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Intrauterine Zika virus infection of pregnant immunocompetent mice models transplacental transmission and adverse perinatal outcomes.

ABSTRACT: Zika virus (ZIKV) crosses the placenta and causes congenital disease. Here we develop an animal model utilizing direct ZIKV inoculation into the uterine wall of pregnant, immunocompetent mice to evaluate transplacental transmission. Intrauterine inoculation at embryonic day (E) 10, but not E14, with African, Asian or American strains of ZIKV reduces fetal viability and increases infection of placental and fetal tissues. ZIKV inoculation at E10 causes placental inflammation, placental dysfunction and reduces neonatal brain cortical thickness, which is associated with increased activation of microglia. Viral antigen localizes in trophoblast and endothelial cells in the placenta, and endothelial, microglial and neural progenitor cells in the fetal brain. ZIKV infection of the placenta increases production of IFN? and expression of IFN-stimulated genes 48?h after infection. This mouse model provides a platform for identifying factors at the maternal-fetal interface that contribute to adverse perinatal outcomes in a host with an intact immune system.

SUBMITTER: Vermillion MS

PROVIDER: S-EPMC5321801 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Intrauterine Zika virus infection of pregnant immunocompetent mice models transplacental transmission and adverse perinatal outcomes.

Vermillion Meghan S MS Lei Jun J Shabi Yahya Y Baxter Victoria K VK Crilly Nathan P NP McLane Michael M Griffin Diane E DE Pekosz Andrew A Klein Sabra L SL Burd Irina I

Nature communications 20170221

Zika virus (ZIKV) crosses the placenta and causes congenital disease. Here we develop an animal model utilizing direct ZIKV inoculation into the uterine wall of pregnant, immunocompetent mice to evaluate transplacental transmission. Intrauterine inoculation at embryonic day (E) 10, but not E14, with African, Asian or American strains of ZIKV reduces fetal viability and increases infection of placental and fetal tissues. ZIKV inoculation at E10 causes placental inflammation, placental dysfunction ...[more]

PMID: 28220786

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Project description:ObjectivesTo estimate the rates of maternal-fetal transmission of Zika virus, adverse fetal/neonatal outcomes, and subsequent rates of asymptomatic/symptomatic congenital Zika virus infections up to the first week of life.DesignCohort study with prospective data collection and subsequent review of fetal/neonatal outcomes.SettingsReferral centre for prenatal diagnosis of the French Guiana Western Hospital.ParticipantsPregnant women at any stage of pregnancy with a laboratory confirmed symptomatic or asymptomatic Zika virus infection during the epidemic period in western French Guiana. The cohort enrolled 300 participants and prospectively followed their 305 fetuses/newborns.Main outcome measuresRate of maternal-fetal transmission of Zika virus (amniotic fluid, fetal and neonatal blood, urine, cerebrospinal fluid, and placentas); clinical, biological, and radiological outcomes (blindly reviewed); and adverse outcomes defined as moderate signs potentially related to congenital Zika syndrome (CZS), severe complications compatible with CZS, or fetal loss. Associations between a laboratory confirmed congenital Zika virus infection and adverse fetal/neonatal outcomes were evaluated.ResultsMaternal-fetal transmission was documented in 26% (76/291) of fetuses/newborns with complete data. Among the Zika virus positive fetuses/newborns, 45% (34/76) presented with no signs/complications at birth, 20% (15/76) with moderate signs potentially related to CZS, 21% (16/76) with severe complications compatible with CZS, and 14% (11/76) with fetal loss. Compared with the Zika virus positive fetuses/neonates, those that were identified as negative for Zika virus (215/291) were less likely to present with severe complications (5%; 10/215) or fetal loss (0.5%; 1/215; relative risk 6.9, 95% confidence interval 3.6 to 13.3). Association between a positive Zika virus test and any adverse fetal/neonatal outcome was also significant (relative risk 4.4, 2.9 to 6.6). The population attributable fraction estimates that a confirmed congenital Zika virus infection contributes to 47% of adverse outcomes and 61% of severe adverse outcomes observed.ConclusionIn cases of a known maternal Zika virus infection, approximately a quarter of fetuses will become congenitally infected, of which a third will have severe complications at birth or fetal loss. The burden of CZS might be lower than initially described in South America and may not differ from other congenital infections.

Project description:Fetal and placental growth disorders are common in maternal human immunodeficiency virus (HIV) infection and can be attributed to both the infection and comorbidities not associated with HIV. We describe placental growth disorders and adverse reproductive outcomes in HIV-infected pregnant women whose delivery occurred between 2001-2014 in Vitoria, Brazil. Cases with gestational age (GA) ? than 22 weeks validated by ultrasonography, with placental and fetal weight dimensions at birth, were studied. Outcomes were summarized as proportions of small (SGA), appropriate (AGA), and large (LGA) for GA when the z-score values were below -1.28, between -1.28 and +1.28, or above +1.28, respectively. Of 187 fetal attachment requisitions, 122(65.2%) women and their newborns participated in the study. The median maternal age was 28 years and 81(66.4%) underwent ? 6 prenatal visits. A total of 81(66.4%) were diagnosed before current pregnancy; 68(55.7%) exhibited criteria for acquired immunodeficiency syndrome (AIDS); 64(52.4%) had detectable viral load; 25(20.5%) cases presented SGA placental weight and 6(4.9%) SGA placental thickness. SGA placental area was observed in 41(33.6%) cases, and among the SGA placental weight cases 12(48%) were also SGA fetal weight. Preterm birth (PTB) occurred in 15.6%(19/122) of cases; perinatal death in 4.1%(5/122) and HIV vertical transmission in 6 of 122 (4.9%). Women, ?36 years old, were 5.7 times more likely to have PTB than those under 36. Also, patients with AIDS-defining criteria were 3.7 times more likely to have PTB. Prenatal care was inversely associated with PTB. Statistically significant associations were observed between AGA placental area and Protease Inhibitor usage and between SGA placental weight and SGA area. We found a prevalence of placental growth disorders in HIV-infected pregnant women and values higher than international reference values. The restriction of placental growth was a common disorder, possibly attributed to virus effects or a combination of antiretroviral regimens.

Project description:Zika virus (ZIKV) is a mosquito-borne flavivirus that is primarily transmitted to humans through the bite of an infected mosquito. ZIKV causes disease in infected humans with added complications of Guillain-Barré syndrome and birth defects in infants born to mothers infected during pregnancy. There are several large immunocompetent animal models for ZIKV including non-human primates (NHPs). NHP models closely reflect human infection; however, due to sample size restrictions, investigations into the effects of transmission route and the impacts on disease dynamics have been understudied. Mice have been widely used for modeling ZIKV infection, yet there are few ZIKV-susceptible immunocompetent mouse models and none of these have been used to investigate sexual transmission. In an effort to identify a small immunocompetent animal model to characterize sexual transmission of ZIKV, we attempt experimental infection of multimammate mice, New Zealand white rabbits, and Hartley guinea pigs. The multimammate mouse is the natural reservoir of Lassa fever virus and has been identified to harbor other human pathogens. Likewise, while NZW rabbits are susceptible to West Nile virus, they have not yet been examined for their susceptibility to infection with ZIKV. Guinea pigs have been successfully used as models for ZIKV infection, but only in immunocompromised life stages (young or pregnant). Here, it was found that the multimammate mouse and New Zealand White (NZW) rabbits are not susceptible ZIKV infection as determined by a lack viral RNA in tissues and fluids collected. Sexually mature male Hartley guinea pigs were inoculated subcutaneously and by mosquito bite, but found to be refractory to ZIKV infection, contrary to findings of other studies in young and pregnant guinea pigs. Interestingly, here it is shown that adult male guinea pigs are not susceptible to ZIKV infection, even when infected by natural route (e.g., mosquito bite). Although a new small animal model for the sexual transmission for ZIKV was not established through this study, these findings provide information on outbred animal species that are not permissive to infection (NZW rabbits and multimammate mice) and new information surrounding limitations of a previously established animal model (guinea pigs).

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Intrauterine Zika virus infection of pregnant immunocompetent mice models transplacental transmission and adverse perinatal outcomes.

Publications

Intrauterine Zika virus infection of pregnant immunocompetent mice models transplacental transmission and adverse perinatal outcomes.

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