Fetal loss in pregnant rhesus macaques infected with high-dose African-lineage Zika virus

Raasch, Lauren E.; Yamamoto, Keisuke; Newman, Christina M.; Rosinski, Jenna R.; Shepherd, Phoenix M.; Razo, Elaina; Crooks, Chelsea M.; Bliss, Mason I.; Breitbach, Meghan E.; Sneed, Emily L.; Weiler, Andrea M.; Zeng, Xiankun; Noguchi, Kevin K.; Morgan, Terry K.; Fuhler, Nicole A.; Bohm, Ellie K.; Alberts, Alexandra J.; Havlicek, Samantha J.; Kabakov, Sabrina; Mitzey, Ann M.; Antony, Kathleen M.; Ausderau, Karla; Mejía, Andrés; Basu, Puja; Simmons, Heather A.; Eickhoff, Jens; Aliota, Matthew T.; Mohr, Emma L.; Friedrich, Thomas C.; Golos, Thaddeus G.; O’Connor, David H.; Dudley, Dawn M.

doi:10.1371/journal.pntd.0010623

Cited by 12 publications

(23 citation statements)

References 45 publications

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“…Within the MFI, viral load data suggests a greater burden of ZIKV RNA in the chorionic plate and placental parenchyma tissue as compared to the decidua, a trend consistent with previous studies that used ZIKV-DAK (Fig 4A) [31]. Viral load data are also consistent with the ISH data from this study, with the strongest ISH signal in the chorionic plate and the stroma of villi in the parenchyma (Fig 4B).…”

Section: Plos Pathogenssupporting

confidence: 90%

“…For this study, twenty-three rhesus macaques were enrolled into one of five Cohorts (Fig 1). Information on the exact timing of infection, treatment with antiretroviral therapy (ART), and pregnancy for all animals is in S2 Table . We reasoned that the impacts of SIV co-infection on ZIKV pathogenesis would be most apparent when ZIKV infection occurs early in pregnancy, so we infected animals at approximately GD 30 (range GD [26][27][28][29][30][31][32][33][34][35][36][37][38] which corresponds to GD 49 in human pregnancy [27]. Cohort III was SIV naive and not treated with ART to control for the potential impacts of ART on ZIKV adverse outcomes.…”

Section: Methodsmentioning

confidence: 99%

“…This neonatal test is well validated and has previously been used to define neonatal development of prenatally ZIKV-exposed infants [16]. The Catwalk XT version 10.6 was modified for infant rhesus macaques and used to assess gait development, as described previously [31,52]. The SNAP was administered at 7, 14, 21, and 28 (+/-2) days of life, and the Catwalk was administered on 14, 21, and 28 days of life.…”

Section: Plos Pathogensmentioning

confidence: 99%

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Frequent first-trimester pregnancy loss in rhesus macaques infected with African-lineage Zika virus

et al. 2023

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In the 2016 Zika virus (ZIKV) pandemic, a previously unrecognized risk of birth defects surfaced in babies whose mothers were infected with Asian-lineage ZIKV during pregnancy. Less is known about the impacts of gestational African-lineage ZIKV infections. Given high human immunodeficiency virus (HIV) burdens in regions where African-lineage ZIKV circulates, we evaluated whether pregnant rhesus macaques infected with simian immunodeficiency virus (SIV) have a higher risk of African-lineage ZIKV-associated birth defects. Remarkably, in both SIV+ and SIV- animals, ZIKV infection early in the first trimester caused a high incidence (78%) of spontaneous pregnancy loss within 20 days. These findings suggest a significant risk for early pregnancy loss associated with African-lineage ZIKV infection and provide the first consistent ZIKV-associated phenotype in macaques for testing medical countermeasures.

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Section: Plos Pathogenssupporting

confidence: 90%

Section: Methodsmentioning

confidence: 99%

Section: Plos Pathogensmentioning

confidence: 99%

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Frequent first-trimester pregnancy loss in rhesus macaques infected with African-lineage Zika virus

et al. 2023

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“…Evidence for the transplacental route of ZIKV vertical transmission is currently sparse in human cases of congenital ZIKV infection and non-human primate (NHP) in vivo studies. To our knowledge, no published results show STB infection in cases of human congenital ZIKV infection, and ZIKV has rarely been found in STBs in NHP studies [11][12][13][14][15]. Reports of the vulnerability of STBs and CTBs to infection have primarily been obtained from ex vivo or in vitro studies using both Asian and Africanlineage ZIKV.…”

Section: Introductionmentioning

confidence: 99%

“…Once the chorionic membrane is infected, the fetus is no longer protected by trophoblasts and ZIKV can, theoretically, easily spread to fetal vessels in the chorionic plate and into the amniotic fluid. Substantial evidence supports that the fetal membranes are susceptible to ZIKV infection [10,11,14,15,17,[22][23][24][25][26][27]. The fetal membranes have been found to be infected in a human case of congenital ZIKV infection that resulted in a miscarriage [22].…”

Section: Introductionmentioning

confidence: 99%

Vertical transmission of African-lineage Zika virus through the fetal membranes in a rhesus Macaque (Macaca mulatta) model

Koenig

Mitzey

Zeng

et al. 2023

Preprint

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Zika virus (ZIKV) can be transmitted vertically from mother to fetus during pregnancy, resulting in a range of outcomes, including severe birth defects and fetal/infant death. Potential pathways of vertical transmission in utero have been proposed but remain undefined. Identifying the timing and routes of vertical transmission of ZIKV may help us identify when interventions would be most effective. Furthermore, understanding what barriers ZIKV overcomes to effect vertical transmission may help improve models for evaluating infection by other pathogens during pregnancy. To determine the pathways of vertical transmission, we inoculated 12 pregnant rhesus macaques with an Africanlineage ZIKV at gestational day 30 (term is 165 days). Eight pregnancies were surgically terminated at either seven or 14 days post-maternal infection. Maternal-fetal interface and fetal tissues and fluids were collected and evaluated with RT-qPCR, in situ hybridization for ZIKV RNA, immunohistochemistry, and plaque assays. Four additional pregnant macaques were inoculated and terminally perfused with 4% paraformaldehyde at three, six, nine, or ten days post-maternal inoculation. For these four cases, the entire fixed pregnant uterus was evaluated with in situ hybridization for ZIKV RNA. We determined that ZIKV can reach the MFI by six days post-infection and infect the fetus by ten days. Infection of the chorionic membrane and the extraembryonic coelomic fluid preceded infection of the fetus and the mesenchymal tissue of the placental villi. We did not find evidence to support a transplacental route of ZIKV vertical transmission via infection of syncytiotrophoblasts or villous cytotrophoblasts. The pattern of infection observed in the maternal-fetal interface provides evidence of vertical ZIKV transmission through the fetal membranes.

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Ultrasound evaluation of normal rhesus macaque fetal biometry and uteroplacental hemodynamics

D’Mello

Hagen

et al. 2023

American J Primatol

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Nonhuman primates are important preclinical models for translational, reproductive, and developmental science. Clinical evaluation of human fetal development is performed using standard sonographic‐derived fetal biometry, assessments of amniotic fluid, and uteroplacental hemodynamics. These noninvasive in utero measurements provide important information regarding fetal growth and pregnancy well‐being. Abnormalities in fetal growth, amniotic fluid volume, or placental vascular function are associated with placental insufficiency and adverse perinatal outcomes including stillbirth. The fetal biometric parameters most commonly assessed are biparietal diameter, head circumference, abdominal circumference, and femur diaphysis length. Evaluation of amniotic fluid volume includes measuring the fluid in four quadrants of the uterus to generate an Amniotic Fluid Index. Measures of uteroplacental hemodynamics typically include doppler assessment of the umbilical artery and ductus venosus, but can also include interrogation of the uterine artery and umbilical vein. In this study, we compile prenatal ultrasound data of fetal biometry, amniotic fluid measurements, and uteroplacental hemodynamics obtained from pregnancy studies conducted at the Oregon National Primate Research Center. The data included are from control unperturbed pregnant animals who have not undergone in utero experimental manipulations. This is the first report of comprehensive sonographic measurements following standardized clinical obstetric protocols utilized in rhesus macaques. The outcome is a large, prenatal ultrasound resource to be used by laboratory animal researchers in future nonhuman primate pregnancy studies for antenatal assessment.

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Fetal loss in pregnant rhesus macaques infected with high-dose African-lineage Zika virus

Cited by 12 publications

References 45 publications

Frequent first-trimester pregnancy loss in rhesus macaques infected with African-lineage Zika virus

Frequent first-trimester pregnancy loss in rhesus macaques infected with African-lineage Zika virus

Vertical transmission of African-lineage Zika virus through the fetal membranes in a rhesus Macaque (Macaca mulatta) model

Ultrasound evaluation of normal rhesus macaque fetal biometry and uteroplacental hemodynamics

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