A Mouse Model of Zika Virus Pathogenesis

Lazear, Helen M.; Govero, Jennifer; Smith, Amber M.; Platt, Derek J.; Fernández, Estefanı́a; Miner, Jonathan J.; Diamond, Michael S.

doi:10.1016/j.chom.2016.03.010

Cited by 835 publications

(1,062 citation statements)

References 67 publications

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“…Thus, mouse models of ZIKV infection necessitate use of genetic deficiencies in IFNAR or antibody blockade of IFNAR 8–10 . To examine immune responses that control ZIKV neuropathogenesis, we first probed the cellular compartment responsible for the type I IFN-dependent block of ZIKV infection using irradiation-induced bone marrow chimeric mice between ZIKV-resistant C57BL/6 CD45.1 (WT) and ZIKV-susceptible interferon α/β receptor-deficient ( Ifnar1 −/− ) mice.…”

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confidence: 99%

Antiviral CD8 T cells induce Zika-virus-associated paralysis in mice

et al. 2017

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Zika virus (ZIKV) is an emerging, mosquito-borne RNA virus. The rapid spread of ZIKV within the Americas has unveiled microcephaly1 and Guillain-Barré syndrome 2,3 as ZIKV-associated neurological complications. Recent reports have further indicated other neurological manifestations to be associated with ZIKV including myelitis 4, meningoencephalitis 5 and fatal encephalitis6. Here, we investigate the neuropathogenesis of ZIKV infection in IFNAR knockout (Ifnar1−/−) mice, an infection model that exhibits high viral burden within the central nervous system (CNS). We show that systemic spread of ZIKV from the site of infection to the brain requires Ifnar1-deficiency in the hematopoietic compartment. However, spread of ZIKV within the CNS is supported by Ifnar1-deficient non-hematopoietic cells. Within this context, ZIKV infection of astrocytes results in breakdown of the blood-brain barrier and a large influx of CD8+ effector T cells. Further, we find antiviral activity of CD8+ T cells within the brain markedly limits ZIKV infection of neurons, but as a consequence instigates ZIKV-associated paralysis. Taken together, our study uncovers mechanisms underlying ZIKV-neuropathogenesis within a susceptible mouse model and suggests BBB breakdown and T cell mediated neuropathology as potential underpinnings of ZIKV-associated neurological complications in humans.

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Antiviral CD8 T cells induce Zika-virus-associated paralysis in mice

et al. 2017

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“…Now Zika virus (ZIKV) enters the stage. Prompted by previous studies in mice, in which the highest ZIKV load was found in the testes 3 , the detection of ZIKV in semen, and data that show male-to-female as each Sertoli cell sustains dozens of germ cells at different stages of their development.…”

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confidence: 98%

A new threat on the horizon — Zika virus and male fertility

Meinhardt

2017

Nat Rev Urol

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“…Prior to the work of Miner and colleagues 3,4 , another team of investigators reported that although ZIKV is able to replicate in a log-fold manner in immortalized human trophoblast cells lines, replication was not as robust in primary human trophoblasts isolated from healthy, term placental donors compared Earlier this year, the Washington University team developed a mouse model of ZIKV infection and demonstrated that peripheral visceral replication of ZIKV is inhibited by the type I interferon response 4 . In mice lacking the IFN α/β receptor 1 (Ifnar1 −/− ), ZIKV infection in adult, non-pregnant mice was associated with neurological destruction, accompanied by high levels of the virus in the brain and spinal cord, as well as in the spleen, testes and serum.…”

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Zika virus — placental passage and permissivity for infection

Suter

Aagaard

2016

Nat Rev Endocrinol

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Zika virus (ZIKV) is an arbovirus that is transmitted to humans by the Aedes mosquito, but can be spread from one human to another, including fetal transmission during pregnancy. Infection of humans with ZIKV, an emerging mosquito-borne Flavivirus, has reached pandemic levels in the Americas, with at least 32 countries or territories reporting infection over the period May 2015 to April 2016 (REF. 1). Although previous outbreaks of ZIKV resembled that of dengue fever and chikungunya, its recent spread to the Americas has revealed an increase in the incidence of congenital microcephaly with brain and ocular malformations, as well as intrauterine growth restriction (IUGR) associated with placental insufficiency, and spontaneous pregnancy loss. As ZIKV RNA has been reported in amniotic fluid, the placenta and fetal neural tissue from women weeks to months after being infected early in gestation 2 , understanding the role of the placenta in alternately facilitating or limiting vertical transmission of ZIKV is of paramount importance. In a recent study published in Cell, Miner and colleagues describe two mouse models of ZIKV infection during pregnancy that are associated with clinically relevant phenotypes in offspring, including growth restriction and placental damage 3 .heterozygous offspring with an intact type I interferon response (Ifnar1 −/+ ). The pregnant Ifnar1 −/− mice were then inoculated with ZIKV on embryonic days 6.5 (E6.5) and E7.5, and pregnancy was allowed to progress until E13.5 or E15.5. The outcomes were devastating: the majority of fetuses were resorbed after in utero demise, similar to the observed pregnancy losses occurring in the current epidemic across the Americas. The remaining fetuses showed evidence of growth restriction and placental damage, including necrotic foci, but without evidence of microcephaly. However, in a second model of ZIKV infection in pregnancy, the investigators treated wild-type pregnant mice with an antibody targeting the IFN α/β receptor 1 1 day before infection with ZIKV at E6.5 and E7.5 and analysed phenotypes on E13.5 and E15.5. This second model was less severe than the first model, as prevalent fetal demise was not observed; however, the fetuses did exhibit IUGR.Despite the 6-8 day interval between initial infection and delivery of the fetuses, a high placental viral load was persistently observed. The mouse placenta consists of three distinct layers, including the maternal layer (decidua), the junctional zone (where the placenta attaches to the uterus) and the labyrinth zone (where the placental villi are bathed in maternal blood and the site of maternal-fetal nutrient and oxygen exchange) 5 . Similar to the human placenta, the mouse placenta consists of highly specialized trophoblast cell types which have distinct roles in invading the maternal decidua, anchoring the placenta to the uterus and forming villi to facilitate nutrient transport. In humans, the placenta has been observed to largely protect against vertical transmission of viruses, although some virus...

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A Mouse Model of Zika Virus Pathogenesis

Cited by 835 publications

References 67 publications

Antiviral CD8 T cells induce Zika-virus-associated paralysis in mice

Antiviral CD8 T cells induce Zika-virus-associated paralysis in mice

A new threat on the horizon — Zika virus and male fertility

Zika virus — placental passage and permissivity for infection

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