Zika Virus Infects Early- and Midgestation Human Maternal Decidual Tissues, Inducing Distinct Innate Tissue Responses in the Maternal-Fetal Interface

Weisblum, Yiska; Oiknine‐Djian, Esther; Vorontsov, Olesya; Haimov‐Kochman, Ronit; Zakay‐Rones, Zichria; Meir, Karen; Shveiky, David; Elgavish, Sharona; Nevo, Yuval; Roseman, Moshe; Bronstein, Michal; Stockheim, David; From, Ido; Eisenberg, Iris; Lewkowicz, Aya; Panet, Amos; Wolf, Dana

doi:10.1128/jvi.01905-16

Cited by 105 publications

(129 citation statements)

References 52 publications

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“…There are unique populations of immune cells in the decidua (Golos et al, 2010) and within the placenta itself, including placental macrophages (Hofbauer cells) (Bulmer and Johnson, 1984). Both cell populations are permissive for ZIKV infection (Quicke et al, 2016; Tang et al, 2016; Weisblum et al, 2017; Jurado et al, 2016), which reinforce the strength and relevance of the NHP model. The long gestation period (165–180 days) of macaques also provides a realistic model for human fetal development.…”

Section: Mechanisms and Consequences Of Maternal-fetal Transmissionsupporting

confidence: 57%

Zika in the Americas, year 2: What have we learned? What gaps remain? A report from the Global Virus Network

et al. 2017

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In response to the outbreak of Zika virus (ZIKV) infection in the Western Hemisphere and the recognition of a causal association with fetal malformations, the Global Virus Network (GVN) assembled an international taskforce of virologists to promote basic research, recommend public health measures and encourage the rapid development of vaccines, antiviral therapies and new diagnostic tests. In this article, taskforce members and other experts review what has been learned about ZIKV-induced disease in humans, its modes of transmission and the cause and nature of associated congenital manifestations. After describing the make-up of the taskforce, we summarize the emergence of ZIKV in the Americas, Africa and Asia, its spread by mosquitoes, and current control measures. We then review the spectrum of primary ZIKV-induced disease in adults and children, sites of persistent infection and sexual transmission, then examine what has been learned about maternal-fetal transmission and the congenital Zika syndrome, including knowledge obtained from studies in laboratory animals. Subsequent sections focus on vaccine development, antiviral therapeutics and new diagnostic tests. After reviewing current understanding of the mechanisms of emergence of Zika virus, we consider the likely future of the pandemic.

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Section: Mechanisms and Consequences Of Maternal-fetal Transmissionsupporting

confidence: 57%

Zika in the Americas, year 2: What have we learned? What gaps remain? A report from the Global Virus Network

et al. 2017

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“…In addition, maternal decidua isolated from early and mid-gestation human pregnancy induce IFN-λ in response to ZIKV infection (Weisblum et al, 2016). Given these studies, we examined the contribution of IFN-λ to ZIKV protection in pregnant mice.…”

Section: Resultsmentioning

confidence: 99%

“…Consistent with this observation, first trimester syncytialized trophoblasts appear resistant to ZIKV infection (Bhatnagar et al, 2017; Ritter et al, 2017), and the syncytium in second trimester human explants constitutively release IFN-λ and do not support ZIKV infection (Corry et al, 2017). In comparison, first- and second-trimester cytotrophoblasts in cell culture are susceptible to ZIKV infection (El Costa et al, 2016; Weisblum et al, 2016). These cells, however, were not evaluated for their ability to produce or respond to IFN-λ.…”

Section: Discussionmentioning

confidence: 99%

“…Beyond this, the placenta, which serves as a physical and immunological barrier, changes dramatically during gestation, particularly between the early (first trimester) and later (second and third trimester) stages of human pregnancy when the intervillous space becomes filled with maternal blood and the placental villi have fully developed (Arora et al, 2017). Isolated human fetal-derived chorionic villi or trophoblast cells obtained later during gestation support less ZIKV infection compared to many non-placental cell types, which likely reflects stage-dependent effects of trophoblast differentiation (Bayer et al, 2016; Corry et al, 2017; Sheridan et al, 2017; Weisblum et al, 2016). The reduced susceptibility to ZIKV infection at later stages of gestation could result from distinct innate immune profiles including production of type III interferon (IFN)-λ (Bayer et al, 2016) or differential expression of putative entry receptors (Tabata et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

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Gestational Stage and IFN-λ Signaling Regulate ZIKV Infection In Utero

Jagger

Miner

Cao

et al. 2017

Cell Host & Microbe

146

183

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SUMMARY Although Zika virus (ZIKV)-induced congenital disease occurs more frequently during early stages of pregnancy, its basis remains undefined. Using established type I interferon (IFN)-deficient mouse models of ZIKV transmission in utero, we found that the placenta and fetus were more susceptible to ZIKV infection at earlier gestational stages. Whereas ZIKV infection at embryonic day 6 (E6) resulted in placental insufficiency and fetal demise, infections at midstage (E9) resulted in reduced cranial dimensions, and infection later in pregnancy (E12) caused no apparent fetal disease. In addition, we found that fetuses lacking type III IFN-λ signaling had increased ZIKV replication in the placenta and fetus when infected at E12, and reciprocally, treatment of pregnant mice with IFN-λ2 reduced ZIKV infection. IFN-λ treatment analogously diminished ZIKV infection in human midgestation fetal- and maternal-derived tissue explants. Our data establish a model of gestational stage-dependence of ZIKV pathogenesis and IFN-λ-mediated immunity at the maternal-fetal interface.

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“…However, congenital Zika virus infection, resulting from transplacental viral transmission, has been associated with microcephaly and an expanding range of neurological abnormalities and birth defects (43,47,48).…”

mentioning

confidence: 99%

Zika Virus Escapes NK Cell Detection by Upregulating Major Histocompatibility Complex Class I Molecules

Glasner

Oiknine‐Djian

Weisblum

et al. 2017

J Virol

Self Cite

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NK cells are innate lymphocytes that participate in many immune processes encompassing cancer, bacterial and fungal infection, autoimmunity, and even pregnancy and that specialize in antiviral defense. NK cells express inhibitory and activating receptors and kill their targets when activating signals overpower inhibitory signals. The NK cell inhibitory receptors include a uniquely diverse array of proteins named killer cell immunoglobulin-like receptors (KIRs), the CD94 family, and the leukocyte immunoglobulin-like receptor (LIR) family. The NK cell inhibitory receptors recognize mostly major histocompatibility complex (MHC) class I (MHC-I) proteins. Zika virus has recently emerged as a major threat due to its association with birth defects and its pandemic potential. How Zika virus interacts with the immune system, and especially with NK cells, is unclear. Here we show that Zika virus infection is barely sensed by NK cells, since little or no increase in the expression of activating NK cell ligands was observed following Zika infection. In contrast, we demonstrate that Zika virus infection leads to the upregulation of MHC class I proteins and consequently to the inhibition of NK cell killing. Mechanistically, we show that MHC class I proteins are upregulated via the RIGI-IRF3 pathway and that this upregulation is mediated via beta interferon (IFN-␤). Potentially, countering MHC class I upregulation during Zika virus infection could be used as a prophylactic treatment against Zika virus.IMPORTANCE NK cells are innate lymphocytes that recognize and eliminate various pathogens and are known mostly for their role in controlling viral infections. NK cells express inhibitory and activating receptors, and they kill or spare their targets based on the integration of inhibitory and activating signals. Zika virus has recently emerged as a major threat to humans due to its pandemic potential and its association with birth defects. The role of NK cells in Zika virus infection is largely unknown. Here we demonstrate that Zika virus infection is almost undetected by NK cells, as evidenced by the fact that the expression of activating ligands for NK cells is not induced following Zika infection. We identified a mechanism whereby Zika virus sensing via the RIGI-IRF3 pathway resulted in IFN-␤-mediated upregulation of MHC-I molecules and inhibition of NK cell activity. Countering MHC class I upregulation and boosting NK cell activity may be employed as prophylactic measures to combat Zika virus infection.KEYWORDS Zika virus, MHC class I, NK cells, NK escape mechanisms N K cells are lymphocytes belonging to the innate immune system. NK cells participate in many immunological activities, from killing cancerous cells (1-7) and fighting bacteria (8-10) and fungi (11) to playing roles in allergy (12) and graft-versushost disease (13). NK cells also play roles in autoimmunity (14-18) and pregnancy (19).

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Zika Virus Infects Early- and Midgestation Human Maternal Decidual Tissues, Inducing Distinct Innate Tissue Responses in the Maternal-Fetal Interface

Cited by 105 publications

References 52 publications

Zika in the Americas, year 2: What have we learned? What gaps remain? A report from the Global Virus Network

Zika in the Americas, year 2: What have we learned? What gaps remain? A report from the Global Virus Network

Gestational Stage and IFN-λ Signaling Regulate ZIKV Infection In Utero

Zika Virus Escapes NK Cell Detection by Upregulating Major Histocompatibility Complex Class I Molecules

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