Abstract There is evidence that the process leading to type 1 diabetes may start in early infancy or even in utero, with a prodrome of variable duration preceding clinical manifestation. The purpose of the present work was to learn more about the occurrence and significance of humoral beta-cell autoimmunity during pregnancy and in infancy, to search for possible signs of prenatal or early postnatal induction of beta-cell autoimmunity and to explore the role of enterovirus infections as potential triggers of such autoimmunity. The population comprised mothers and their newborn infants from families with type 1 diabetes who had entered the first (n=20) or the second pilot study (n=208) of the Trial to Reduce IDDM in the Genetically at Risk (TRIGR). Almost 40% of the mothers with type 1 diabetes had antibodies to islet cells (ICA), 55% to glutamic acid decarboxylase (GADA) and 54% to the IA-2 protein (IA-2A) in the two samples taken during pregnancy, where the frequencies for the unaffected mothers were 5%, 5% and 3%, respectively. All autoantibody specificities were detected in the cord blood largely at the same frequencies as in the maternal circulation. In addition, ICA was found in 2.7%, GADA in 0.6%, IA-2A in 0.3% and insulin autoantibodies (IAA) in 0.1% out of a series of 1002 cord blood samples from infants representing the normal population. None of the infants of the autoantibody-negative mothers in these series had autoantibodies detectable in their cord blood. The rate of decline of transplacentally transferred autoantibodies during the first months of life was observed to be similar to that reported for the disappearance of maternally acquired IgG antibodies, the estimated mean elimination time ranging from 3.1-4.5 months. The higher the initial autoantibody level, the longer was the elimination time, and transplacentally transferred autoantibodies were occasionally detected up to the age of 9-12 months, and even at 15 months in a very few cases. The peak incidence of enterovirus RNA in serum was observed at the age of 6-12 months, while that of infections, based on changes in antibody titres, was seen at the age of 18 months. The frequency of enterovirus infections in the autoantibody-positive infants during the 6 months before the appearance of the first autoantibodies was almost three times higher than in age-matched infants testing negative for autoantibodies. These observations suggest that pregnancy does not have any strong modulating effect on the prevalence and titres of diabetes-associated autoantibodies. If such autoantibodies are present in the mother, most of them are transferred to the foetal circulation and are detectable in the cord blood. No signs of foetal induction of beta-cell autoimmunity were observed, indicating that such a phenomenon is extremely rare. Most of the transplacentally transferred autoantibodies disappear within the first 3-6 months of postnatal life, but they may persist even up to the age of 15 months in exceptional cases, suggesting that the optimal age for the initiation of large-scale screening in the general population is 18-24 months. The temporal association between enterovirus infections and the first signs of beta-cell autoimmunity supports the hypothesis that enteroviruses may induce a primary beta-cell insult.

Appendices data can be found at: A: http://dx.doi.org/10.15142/T35P49 B: http://dx.doi.org/10.15142/T3201B C: http://dx.doi.org/10.15142/T3X59V D: http://dx.doi.org/10.15142/T3SG6K F: http://dx.doi.org/10.15142/T3NP4N

La surexpression de protéines d’efflux, et tout particulièrement la P-glycoprotéine, est impliquée dans la multidrug résistance. Dans cette thèse, nous démontrons que le vandetanib, inhibiteur de tyrosine kinase, est à la fois substrat et inhibiteur de la P-glycoprotéine et qu’il est capable de réverser in vitro la résistance à la doxorubicine liée à la surexpression de la P-glycoprotéine.Nous nous sommes également intéressés à l’étude du passage transplacentaire du vandetanib et nous montrons que ce médicament traverse la barrière placentaire. / Overexpression of ABC transporters, especially P-glycoprotein, is involved in multidrug resistance. In this study, we demonstrate that vandetanib, a tyrosine kinase inhibitor, is both substrate and inhibitor of P-glycoprotein and is able to reverse in vitro resistance to doxorubicin, linked to overexpression of P-glycoprotein.We also studied the placental transfer of vandetanib and we show that this drug crosses the placenta.

Submitted by Felipe dos Santos Gomes (felipesantosg@yahoo.com.br) on 2018-06-05T14:18:52Z No. of bitstreams: 1 Dissertação Felipe dos Santos Gomes.pdf: 1189458 bytes, checksum: 7917af6743501bdde9a3c3a0112e23aa (MD5) / Approved for entry into archive by Alexandra Maria Donadon Lusser Segali null (alexmar@fcav.unesp.br) on 2018-06-05T18:53:33Z (GMT) No. of bitstreams: 1 gomes_fs_me_jabo.pdf: 1233173 bytes, checksum: 9619264fd2c88aa95c12e3757010eed9 (MD5) / Made available in DSpace on 2018-06-05T18:53:33Z (GMT). No. of bitstreams: 1 gomes_fs_me_jabo.pdf: 1233173 bytes, checksum: 9619264fd2c88aa95c12e3757010eed9 (MD5) Previous issue date: 2018-05-04 / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / A infecção persistente ao vírus da diarreia viral bovina (BVDV) pode viabilizar a disseminação do vírus no rebanho, assim como interferir no controle da infecção. Ao mesmo tempo, em suínos, a presença de soropositivos para BVDV pode causar transtornos aos inquéritos sorológicos para a peste suína clássica (PSC). Este trabalho teve como objetivo determinar a condição de persistentemente infectado em leitões nascidos de porcas infectadas experimentalmente pelo vírus da diarreia viral bovina. Foram selecionadas seis porcas prenhes para este estudo que foram divididas em dois grupos, sendo um grupo inoculado com BVDV-2 (G1; n=4) aos 45 dias de gestação, e um grupo controle (G2; n=2). Foram realizadas avaliações clínicas nas porcas diariamente. Os neonatos foram monitorados durante 35 dias, em que foram realizadas avaliações clínicas rotineiras e colheita de suabes nasal dos leitões e de amostras de sangue venoso das porcas e dos leitões para obtenção de sangue total e soro a cada 72 horas. Foram realizados testes de RT-PCR para diagnóstico direto, e virusneutralização para avaliação sorológica. As porcas apresentaram soroconversão entre o 17ºdia pós-infecção (dpi) e o 22ºdpi, mas não foi detectada viremia. Nenhum leitão apresentou títulos de anticorpos ou viremia ao nascimento. Não ocorreu a transmissão transplacentária do vírus, portanto, não foi possível observar animais PI. / The persistently infection to bovine viral diarrhea virus (BVDV) can enable the spread of virus in the herd, as well as interfere in the control of infection. Concurrently, the presence of seropositive pigs may interfere with serological surveys for classical swine fever (CSF). This project aimed to determine the condition of persistently infected in piglets born from gilts infected with bovine viral diarrhea. BVDV-2 was inoculated in four pregnant gilts (G1; n=4), and a placebo was administered in two gilts, which were the control group (G2; n=2). Clinical evaluations were daily performed in the gilts. The newborns were monitored during 35 days, with clinical evaluation and whole blood, serum and nasal swabs sampling every 72 hours. RT-PCR and virus neutralization tests (VN) were performed. The gilts presented seroconversion between 17º dpi and 22ºdpi, but no viremia was detected. No piglets presented antibody titers or viremia at birth. Transplacental transmission of the virus did not occur, therefore, PI animals could not be observed. / FAPESP: 16/214212

Submitted by Claudia Rocha (claudia.rocha@udesc.br) on 2018-03-16T16:12:04Z No. of bitstreams: 1 PGCA17MA223.pdf: 789583 bytes, checksum: 826470c73aedad966296545af60b30b8 (MD5) / Made available in DSpace on 2018-03-16T16:12:04Z (GMT). No. of bitstreams: 1 PGCA17MA223.pdf: 789583 bytes, checksum: 826470c73aedad966296545af60b30b8 (MD5) Previous issue date: 2017-02-10 / In order to assess the possibility of congenital transmission of Neospora caninum in the ovine species and the implications of the infection of the agent in different stages of pregnancy, eleven fertile, serologically negative to N. caninum and Toxoplasma gondii, were distributed in five groups (A = 3 animals, B, C, D and E = 2 animals each one). Group A was inoculated intravenously with 1x107 tachyzoites of N. caninum strain Nc-1, which was insufficient for the detection of seroconversion. The animals of groups B, C and D were inoculated with 2x107 tachyzoites. Group E was maintained as control (not inoculated). The animals of group A were inoculated 30 days before mating, and groups B, C and D at 65, 100 and 120 days of pregnancy, respectively. Animal blood samples were collected on days -2, 2, 5, 7, 14, 21, 28, 35, 42 days postinfection (DPI) to perform complete blood count (CBC) and to obtain serum for the IgG antibody test by Indirect Fluorescent Antibody Test (IFAT). Clinical examinations (body temperature and heart and respiratory rates) were performed daily between -2 and 14 DPI and, thereafter, weekly until the end of the experiment (42 DPI). From lambs born alive, clinical examination, blood collection for IFAT and CBC were performed. After euthanasia, lambs were necropsied and organs (CNS, liver, heart, lung and placenta) were collected for histopathological examination. All the ewes of Groups B, C and D seroconverted. The animals of groups A and E remained seronegative throughout the experiment. No clinical or hematological changes were observed due to inoculation in the ewes, except for one ewe from group B that presented retained placenta. One lamb born from Group B was seroreagent (precolostral) to N. caninum by IFAT (1:400), indicating transplacental transmission, in addition to presenting hypothermia and low birth weight. Another lamb from group B and one from group C were also seropositive, but they drank colostrum. One lamb from Group C (100 days of gestation) and twin lambs from Group D (120 days of gestation) did not drink colostrum and were seronegative. One Group D lamb was seronegative even after ingesting colostrum. There were no haematological and pathological changes in any of the lambs of all groups. The results demonstrate the occurrence of transplacental transmission of N. caninum in a ewe inoculated at 65 days of gestation and suggest that the same occurred with two other ewes (inoculated at 65 and 100 days of gestation), however, higher specificity tests (PCR) are necessary for the confirmation of congenital transmission in these animals, which, although seropositive, drank colostrum prior to collection of blood / Com o objetivo de avaliar a possibilidade de transmissão congênita de Neospora caninum na espécie ovina e as implicações da infecção do agente em diferentes estádios da gestação, onze ovelhas férteis, sorologicamente negativas para N. caninum e Toxoplasma gondii, foram distribuídas em cinco grupos (A= 3 animais, B, C, D e E = 2 animais cada). O Grupo A foi inoculado intravenosamente com 1x107 taquizoítos da cepa Nc-1 de N. caninum, sendo esta dose insuficiente para a detecção de soroconversão. Os animais dos grupos B, C e D foram inoculados com 2x107 taquizoítos. O Grupo E foi mantido como controle (não inoculado). Os animais do grupo A foram inoculados 30 dias antes da cobertura, e os grupos B, C e D aos 65, 100 e 120 dias de gestação, respectivamente. Amostras de sangue dos animais foram colhidas nos dias -2, 2, 5, 7, 14, 21, 28, 35, 42 dias pós-infecção (DPI) para realização de hemogramas e obtenção de soro para a pesquisa de anticorpos IgG por meio da Reação de Imunofluorescência Indireta (RIFI). Exames clínicos (temperatura corporal e frequências cardíaca e respiratória) foram realizados diariamente entre -2 e 14 DPI e, na sequência, semanalmente até o final do experimento (42 DPI). Dos cordeiros nascidos, realizou-se exame clínico, colheita de sangue para realização da RIFI e hemograma. Após eutanásia, os cordeiros foram necropsiados e órgãos foram colhidos (SNC, fígado, coração, pulmão e placenta) para exame histopatológico. Todas as ovelhas dos Grupos B, C e D soroconverteram. Os animais dos grupos A e E mantiveram-se soronegativos ao longo de todo o experimento. Não foram observadas alterações clínicas ou hematológicas decorrentes da inoculação nas ovelhas, com exceção de uma ovelha do grupo B que apresentou retenção de placenta. Uma cordeira nascida do Grupo B foi sororreagente (pré-colostral) para N. caninum pela RIFI (1:400), indicando transmissão transplacentária, além de apresentar hipotermia e baixo peso ao nascer. Outro cordeiro do grupo B e um do grupo C também foram soropositivos, entretanto mamaram colostro. Um cordeiro do Grupo C (100 dias de gestação) e os dois cordeiros gêmeos do Grupo D (120 dias de gestação) não mamaram o colostro e foram soronegativos. Um cordeiro do Grupo D apresentou-se soronegativo mesmo após ter ingerido o colostro. Não houve alterações hematológicas e patológicas em nenhum dos cordeiros de todos os grupos. Os resultados demonstram ocorrência de transmissão transplacentária de N. caninum em uma ovelha inoculada aos 65 dias de gestação e sugerem que o mesmo ocorreu com outras duas ovelhas (inoculadas aos 65 e aos 100 dias de gestação), no entanto, testes com maior especificidade (PCR) são necessários para a confirmação da transmissão congênita nestes animais que, embora soropositivos, mamaram o colostro antes da colheita do sangue

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22686号 / 医博第4630号 / 新制||医||1045(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 生田 宏一, 教授 竹内 理, 教授 杉田 昌彦 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

La Fièvre Catarrhale Ovine est une arbovirose due à un Orbivirus touchant les ruminants. Récemment, une épizootie majeure, notamment due au sérotype 8 du virus (BTV-8), a touché les ruminants Européens. Ce sérotype a présenté plusieurs particularités telles que le spectre d’hôte original, et la transmission transplacentaire. L’impact de l’infection par le BTV-8 chez le caprin a été étudiée dans ce travail d’un point de vue clinique, virologique, hématologique et sérologique, et notamment pour ce dernier aspect à travers le développement de deux outils sérologiques. L’impact d’une infection maternelle sur le fœtus a également été étudié.Ces travaux ont confirmé que l’impact de l’infection par le BTV-8 chez les caprins est modéré, tant d’un point de vue clinique que d’un point de vue hématologique. Ce travail a également permis de faire ressortir plusieurs connaissances nouvelles: un impact modéré sur les comptages leucocytaires ; une transmission transplacentaire du virus lors d’infection en milieu de gestation ; une détection du virus dans la semence ; une possible transmission « directe », non vectorielle.Ces 3 dernières constatations n’avaient jusqu’alors pas été rapportées dans la littérature chez les caprins, mais avaient été observées chez les ovins et les bovins. Ceci confirme que, même si les caprins sont des animaux sensibles mais que l’impact clinique est limité, la plupart des caractéristiques faisant la spécificité de l’infection par la souche européenne du BTV-8 peuvent également être retrouvées dans cette espèce. Néanmoins, l’absence de description de ces particularités dans des conditions d’infection naturelle ne permet pas de conclure quant à leur impact sur le terrain.Des outils sérologiques ont été également développés afin d’étudier les propriétés antigéniques des protéines virales chez le caprin. La production des protéines recombinantes NS1, NS3, VP7 et VP2 en système baculovirus, et de la protéine NS2 en système E. coli, ont permis l’obtention de protéines recombinantes. Ces 5 protéines recombinantes ont permis le développement de tests sérologiques permettant d’étudier leurs propriétés antigéniques et la cinétique d’apparition des anticorps après vaccination ou/et infection par le BTV-8 chez le caprin.Dans un premier temps, des tests ELISA indirect NS1, NS2, NS3, VP7 et VP2 ont été développés, et la capacité des tests ELISA NS et VP7 à permettre une différenciation entre les animaux infectés et vaccinés a été évaluée. Cependant, des anticorps anti-NS2 et NS3 ont été détectés dans les sérums d’animaux vaccinés et une faible réponse obtenue en ELISA NS1 chez les animaux infectés rend difficile l’utilisation d’un test ELISA DIVA basé sur ces 3 protéines non structurales. Enfin, une réponse en anticorps anti-VP2 est détectée par le test ELISA VP2 après vaccination et après épreuve virulente, suggérant une détection d’anticorps spécifiques de type par ce test.Dans un second temps, un test Luminex multiplex, basé sur l’utilisation des protéines VP7 et VP2 a été développé. Le Luminex VP7 présente une très bonne corrélation avec l’ELISA VP7 lorsque les sérums d’animaux infectés sont testés, avec une aire sous la courbe de 0,987. Les performances de ce test paraissent cependant modérées lorsque des sérums issus d’animaux ayant reçu une unique injection vaccinale sont testés. Le Luminex VP2 présente des performances également excellentes, avec une aire sous la courbe de 0,978. Les VPP et VPN ont été calculées pour des prévalences très faibles (0,5%, correspondant à la prévalence devant être détectée par le screening sérologique d’animaux sentinelles) : la VPP est alors très faible mais la VPN est très élevée (99,99% pour VP7, 99,95% pour VP2). Le test Luminex multiplex développé, caractérisé par une VPN très élevée, permet d’exclure avec confiance la présence du BTV-8 dans une région indemne lors de résultat négatif, correspondant parfaitement aux objectifs assignés. / Bluetongue is an infectious non contagious arbovirosis caused by Bluetongue virus (BTV), belonging to the genus Orbivirus. Recently, a major epizooty, due to BTV-8, was encountered in European ruminants. This serotype presented several original features such as an original host spectrum and transplacental transmission. This work consisted in studying the impact of BTV-8 infection in goats from a clinical, virological, haematological and serological (after development of two new serological tests) point of view, because of the lack of knowledge in this specie. The impact on foetuses of infection during gestation was also studied.The different animal studies realised confirmed that the BTV-8 infection has a moderate impact in goats from a clinical and haematological point of view. These studies led to obtain new information about BTV-8 impact: moderate impact on leucocytes counts; transplacental transmission of the virus when infection occurs in mid-pregnancy; detection of BTV-8 in bucks’ semen; direct, non vectorial transmission. The last 3 results had never been described in goats with BTV-8 before but had been encountered in sheep and cattle: it proves that, even if goats are susceptible to the infection but are less affected by the virus, most of feature of BTV-8 North European strain can also be encountered in this specie. However, these features have not been described in natural conditions, making impossible to conclude on their impact in the field.In a second part of this thesis, serological tool have been developed in order to study antigenic properties of viral proteins in goats. Recombinant proteins NS1, NS3, VP7 and VP2 were produced in baculovirus system, while NS2 was produced in E. coli system. These recombinant proteins were used to develop serological test in order to study antigenic properties and the kinetic of antibodies response against this 5 proteins after vaccination against and infection by BTV-8 in goats.In a first part, indirect ELISA NS1, NS2, NS3, VP7 and VP2 were developed, and the opportunity to develop DIVA ELISA test using NS and VP ELISA was evaluated. However, detection of antibodies against NS2 and NS3 in vaccinated animals, and the difficulties to detect antibodies against NS1 in infected animals led us to conclude that a DIVA ELISA test using non-structural proteins was difficult. Finally, it was possible to detect antibodies against VP2 in infected and vaccinated animals using our VP2 ELISA, suggesting a detection of antibodies specific of serotype by this test.In a second part, a multiplex Luminex test, using VP7 and VP2, was developed. This test has, for VP7 detection, a strong correlation with cELISA VP7, with an area under the curve of 0.987. Luminex VP7 performance is moderate when sera from goats having only one vaccine administration were tested. Concerning Luminex VP2, test performance are also excellent with an area under the curve of 0.978. When a prevalence of 0.5% was applied (prevalence that should be detected by serological screening in Europe), de predictive negative value was very high (99.99% for Luminex VP7; 99.95% for Luminex VP2). The Luminex test developed, with a very high PNV, can exclude with a high level of confidence the presence of BTV-8 in a free-area.

Os tripanosomas são parasitas hemoflagelados com importância médica para humanos e animais domésticos. Surtos de infecções agudas graves por T.vivax têm sido relatados em todo Brasil onde perdas econômicas e falhas reprodutivas são observadas. Neste trabalho, uma infecção experimental por T. vivax em ovinos confirmou sua transmissão transplacentária. Em relação à epidemiologia de T. vivax, para entender o papel dos jumentos em surtos no Semiárido Brasileiro, foram realizados ensaios parasitológicos e moleculares em infecções naturais e experimentais. Nossos resultados mostraram animais assintomáticos, portanto, podem atuar como potenciais reservatórios. Além disso, estudos filogenéticos revelaram uma diversidade genética inesperada em tripanossomas no Leste da África, especialmente em moscas tsé-tsé. Novos genótipos de T. vivax foram caracterizados e tripanossomas do subgênero Nanomonnas se mostraram prevalentes nestas infecções. Nesta abordagem, conseguimos identificar T. suis e novas espécies do subgênero Pycnomonas presentes em animais selvagens e domésticos. / Trypanosomes are hemoflagellates parasites with medical importance to humans and domestic animals. Outbreaks of severe acute infections by T. vivax have been reported throughout Brazil, where economic loss and reproductive failure are observed. In this study, an experimental infection by T. vivax in sheep confirmed the transplacental transmission of this parasite. Regarding T. vivax epidemiology, to understand the role played by donkeys in outbreaks in the Brazilian Semiarid, we performed parasitological and molecular assays in naturally and experimentally infections. Our findings show that infected donkeys are asymptomatic and, thus, are potential reservoirs. In addition, phylogenetic studies have revealed an unexpected genetic diversity in East Africa, especially in tsetse flies. New genotypes of T. vivax were characterized and trypanosomes of the subgenus Nanomonnas were prevalent in these infections. In this approach, we can identify T. suis and new species of the subgenus Pycnomonas present in wild and domestic animals.

As espécies Klebsiella pneumoniae, Escherichia coli e Pseudomonas aeruginosa são responsáveis por infecções neonatais hospitalares. Lipopolissacarídeo (LPS) é o principal indutor de respostas inflamatórias. Os objetivos foram avaliar a transferência placentária de IgG reativa ao LPS de K. pneumoniae, E. coli O111, O26 e O6 e P. aeruginosa empregando ELISA para dosar IgG em soro materno e de cordão de 29 neonatos pré-termos e 32 a termo; analisar IgM total e específica no soro materno; e investigar a influência das patologias apresentadas pelas mães na transferência placentária. Concentrações de IgG total foram reduzidas em pré-termos como esperado, porem índices de transferência placentária de IgG total e IgG anti-LPS foram sistematicamente reduzidos quando comparados aos neonatos a termo. Níveis de IgM total e anti-LPS foram equivalentes em mães de ambos os grupos. As patologias das mães influenciaram os níveis de IgM no grupo de mães de pré-termos. Estes resultados indicam uma imunidade adquirida deficiente pelo grupo pré-termo aumentando os riscos de infecção. / Klebsiella pneumoniae, Escherichia coli and Pseudomonas aeruginosa species are responsible for neonatal nosocomial infections. Bacterial lipopolysaccharide (LPS) is the major inducer of the inflammatory responses. The aims were to evaluate the placental transfer of IgG reactive to LPS present in K. pneumoniae, in E. coli O111, O26 and O6 and in P. aeruginosa employing ELISA to detect IgG in maternal and cord sera from 29 preterm and 32 term neonates; to analyze total and specific IgM on the mothers sera; and to investigate the influence of the pathologies presented by some mothers in the placental transfer. Total IgG concentrations were reduced in preterm neonates as expected, but placental transfer indexes of total and anti-LPS IgG were systematically reduced when compared with term neonates. Total and anti-LPS IgM levels were equivalent on mothers of both groups. The mothers pathologies influenced only the IgM levels in the preterm mothers group. These results indicate a deficient acquired immunity by the preterm group increasing the risk of infection.

Made available in DSpace on 2016-08-15T20:31:12Z (GMT). No. of bitstreams: 1 TacianaMFS_DISSERT.pdf: 5120739 bytes, checksum: 32c27cee135df1f36b3fe8821e9ab1ca (MD5) Previous issue date: 2012-05-25 / This study aimed to investigate the effect of experimental infection with Trypanosoma vivax in ewes at different stages of pregnancy, to determine the pathogenesis of reproductive failure, and confirm transplacental transmission by PCR. A total of 12 pregnant ewes twelve, adults into three groups G1, consisting of three ewes infected in the first third of pregnancy, G2, consisting of three infected ewes in the final third of gestation, and G3, consisting of six non-infected sheep (control group .) Each ewes G1 and G2 were inoculated with trypomastigotes 1.25 x105. Clinical examination, assessment of hematocrit, serum chemistry, determination of plasma progesterone and parasitemia were determined daily. Pathological examinations were conducted of the fetus, placenta, umbilical cord blood and DNA detection of the parasite in the placenta, amniotic fluid, blood and tissues of fetuses. The parasitaemia was high, reaching peaks of 2.7 x106, being persistent throughout the experimental period. The infection was characterized by the ewes mortality and perinatal mortality in the first third; abortion and perinatal mortality in the final third of gestation. The factors possibly related maternal reproductive failures were low body score, hematocrit, serum glucose, total protein, cholesterol and progesterone. The presence of DNA of T. vivax in the blood and tissues of fetuses, placenta and amniotic fluid, confirming transplacental transmission of the parasite. The presence of histological lesions in the fetal organs and placenta suggest the involvement of the parasite in the pathophysiological mechanism of reproductive damage / O presente estudo teve como objetivo investigar o efeito da infecção experimental por Trypanosoma vivax em ovelhas em diferentes fases da gestação, determinar a patogênese das falhas reprodutivas, e confirmar a transmissão transplacentária por PCR. Foram utilizadas 12 doze ovelhas prenhas, adultas em três grupos experimentais G1, formado por três ovelhas infectadas no terço inicial da gestação; G2, composto por três ovelhas infectadas no terço final da gestação; e G3, constituído por seis ovinos não infectados (grupo controle). Cada ovelha do G1 e G2 foi inoculada com 1,25x105 tripomastigotas. Exames clínicos, avaliação do hematócrito, bioquímica sérica, determinação da concentração plasmática de progesterona e parasitemia foram determinados diariamente. Foram realizados exames anatomopatológicos dos fetos, placenta, cordão umbilical e pesquisa de DNA do parasita na placenta, liquido amniótico, sangue e tecidos dos fetos. A parasitemia foi alta, alcançando picos de 2,7x106, sendo persistente durante todo o período experimental. A infecção foi caracterizada por mortalidade das ovelhas e mortalidade perinatal no terço inicial; aborto e mortalidade perinatal no terço final da gestação. Os fatores possivelmente relacionados com as falhas reprodutivas maternas foram baixos escore corporal, hematócrito, níveis séricos de glicose, proteína total, colesterol e progesterona. A presença do DNA do T. vivax no sangue e tecidos de fetos, placenta e liquido amniótico, confirma a transmissão transplacentária do parasita. A presença de lesões histológicas nos órgãos fetais e placenta sugerem a participação do parasita no mecanismo etiopatogênico de danos reprodutivos