Herpesvírus bovino tipos 1, 2 e 5: sensibilidade a antivirais in vitro, patogenia e terapêutica experimental em coelhos
Autor(a) principal: | |
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Data de Publicação: | 2009 |
Tipo de documento: | Tese |
Idioma: | por |
Título da fonte: | Manancial - Repositório Digital da UFSM |
Texto Completo: | http://repositorio.ufsm.br/handle/1/4039 |
Resumo: | Aspects of bovine herpesvirus 5 (BoHV-5) pathogenesis and experimental therapies against BoHV-1 and BoHV-5 were investigated in vitro and in inoculated rabbits. In chapter 1, we investigated the role of nitric oxide (NO), a component of innate immunity against pathogens, in the neurological disease by BoHV-5 in rabbits. Spectrophotometry for NO products revealed that NO levels were significantly increased in several regions of the brain of rabbits with neurological disease [F(4, 40)=3.33; P<0.02]. Quantification of NO levels in the brain at different time points after virus inoculation revealed a gradual increase [F(12, 128)=2.82; P<0,003], correlated spatially and temporally with virus dissemination within the brain and preceding the development of neurological signs. Thus, we propose that the overproduction of NO in the brain of BoHV-5-infected rabbits may participate in the pathogenesis of neurological disease. In chapter 2, the activity of three anti-herpetic drugs was tested against BoHV-1, BoHV-2 and BoHV-5 in vitro by plaque reduction assay. Acyclovir was moderately active against the three viruses; Gancyclovir was moderately effective against BoHV-2, and to a lesser extent against BoHV-5, being poorly active against BoHV-1. Foscarnet (PFA) exhibited the most pronounced antiviral activity, being the only drug that, at the concentration of 100 ìg/mL, completely inhibited plaque formation by all three viruses. In chapter 3, we report the activity of PFA in rabbits inoculated with BoHV-1 or BoHV-5. Rabbits inoculated with BoHV-5 and treated with 100 mg/kg of PFA presented mortality rates (11/22 or 50%) statistically lower than non-treated controls (21/22 ou 95.4%) (P<0.0008). A significant reduction in the mean virus titers was observed at day 3 pi, the peak of virus shedding [F(9,108) = 2,23; P<0.03]. Reduction in virus shedding, frequency, severity and duration of ocular signs were also observed in rabbits inoculated with BoHV-1 into the conjunctival sac, comparing to the controls. The prolonged incubation period and the reduction in the duration of the clinical course of the PFA-treated group was significant (P<0.005 and P<0.04, respectively). Therefore, the activity of PFA in vivo against BoHV-1 and BoHV-5 may be exploited in further experimental therapies. In chapter 4, we investigated the effect of the inhibition of the inducible isoform of nitric oxide synthase (iNOS), associated or not with PFA treatment, on neurological infection by BoHV-5 in rabbits. Groups of BoHV-5-inoculated rabbits were treated with the iNOS inhibitor aminoguanidine (AG); with PFA; with both drugs; or maintained as virus controls. Morbidity and mortality rates were 100% (6/6) in the groups AG and CV, 66.7% (4/6) in the group PFA and 83.3% (5/6) in the group AG+PFA. The incubation period was significantly lower (P<0.05) and the onset of neurological disease occurred earlier and was more severe in the group AG. These results demonstrate that treatment with PFA reduced morbidity and mortality rates associated to BoHV-5 infection, that AG treatment anticipated the development of neurological signs, and that the development of neurolocial disease was delayed in the group treated with both drugs. Taken together, these results contribute to the knowledge of the pathogenesis of BoHV-5 neurological disease and pave the way for other experimental pathogenesis and therapy studies. |
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Herpesvírus bovino tipos 1, 2 e 5: sensibilidade a antivirais in vitro, patogenia e terapêutica experimental em coelhosBovine herpesviruses 1, 2 and 5: sensitivity to antivirals in vitro, pathogenesis and experimental therapy in rabbitsÓxido nítricoINOSNNOSBoHV-5BoHV-1CoelhosPatogeniaAntiviralFoscarnetGanciclovirAciclovirNitric oxideRabbitsPathogenesisAntiviral activityFoscarnetGancyclovirAcyclovirCNPQ::CIENCIAS AGRARIAS::MEDICINA VETERINARIAAspects of bovine herpesvirus 5 (BoHV-5) pathogenesis and experimental therapies against BoHV-1 and BoHV-5 were investigated in vitro and in inoculated rabbits. In chapter 1, we investigated the role of nitric oxide (NO), a component of innate immunity against pathogens, in the neurological disease by BoHV-5 in rabbits. Spectrophotometry for NO products revealed that NO levels were significantly increased in several regions of the brain of rabbits with neurological disease [F(4, 40)=3.33; P<0.02]. Quantification of NO levels in the brain at different time points after virus inoculation revealed a gradual increase [F(12, 128)=2.82; P<0,003], correlated spatially and temporally with virus dissemination within the brain and preceding the development of neurological signs. Thus, we propose that the overproduction of NO in the brain of BoHV-5-infected rabbits may participate in the pathogenesis of neurological disease. In chapter 2, the activity of three anti-herpetic drugs was tested against BoHV-1, BoHV-2 and BoHV-5 in vitro by plaque reduction assay. Acyclovir was moderately active against the three viruses; Gancyclovir was moderately effective against BoHV-2, and to a lesser extent against BoHV-5, being poorly active against BoHV-1. Foscarnet (PFA) exhibited the most pronounced antiviral activity, being the only drug that, at the concentration of 100 ìg/mL, completely inhibited plaque formation by all three viruses. In chapter 3, we report the activity of PFA in rabbits inoculated with BoHV-1 or BoHV-5. Rabbits inoculated with BoHV-5 and treated with 100 mg/kg of PFA presented mortality rates (11/22 or 50%) statistically lower than non-treated controls (21/22 ou 95.4%) (P<0.0008). A significant reduction in the mean virus titers was observed at day 3 pi, the peak of virus shedding [F(9,108) = 2,23; P<0.03]. Reduction in virus shedding, frequency, severity and duration of ocular signs were also observed in rabbits inoculated with BoHV-1 into the conjunctival sac, comparing to the controls. The prolonged incubation period and the reduction in the duration of the clinical course of the PFA-treated group was significant (P<0.005 and P<0.04, respectively). Therefore, the activity of PFA in vivo against BoHV-1 and BoHV-5 may be exploited in further experimental therapies. In chapter 4, we investigated the effect of the inhibition of the inducible isoform of nitric oxide synthase (iNOS), associated or not with PFA treatment, on neurological infection by BoHV-5 in rabbits. Groups of BoHV-5-inoculated rabbits were treated with the iNOS inhibitor aminoguanidine (AG); with PFA; with both drugs; or maintained as virus controls. Morbidity and mortality rates were 100% (6/6) in the groups AG and CV, 66.7% (4/6) in the group PFA and 83.3% (5/6) in the group AG+PFA. The incubation period was significantly lower (P<0.05) and the onset of neurological disease occurred earlier and was more severe in the group AG. These results demonstrate that treatment with PFA reduced morbidity and mortality rates associated to BoHV-5 infection, that AG treatment anticipated the development of neurological signs, and that the development of neurolocial disease was delayed in the group treated with both drugs. Taken together, these results contribute to the knowledge of the pathogenesis of BoHV-5 neurological disease and pave the way for other experimental pathogenesis and therapy studies.Coordenação de Aperfeiçoamento de Pessoal de Nível SuperiorAspectos da patogenia da infecção neurológica pelo herpesvírus bovino 5 (BoHV-5) e terapias experimentais contra o BoHV-1 e BoHV-5 foram estudados in vitro e em coelhos inoculados. O capítulo 1 relata a investigação do papel do óxido nítrico (NO), um componente da imunidade inata contra patógenos, na doença neurológica produzida pelo BoHV-5 em coelhos. Espectrofotometria para os produtos de degradação do NO revelou um aumento significativo nos seus níveis em várias regiões do encéfalo de coelhos infectados (F(4, 40)=3.33; P<0,02). A quantificação do NO no encéfalo nos dias seguintes à inoculação viral revelou um aumento gradativo (F(12, 128)=2.82; P<0,003), correlacionado temporal e espacialmente com a invasão e disseminação viral, e precedendo o desenvolvimento de sinais neurológicos. Sugere-se, assim, que a produção aumentada de NO em resposta à infecção possa participar da patogenia dessa doença neurológica. No capítulo 2, investigou-se a atividade de três fármacos antivirais frente ao BoHV-1, BoHV-2 e BoHV-5 in vitro pelo teste de redução do número de placas. O Aciclovir foi moderadamente ativo frente aos três vírus; o Ganciclovir apresentou atividade moderada frente ao BoHV-2 e, em menor grau, contra o BoHV-5, sendo ineficaz frente ao BoHV-1. O Foscarnet (PFA) apresentou a atividade antiviral mais pronunciada, sendo o único fármaco que, na concentração de 100 μg/mL, inibiu completamente a produção de placas pelos três herpesvírus bovinos. No capítulo 3, investigou-se a atividade do PFA em coelhos inoculados com o BoHV-1 ou BoHV-5. Coelhos inoculados com o BoHV-5 e tratados com 100 mg/kg do PFA apresentaram índices de mortalidade (11/22; 50%) estatisticamente inferiores aos controles não-tratados (21/22; 93,7%) (P<0,0008). Uma redução significativa no título médio de vírus foi observada no dia 3 pi, pico da excreção viral [F(9,108) = 2,23; P<0,03]. Em coelhos inoculados no saco conjuntival com o BoHV-1 e tratados com o PFA, foram observadas reduções na excreção viral, na frequência, severidade comparando-se com o grupo controle. O período de incubação prolongado e a redução na duração do curso clínico no grupo tratado foi significante (P<0,005 e P<0,04, respectivamente). A atividade antiviral do PFA in vivo contra o BoHV-1 e BoHV-5 abre a perspectiva para outras terapias experimentais. No capítulo 4, investigou-se o efeito da inibição da isoforma induzível da enzima óxido nítrico sintase (iNOS), associada ou não ao tratamento com o PFA, na infecção neurológica pelo BoHV-5 em coelhos. Grupos de coelhos inoculados com o BoHV-5 foram tratados com o inibidor da iNOS aminoguanidina (AG); com PFA; com ambos os fármacos; ou não receberam tratamento. Os índices de morbidade e mortalidade foram de 100% (6/6) nos grupos AG e controle; 66,7% (4/6) no grupo PFA e 83,3% (5/6) no grupo AG+PFA. O período de incubação foi significativamente menor (P<0,05) e os sinais neurológicos foram mais precoces e severos nos animais do grupo AG. Portanto, o tratamento com PFA reduziu a morbidade e mortalidade associadas com a infecção pelo BoHV-5; o tratamento com AG resultou no agravamento e na antecipação do quadro neurológico e no grupo tratado com ambos os fármacos observou-se um desenvolvimento mais tardio dos sinais neurológicos. Esses resultados contribuem para o conhecimento da patogenia da doença neurológica pelo BoHV-5 e abrem perspectivas para estudos adicionais de patogenia e terapêutica anti-herpesvírus.Universidade Federal de Santa MariaBRMedicina VeterináriaUFSMPrograma de Pós-Graduação em Medicina VeterináriaFlores, Eduardo Furtadohttp://lattes.cnpq.br/0446078331070694Weiblen, Rudihttp://lattes.cnpq.br/7946350215388090Botton, Sonia de Avilahttp://lattes.cnpq.br/0814772095155945Caron, Luizinhohttp://lattes.cnpq.br/9334336945441958Carregaro, Valéria Maria Larahttp://lattes.cnpq.br/6306187042995839Dezengrini, Renata2010-02-082010-02-082009-12-16info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisapplication/pdfapplication/pdfDEZENGRINI, Renata. Bovine herpesviruses 1, 2 and 5: sensitivity to antivirals in vitro, pathogenesis and experimental therapy in rabbits. 2009. 132 f. Tese (Doutorado em Medicina Veterinária) - Universidade Federal de Santa Maria, Santa Maria, 2009.http://repositorio.ufsm.br/handle/1/4039porinfo:eu-repo/semantics/openAccessreponame:Manancial - Repositório Digital da UFSMinstname:Universidade Federal de Santa Maria (UFSM)instacron:UFSM2022-08-25T18:15:43Zoai:repositorio.ufsm.br:1/4039Biblioteca Digital de Teses e Dissertaçõeshttps://repositorio.ufsm.br/ONGhttps://repositorio.ufsm.br/oai/requestatendimento.sib@ufsm.br||tedebc@gmail.comopendoar:2022-08-25T18:15:43Manancial - Repositório Digital da UFSM - Universidade Federal de Santa Maria (UFSM)false |
dc.title.none.fl_str_mv |
Herpesvírus bovino tipos 1, 2 e 5: sensibilidade a antivirais in vitro, patogenia e terapêutica experimental em coelhos Bovine herpesviruses 1, 2 and 5: sensitivity to antivirals in vitro, pathogenesis and experimental therapy in rabbits |
title |
Herpesvírus bovino tipos 1, 2 e 5: sensibilidade a antivirais in vitro, patogenia e terapêutica experimental em coelhos |
spellingShingle |
Herpesvírus bovino tipos 1, 2 e 5: sensibilidade a antivirais in vitro, patogenia e terapêutica experimental em coelhos Dezengrini, Renata Óxido nítrico INOS NNOS BoHV-5 BoHV-1 Coelhos Patogenia Antiviral Foscarnet Ganciclovir Aciclovir Nitric oxide Rabbits Pathogenesis Antiviral activity Foscarnet Gancyclovir Acyclovir CNPQ::CIENCIAS AGRARIAS::MEDICINA VETERINARIA |
title_short |
Herpesvírus bovino tipos 1, 2 e 5: sensibilidade a antivirais in vitro, patogenia e terapêutica experimental em coelhos |
title_full |
Herpesvírus bovino tipos 1, 2 e 5: sensibilidade a antivirais in vitro, patogenia e terapêutica experimental em coelhos |
title_fullStr |
Herpesvírus bovino tipos 1, 2 e 5: sensibilidade a antivirais in vitro, patogenia e terapêutica experimental em coelhos |
title_full_unstemmed |
Herpesvírus bovino tipos 1, 2 e 5: sensibilidade a antivirais in vitro, patogenia e terapêutica experimental em coelhos |
title_sort |
Herpesvírus bovino tipos 1, 2 e 5: sensibilidade a antivirais in vitro, patogenia e terapêutica experimental em coelhos |
author |
Dezengrini, Renata |
author_facet |
Dezengrini, Renata |
author_role |
author |
dc.contributor.none.fl_str_mv |
Flores, Eduardo Furtado http://lattes.cnpq.br/0446078331070694 Weiblen, Rudi http://lattes.cnpq.br/7946350215388090 Botton, Sonia de Avila http://lattes.cnpq.br/0814772095155945 Caron, Luizinho http://lattes.cnpq.br/9334336945441958 Carregaro, Valéria Maria Lara http://lattes.cnpq.br/6306187042995839 |
dc.contributor.author.fl_str_mv |
Dezengrini, Renata |
dc.subject.por.fl_str_mv |
Óxido nítrico INOS NNOS BoHV-5 BoHV-1 Coelhos Patogenia Antiviral Foscarnet Ganciclovir Aciclovir Nitric oxide Rabbits Pathogenesis Antiviral activity Foscarnet Gancyclovir Acyclovir CNPQ::CIENCIAS AGRARIAS::MEDICINA VETERINARIA |
topic |
Óxido nítrico INOS NNOS BoHV-5 BoHV-1 Coelhos Patogenia Antiviral Foscarnet Ganciclovir Aciclovir Nitric oxide Rabbits Pathogenesis Antiviral activity Foscarnet Gancyclovir Acyclovir CNPQ::CIENCIAS AGRARIAS::MEDICINA VETERINARIA |
description |
Aspects of bovine herpesvirus 5 (BoHV-5) pathogenesis and experimental therapies against BoHV-1 and BoHV-5 were investigated in vitro and in inoculated rabbits. In chapter 1, we investigated the role of nitric oxide (NO), a component of innate immunity against pathogens, in the neurological disease by BoHV-5 in rabbits. Spectrophotometry for NO products revealed that NO levels were significantly increased in several regions of the brain of rabbits with neurological disease [F(4, 40)=3.33; P<0.02]. Quantification of NO levels in the brain at different time points after virus inoculation revealed a gradual increase [F(12, 128)=2.82; P<0,003], correlated spatially and temporally with virus dissemination within the brain and preceding the development of neurological signs. Thus, we propose that the overproduction of NO in the brain of BoHV-5-infected rabbits may participate in the pathogenesis of neurological disease. In chapter 2, the activity of three anti-herpetic drugs was tested against BoHV-1, BoHV-2 and BoHV-5 in vitro by plaque reduction assay. Acyclovir was moderately active against the three viruses; Gancyclovir was moderately effective against BoHV-2, and to a lesser extent against BoHV-5, being poorly active against BoHV-1. Foscarnet (PFA) exhibited the most pronounced antiviral activity, being the only drug that, at the concentration of 100 ìg/mL, completely inhibited plaque formation by all three viruses. In chapter 3, we report the activity of PFA in rabbits inoculated with BoHV-1 or BoHV-5. Rabbits inoculated with BoHV-5 and treated with 100 mg/kg of PFA presented mortality rates (11/22 or 50%) statistically lower than non-treated controls (21/22 ou 95.4%) (P<0.0008). A significant reduction in the mean virus titers was observed at day 3 pi, the peak of virus shedding [F(9,108) = 2,23; P<0.03]. Reduction in virus shedding, frequency, severity and duration of ocular signs were also observed in rabbits inoculated with BoHV-1 into the conjunctival sac, comparing to the controls. The prolonged incubation period and the reduction in the duration of the clinical course of the PFA-treated group was significant (P<0.005 and P<0.04, respectively). Therefore, the activity of PFA in vivo against BoHV-1 and BoHV-5 may be exploited in further experimental therapies. In chapter 4, we investigated the effect of the inhibition of the inducible isoform of nitric oxide synthase (iNOS), associated or not with PFA treatment, on neurological infection by BoHV-5 in rabbits. Groups of BoHV-5-inoculated rabbits were treated with the iNOS inhibitor aminoguanidine (AG); with PFA; with both drugs; or maintained as virus controls. Morbidity and mortality rates were 100% (6/6) in the groups AG and CV, 66.7% (4/6) in the group PFA and 83.3% (5/6) in the group AG+PFA. The incubation period was significantly lower (P<0.05) and the onset of neurological disease occurred earlier and was more severe in the group AG. These results demonstrate that treatment with PFA reduced morbidity and mortality rates associated to BoHV-5 infection, that AG treatment anticipated the development of neurological signs, and that the development of neurolocial disease was delayed in the group treated with both drugs. Taken together, these results contribute to the knowledge of the pathogenesis of BoHV-5 neurological disease and pave the way for other experimental pathogenesis and therapy studies. |
publishDate |
2009 |
dc.date.none.fl_str_mv |
2009-12-16 2010-02-08 2010-02-08 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/doctoralThesis |
format |
doctoralThesis |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
DEZENGRINI, Renata. Bovine herpesviruses 1, 2 and 5: sensitivity to antivirals in vitro, pathogenesis and experimental therapy in rabbits. 2009. 132 f. Tese (Doutorado em Medicina Veterinária) - Universidade Federal de Santa Maria, Santa Maria, 2009. http://repositorio.ufsm.br/handle/1/4039 |
identifier_str_mv |
DEZENGRINI, Renata. Bovine herpesviruses 1, 2 and 5: sensitivity to antivirals in vitro, pathogenesis and experimental therapy in rabbits. 2009. 132 f. Tese (Doutorado em Medicina Veterinária) - Universidade Federal de Santa Maria, Santa Maria, 2009. |
url |
http://repositorio.ufsm.br/handle/1/4039 |
dc.language.iso.fl_str_mv |
por |
language |
por |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf application/pdf |
dc.publisher.none.fl_str_mv |
Universidade Federal de Santa Maria BR Medicina Veterinária UFSM Programa de Pós-Graduação em Medicina Veterinária |
publisher.none.fl_str_mv |
Universidade Federal de Santa Maria BR Medicina Veterinária UFSM Programa de Pós-Graduação em Medicina Veterinária |
dc.source.none.fl_str_mv |
reponame:Manancial - Repositório Digital da UFSM instname:Universidade Federal de Santa Maria (UFSM) instacron:UFSM |
instname_str |
Universidade Federal de Santa Maria (UFSM) |
instacron_str |
UFSM |
institution |
UFSM |
reponame_str |
Manancial - Repositório Digital da UFSM |
collection |
Manancial - Repositório Digital da UFSM |
repository.name.fl_str_mv |
Manancial - Repositório Digital da UFSM - Universidade Federal de Santa Maria (UFSM) |
repository.mail.fl_str_mv |
atendimento.sib@ufsm.br||tedebc@gmail.com |
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1805922101515780096 |