Vaginal Exposure to Zika Virus during Pregnancy Leads to Fetal Brain Infection

Yockey, Laura J.; Varela, Luis; Rakib, Tasfia; Khoury-Hanold, William; Fink, Susan L.; Stutz, Bernardo; Szigeti‐Buck, Klara; Pol, Anthony van den; Lindenbach, Brett D.; Horváth, Tamas L.; Iwasaki, Akiko

doi:10.1016/j.cell.2016.08.004

Cited by 339 publications

(457 citation statements)

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“…ZIKV stocks were grown in C636 cells and titered by plaque assay within Vero cells (ATCC CCL-81) as previously described 21 . C6/36 mosquito cells ( Aedes albopictus ) (ATCC CRL-1660) were maintained in Dulbecco’s Modified Eagle’s Medium (GIBCO) supplemented with 10% heat-inactivated fetal bovine serum, 1% penicillin/streptomycin (GIBCO) and 1% tryptose phosphate broth (Sigma) at 30 °C.…”

Section: Methodsmentioning

confidence: 99%

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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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Section: Methodsmentioning

confidence: 99%

“…cDNA was synthesized using iScript cDNA synthesis kit (Bio-Rad) with quantitative PCR being performed using SYBR-Green (Bio-Rad) or PrimeTime master mix (Integrated DNA Technologies) on a CFX Connect instrument (Bio-Rad). ZIKV RNA was detected using primers designed to NS5 21 , with limit of detection determined as previously described 21 .…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2017

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“…The aim of our work is to present the epidemiological consequences of possible sustained sexual transmission. While there are many unknowns, recent work shows (i) multiple anecdotal cases of sexual transmission of ZIKV in humans (25,(29)(30)(31), (ii) multiple separate animal models showing sexual transmission (32)(33)(34), (iii) strong asymmetries between durations of ZIKV shedding in semen and vaginal secretions (20,21), and (iv) differential risk between sexes for ZIKV infection in sexually active populations. Indeed, recent work has identified 90% more ZIKV infections in women between Fig.…”

Section: Discussionmentioning

confidence: 99%

Asymmetric percolation drives a double transition in sexual contact networks

Allard

Althouse

Scarpino

2017

Proc. Natl. Acad. Sci. U.S.A.

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Zika virus (ZIKV) exhibits unique transmission dynamics in that itis concurrently spread by a mosquito vector and through sexual contact. Due to the highly asymmetric durations of infectiousness between males and females-it is estimated that males are infectious for periods up to 10 times longer than females-we show that this sexual component of ZIKV transmission behaves akin to an asymmetric percolation process on the network of sexual contacts. We exactly solve the properties of this asymmetric percolation on random sexual contact networks and show that this process exhibits two epidemic transitions corresponding to a core-periphery structure. This structure is not present in the underlying contact networks, which are not distinguishable from random networks, and emerges because of the asymmetric percolation. We provide an exact analytical description of this double transition and discuss the implications of our results in the context of ZIKV epidemics. Most importantly, our study suggests a bias in our current ZIKV surveillance, because the community most at risk is also one of the least likely to get tested.A bstract modeling of epidemics on networks remains an active field, because some of the most basic features of epidemics are still misunderstood. The classic model is quite simple (1): disease spreads stochastically with a fixed transmission probability, T , through contacts around a given patient zero. The outbreak dies quickly if T is too small but spreads to a macroscopic fraction S of the entire population if T is larger than a threshold Tc. At Tc, most of the typical insights from phase transition theory are valuable. For instance, the sizes of microscopic outbreaks follow a power law distribution, such that the expected size of microscopic outbreaks, s , indicates the position of a phase transition. Indeed, as T increases, s monotonically increases, diverges exactly at Tc, and then monotonically goes down; meanwhile, the expected macroscopic epidemic size, S , starts increasing monotonically at Tc.However, simple modifications to this model can dramatically alter its phenomenology. The epidemic threshold can vanish in networks with a scale-free degree distribution (2) or in growing networks (3). The phase transition can be discontinuous in the case of complex contagions with threshold exposition or reinforcement (4), interacting epidemics (5, 6), or adaptive networks (7-9). Recently, a unique phenomenon of double-phase transitions has also been observed numerically when networks have a very heterogeneous and clustered structure (10, 11).The current Zika virus (ZIKV) epidemic exhibits two unique properties. First, while the main transmission pathway for ZIKV is through a mosquito vector [predominantly Aedes aegypti or Aedes albopictus (13, 14)], a feature which has its own type of well-studied model and behavior (14-16), it can also spread through sexual contacts (17, 18). Second, the probability of sexual transmission is highly asymmetric between males and females. Although this is also true for ot...

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“…Immunofluorescent staining and Western blotting were conducted as described before (28,29). Primary and secondary antibodies used in Western blotting and immunostainings are summarized SI Appendix, Table S4.…”

Section: Methodsmentioning

confidence: 99%

“…Mouse models have not been altogether helpful in this respect, in part because the development of the placenta follows a different progression than in humans and also because many mouse strains are resistant to ZIKV infection, including the C57/B6 strain used so widely (9). However, mice engineered or treated in such a manner that they are unable to mount a normal antiviral response are susceptible (25,26) and can transmit the virus to their fetuses, allowing effects on the brain to be assessed (27,28). The latter studies also implicated an appropriate IFN response by the placenta as being at least partially responsible for protecting the fetus from ZIKV.…”

Section: Significancementioning

confidence: 99%

Vulnerability of primitive human placental trophoblast to Zika virus

Sheridan

Yunusov

Balaraman

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

157

155

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Infection of pregnant women by Asian lineage strains of Zika virus (ZIKV) has been linked to brain abnormalities in their infants, yet it is uncertain when during pregnancy the human conceptus is most vulnerable to the virus. We have examined two models to study susceptibility of human placental trophoblast to ZIKV: cytotrophoblast and syncytiotrophoblast derived from placental villi at term and colonies of trophoblast differentiated from embryonic stem cells (ESC). The latter appear to be analogous to the primitive placenta formed during implantation. The cells from term placentas, which resist infection, do not express genes encoding most attachment factors implicated in ZIKV entry but do express many genes associated with antiviral defense. By contrast, the ESC-derived trophoblasts possess a wide range of attachment factors for ZIKV entry and lack components of a robust antiviral response system. These cells, particularly areas of syncytiotrophoblast within the colonies, quickly become infected, produce infectious virus and undergo lysis within 48 h after exposure to low titers (multiplicity of infection > 0.07) of an African lineage strain (MR766 Uganda: ZIKVU) considered to be benign with regards to effects on fetal development. Unexpectedly, lytic effects required significantly higher titers of the presumed more virulent FSS13025 Cambodia (ZIKVC). Our data suggest that the developing fetus might be most vulnerable to ZIKV early in the first trimester before a protective zone of mature villous trophoblast has been established. Additionally, MR766 is highly trophic toward primitive trophoblast, which may put the early conceptus of an infected mother at high risk for destruction.

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Vaginal Exposure to Zika Virus during Pregnancy Leads to Fetal Brain Infection

Cited by 339 publications

References 53 publications

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

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

Asymmetric percolation drives a double transition in sexual contact networks

Vulnerability of primitive human placental trophoblast to Zika virus

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