=0.022), and to the degree of gingivitis (p<0.001), being that the FIV infected cats were the ones that presented the more severe degrees of gingivitis. Therefore, in the group of animals infected by the FIV it was possible to observe a greater occurrence of FCV and the presence of gingivitis. Additionally, the degree of gingivitis is directly related to the FCV infection (p<0.001), where the animals that tested positive for this virus presented more severe degree of gingivitis. From the present study, it was possible to conclude that the occurrence of infection due to the FCV is directly related to FGSC in felines and that the occurrence of FCV was significant in animals that presented more severe degrees of gingivitis. Moreover, the cats that presented more severe degrees of gingivitis were the ones that presented lower values of lymphocytes T CD4+ and greater occurrence of FCV infection. However, it is not possible to know whether the co-infection due to the FIV and the FCV was responsible for the worsening of the gingivitis and of the immune condition of the cats, or if the immune system dysfunction caused by the FIV predisposed the FCV infection, leading to the aggravation of the oral lesions.

No description available.