RESUMEN
The absence of an adequate animal model for studies has limited the understanding of congenital Zika syndrome (CZS) in humans during the outbreak in America. In this study, we used squirrel monkeys (Saimiri collinsi), a neotropical primate (which mimics the stages of human pregnancy), as a model of Zika virus (ZIKV) infection. Seven pregnant female squirrel monkeys were experimentally infected at three different gestational stages, and we were able reproduce a broad range of clinical manifestations of ZIKV lesions observed in newborn humans. Histopathological and immunohistochemical analyses of early-infected newborns (2/4) revealed damage to various areas of the brain and ZIKV antigens in the cytoplasm of neurons and glial cells, indicative of CZS. The changes caused by ZIKV infection were intrauterine developmental delay, ventriculomegaly, simplified brain gyri, vascular impairment and neuroprogenitor cell dysfunction. Our data show that the ZIKV infection outcome in squirrel monkeys is similar to that in humans, indicating that this model can be used to help answer questions about the effect of ZIKV infection on neuroembryonic development and the morphological changes induced by CZS.
Asunto(s)
Encéfalo , Complicaciones Infecciosas del Embarazo , Infección por el Virus Zika , Virus Zika , Animales , Animales Recién Nacidos , Encéfalo/embriología , Encéfalo/patología , Encéfalo/virología , Femenino , Embarazo , Complicaciones Infecciosas del Embarazo/patología , Complicaciones Infecciosas del Embarazo/virología , Saimiri , Síndrome , Infección por el Virus Zika/embriología , Infección por el Virus Zika/patologíaRESUMEN
Importance: The evolution of fetal brain injury by Zika virus (ZIKV) infection is not well described. Objectives: To perform longitudinal neuroimaging of fetuses and infants exposed to in utero maternal ZIKV infection using concomitant magnetic resonance imaging (MRI) and ultrasonography (US), as well as to determine the duration of viremia in pregnant women with ZIKV infection and whether the duration of viremia correlated with fetal and/or infant brain abnormalities. Design, Setting, and Participants: A cohort of 82 pregnant women with clinical criteria for probable ZIKV infection in Barranquilla, Colombia, and Washington, DC, were enrolled from June 15, 2016, through June 27, 2017, with Colombian women identified by community recruitment and physician referral and travel-related cases of American women recruited from a Congenital Zika Program. Interventions and Exposures: Women received 1 or more MRI and US examinations during the second and/or third trimesters. Postnatally, infants underwent brain MRI and cranial US. Blood samples were tested for ZIKV. Main Outcomes and Measures: The neuroimaging studies were evaluated for brain injury and cerebral biometry. Results: Of the 82 women, 80 were from Colombia and 2 were from the United States. In 3 of 82 cases (4%), fetal MRI demonstrated abnormalities consistent with congenital ZIKV infection. Two cases had heterotopias and malformations in cortical development and 1 case had a parietal encephalocele, Chiari II malformation, and microcephaly. In 1 case, US results remained normal despite fetal abnormalities detected on MRI. Prolonged maternal polymerase chain reaction positivity was present in 1 case. Of the remaining 79 cases with normal results of prenatal imaging, postnatal brain MRI was acquired in 53 infants and demonstrated mild abnormalities in 7 (13%). Fifty-seven infants underwent postnatal cranial US, which detected changes of lenticulostriate vasculopathy, choroid plexus cysts, germinolytic/subependymal cysts, and/or calcification in 21 infants (37%). Conclusions and Relevance: In a cohort of pregnant women with ZIKV infection, prenatal US examination appeared to detect all but 1 abnormal fetal case. Postnatal neuroimaging in infants who had normal prenatal imaging revealed new mild abnormalities. For most patients, prenatal and postnatal US may identify ZIKV-related brain injury.
Asunto(s)
Encéfalo/diagnóstico por imagen , Imagen por Resonancia Magnética , Malformaciones del Sistema Nervioso/diagnóstico por imagen , Neuroimagen/métodos , Complicaciones Infecciosas del Embarazo , Ultrasonografía Prenatal , Infección por el Virus Zika/diagnóstico por imagen , Adulto , Biomarcadores/sangre , Encéfalo/anomalías , Encéfalo/embriología , Encéfalo/virología , Colombia , District of Columbia , Femenino , Desarrollo Fetal , Humanos , Recién Nacido , Estudios Longitudinales , Masculino , Malformaciones del Sistema Nervioso/embriología , Malformaciones del Sistema Nervioso/virología , Embarazo , Complicaciones Infecciosas del Embarazo/sangre , Complicaciones Infecciosas del Embarazo/diagnóstico , Complicaciones Infecciosas del Embarazo/virología , Segundo Trimestre del Embarazo , Tercer Trimestre del Embarazo , Estudios Prospectivos , Enfermedad Relacionada con los Viajes , Viremia/sangre , Viremia/diagnóstico , Infección por el Virus Zika/sangre , Infección por el Virus Zika/embriología , Infección por el Virus Zika/virologíaRESUMEN
OBJECTIVE: To evaluate the fetal brain in pregnant women infected with Zika virus in a limited-resource setting. METHODS: In an observational study in Trinidad and Tobago, 100 pregnant women infected with Zika virus who were referred for fetal medicine services provided by a single clinician were enrolled from March 31 to September 2, 2016. Two-dimensional ultrasonography was undertaken. RESULTS: The women were aged 17-41 years (mean 27.5 ± 5.7). Six cases of fetal brain abnormalities consistent with Zika infection were detected before 26 gestational weeks. The gestational period at infection and time of presentation ranged, respectively, from 7+3 to 16+0 weeks and from 23+2 to 25+5 weeks. In all cases, centiles of the biparietal diameter and head circumference decreased progressively over time to below the third centile. The skull contour appeared irregular, owing to collapse or overlap of the fetal skull bones. In four cases, brain anomalies were not obvious on the transabdominal scan but were diagnosed on the transvaginal scan. In a further two cases, brain abnormalities presented after 26 weeks of gestation. CONCLUSION: Overall, 8.0% of women infected with Zika virus had fetuses with brain abnormalities suggestive of Zika congenital syndrome. Six cases were detected before 26 weeks and two cases after 26 weeks.
Asunto(s)
Encéfalo/diagnóstico por imagen , Enfermedades Fetales/diagnóstico por imagen , Feto/diagnóstico por imagen , Ultrasonografía Prenatal/métodos , Infección por el Virus Zika/diagnóstico por imagen , Adolescente , Adulto , Encéfalo/anomalías , Encéfalo/embriología , Cefalometría/métodos , Femenino , Enfermedades Fetales/virología , Feto/virología , Edad Gestacional , Humanos , Embarazo , Complicaciones Infecciosas del Embarazo/diagnóstico por imagen , Complicaciones Infecciosas del Embarazo/virología , Trinidad y Tobago , Adulto Joven , Virus Zika , Infección por el Virus Zika/embriologíaRESUMEN
The teratogenic mechanisms triggered by ZIKV are still obscure due to the lack of a suitable animal model. Here we present a mouse model of developmental disruption induced by ZIKV hematogenic infection. The model utilizes immunocompetent animals from wild-type FVB/NJ and C57BL/6J strains, providing a better analogy to the human condition than approaches involving immunodeficient, genetically modified animals, or direct ZIKV injection into the brain. When injected via the jugular vein into the blood of pregnant females harboring conceptuses from early gastrulation to organogenesis stages, akin to the human second and fifth week of pregnancy, ZIKV infects maternal tissues, placentas and embryos/fetuses. Early exposure to ZIKV at developmental day 5 (second week in humans) produced complex manifestations of anterior and posterior dysraphia and hydrocephalus, as well as severe malformations and delayed development in 10.5 days post-coitum (dpc) embryos. Exposure to the virus at 7.5-9.5 dpc induces intra-amniotic hemorrhage, widespread edema, and vascular rarefaction, often prominent in the cephalic region. At these stages, most affected embryos/fetuses displayed gross malformations and/or intrauterine growth restriction (IUGR), rather than isolated microcephaly. Disrupted conceptuses failed to achieve normal developmental landmarks and died in utero. Importantly, this is the only model so far to display dysraphia and hydrocephalus, the harbinger of microcephaly in humans, as well as arthrogryposis, a set of abnormal joint postures observed in the human setting. Late exposure to ZIKV at 12.5 dpc failed to produce noticeable malformations. We have thus characterized a developmental window of opportunity for ZIKV-induced teratogenesis encompassing early gastrulation, neurulation and early organogenesis stages. This should not, however, be interpreted as evidence for any safe developmental windows for ZIKV exposure. Late developmental abnormalities correlated with damage to the placenta, particularly to the labyrinthine layer, suggesting that circulatory changes are integral to the altered phenotypes.
Asunto(s)
Artrogriposis/virología , Modelos Animales de Enfermedad , Hidrocefalia/virología , Complicaciones Infecciosas del Embarazo/virología , Infección por el Virus Zika/virología , Virus Zika/fisiología , Animales , Artrogriposis/embriología , Artrogriposis/inmunología , Artrogriposis/patología , Femenino , Humanos , Hidrocefalia/embriología , Hidrocefalia/inmunología , Hidrocefalia/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Placenta/anomalías , Placenta/inmunología , Placenta/virología , Embarazo , Complicaciones Infecciosas del Embarazo/inmunología , Complicaciones Infecciosas del Embarazo/patología , Teratógenos/análisis , Infección por el Virus Zika/embriología , Infección por el Virus Zika/inmunología , Infección por el Virus Zika/patologíaRESUMEN
Zika virus (ZIKV), a mosquito-borne flavivirus, belongs to the Flaviviridae family, genus Flavivirus. ZIKV was initially isolated in 1947 from a sentinel monkey in the Zika forest, Uganda. Little clinical importance was attributed to ZIKV, once only few symptomatic cases were reported in some African and Southeast Asiatic countries. This situation changed in 2007, when a large outbreak was registered on the Yap Island, Micronesia, caused by the Asian ZIKV lineage. Between 2013 and 2014, ZIKV spread explosively and caused many outbreaks in different islands of the Southern Pacific Ocean and in 2015 autochthonous transmission was reported in Brazil. Currently, Brazil is the country with the highest number of ZIKV-positive cases in Latin America. Moreover, for the first time after the discovery of ZIKV, the Brazilian scientists are studying the possibility for the virus to cause severe congenital infection related to microcephaly and serious birth defects due to the time-spatial coincidence of the alarming increase of newborns with microcephaly and the Brazilian ZIKV epidemic. The present review summarizes recent information for ZIKV epidemiology, clinical picture, transmission, diagnosis and the consequences of this emerging virus in Brazil.
Asunto(s)
Epidemias , Infección por el Virus Zika , Virus Zika , Animales , Brasil/epidemiología , Humanos , Recién Nacido , Microcefalia/epidemiología , Microcefalia/virología , Virus Zika/genética , Infección por el Virus Zika/embriología , Infección por el Virus Zika/transmisión , Infección por el Virus Zika/virologíaAsunto(s)
Modelos Animales de Enfermedad , Epidemias , Ratones , Microcefalia/epidemiología , Complicaciones Infecciosas del Embarazo/epidemiología , Infección por el Virus Zika/epidemiología , Animales , Brasil/epidemiología , Causalidad , Femenino , Humanos , Transmisión Vertical de Enfermedad Infecciosa , Microcefalia/embriología , Embarazo , Infección por el Virus Zika/embriologíaRESUMEN
Este protocolo tem como objetivo prover os profissionais de saúde e áreas técnicas de vigilância em saúde com informações gerais, orientações técnicas e diretrizes relacionadas às ações de vigilância de microcefalias e/ou alterações do sistema nervoso central (SNC) sugestivas de infecção congênita em todo território nacional. Deve ser ressaltado que as informações e recomendações aqui presentes e agora divulgadas foram fundamentadas e estabelecidas a partir das discussões conduzidas entre áreas técnicas do Ministério da Saúde do Brasil e especialistas de diversas áreas da medicina, epidemiologia, estatística, geografia e laboratório, além de representantes das Secretarias de Saúde de Estados e Municípios afetados. O Sistema Único de Saúde (SUS) avança para elucidação desse evento e a cada dia acumula novas evidências a partir das investigações realizadas desde outubro de 2015,quando o Ministério da Saúde recebeu as primeiras notificações da Secretaria de Saúde do Estado de Pernambuco. Essa evidências passam pelo reconhecimento da relação entre a presença do vírus e a ocorrência de microcefalias e óbitos, a comprovação de que o vírus atravessa a barreira placentária, a identificação do vírus Zika em natimortos e recém-nascidos com microcefalia e/ou outras malformações do SNC, dentre outras. Esse reconhecimento é inédito na literatura nacional e internacional e só foi possível pelo empenho...
Asunto(s)
Humanos , Femenino , Embarazo , Recién Nacido , Complicaciones del Embarazo/virología , Infección por el Virus Zika/diagnóstico , Infección por el Virus Zika/epidemiología , Microcefalia/epidemiología , Guías como Asunto/políticas , Vigilancia en Salud Pública/métodos , Brasil/epidemiología , Infección por el Virus Zika/embriología , Microcefalia/embriología , Microcefalia/prevención & control , Pruebas Serológicas/métodosRESUMEN
Zika virus (ZIKV), a mosquito-borne flavivirus, belongs to the Flaviviridae family, genus Flavivirus. ZIKV was initially isolated in 1947 from a sentinel monkey in the Zika forest, Uganda. Little clinical importance was attributed to ZIKV, once only few symptomatic cases were reported in some African and Southeast Asiatic countries. This situation changed in 2007, when a large outbreak was registered on the Yap Island, Micronesia, caused by the Asian ZIKV lineage. Between 2013 and 2014, ZIKV spread explosively and caused many outbreaks in different islands of the Southern Pacific Ocean and in 2015 autochthonous transmission was reported in Brazil. Currently, Brazil is the country with the highest number of ZIKV-positive cases in Latin America. Moreover, for the first time after the discovery of ZIKV, the Brazilian scientists are studying the possibility for the virus to cause severe congenital infection related to microcephaly and serious birth defects due to the time-spatial coincidence of the alarming increase of newborns with microcephaly and the Brazilian ZIKV epidemic. The present review summarizes recent information for ZIKV epidemiology, clinical picture, transmission, diagnosis and the consequences of this emerging virus in Brazil.