Zika virus infection in immunocompetent pregnant mice causes fetal damage and placental pathology in the absence of fetal infection
Open accessAbstract
Zika virus (ZIKV) infection during human pregnancy may cause diverse and serious congenital defects in the developing fetus. Previous efforts to generate animal models of human ZIKV infection and clinical symptoms often involved manipulating mice to impair their Type I interferon (IFN) signaling, thereby allowing enhanced infection and vertical transmission of virus to the embryo. Here, we show that even pregnant mice competent to generate Type I IFN responses that can limit ZIKV infection nonetheless develop profound placental pathology and high frequency of fetal demise. We consistently found that maternal ZIKV exposure led to placental pathology and that ZIKV RNA levels measured in maternal, placental or embryonic tissues were not predictive of the pathological effects seen in the embryos. Placental pathology included trophoblast hyperplasia in the labyrinth, trophoblast giant cell necrosis in the junctional zone, and loss of embryonic vessels. Our findings suggest that, in this context of limited infection, placental pathology rather than embryonic/fetal viral infection may be a stronger contributor to adverse pregnancy outcomes in mice. Our finding demonstrates that in immunocompetent mice, direct viral infection of the embryo is not essential for fetal demise. Our immunologically unmanipulated pregnancy mouse model provides a consistent and easily measurable congenital abnormality readout to assess fetal outcome, and may serve as an additional model to test prophylactic and therapeutic interventions to protect the fetus during pregnancy, and for studying the mechanisms of ZIKV congenital immunopathogenesis.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The ICR suckling mice model is immunocompetent and has allowed researchers to investigate interferon-dependent antiviral compounds or vaccines.
“The ICR suckling mice model are the immunocompetent mice, which have allowed researchers to investigate the interferon-dependent antiviral compounds or vaccine [20, 35].”
From ICR suckling mouse model of Zika virus infection for disease modeling and drug validation (2018) · cites this paper as [35]
The Materials and methods section (page unavailable) identifies the study’s mice as pregnant C57BL/6J mice, not ICR suckling mice. The Discussion (page unavailable) proposes this immunocompetent pregnancy model as a platform for preclinical vaccine and therapeutic testing, but does not say it has been used to investigate interferon-dependent antiviral compounds or vaccines. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Zika Virus Infection in Pregnant Women in Rio de Janeiro
Brasil, P., Pereira, J. P., Moreira, M. E. L., Nogueira, R. M. R., Damasceno, L. S., Wakimoto, M. D., Rabello, R. S., Gaw, S. L., Halai, U., Salles, T. R. S., et al. (2016) · New England Journal of Medicine · doi:10.1056/nejmoa1602412 · Cited by 2,190 · see citing works
Lanciotti, R. S., Kosoy, O. L., Laven, J. J., Velez, J. O., Lambert, A. J., Johnson, A. J., Stanfield, S. M., & Duffy, M. R. (2008) · Emerging infectious diseases · doi:10.3201/eid1408.080287 · Cited by 2,173 · see citing works
Zika Virus and Birth Defects — Reviewing the Evidence for Causality
Rasmussen, S. A., Jamieson, D. J., Honein, M. A., & Petersen, L. R. (2016) · New England Journal of Medicine · doi:10.1056/nejmsr1604338 · Cited by 1,988 · see citing works
The Brazilian Zika virus strain causes birth defects in experimental models
Cugola, F. R., Fernandes, I. R., Russo, F. B., Freitas, B. C., Dias, J. L. M., Guimarães, K. P., Benazzato, C., Almeida, N., Pignatari, G. C., Romero, S., et al. (2016) · Nature · doi:10.1038/nature18296 · Cited by 1,326 · see citing works
Petersen, L. R., Jamieson, D. J., Powers, A. M., & Honein, M. A. (2016) · New England Journal of Medicine · doi:10.1056/nejmra1602113 · Cited by 1,180 · see citing works
A Mouse Model of Zika Virus Pathogenesis
Lazear, H. M., Govero, J., Smith, A. M., Platt, D. J., Fernandez, E., Miner, J. J., & Diamond, M. S. (2016) · Cell Host & Microbe · doi:10.1016/j.chom.2016.03.010 · Cited by 909 · see citing works
Zika Virus Infection during Pregnancy in Mice Causes Placental Damage and Fetal Demise
Miner, J. J., Cao, B., Govero, J., Smith, A. M., Fernández, E., Cabrera, O. H., Garber, C., Elam-Noll, M., Klein, R. S., Noguchi, K. K., et al. (2016) · Cell · doi:10.1016/j.cell.2016.05.008 · Cited by 817 · see citing works
Zika Virus Targets Human STAT2 to Inhibit Type I Interferon Signaling
Grant, A., Ponia, S. S., Tripathi, S., Balasubramaniam, V. R. M. T., Miorin, L., Sourisseau, M., Schwarz, M. C., Sánchez‐Seco, M. P., Evans, M. J., Best, S. M., et al. (2016) · Cell Host & Microbe · doi:10.1016/j.chom.2016.05.009 · Cited by 789 · see citing works
Zika Virus Disrupts Neural Progenitor Development and Leads to Microcephaly in Mice
Li, C., Xu, D., Ye, Q., Hong, S., Jiang, Y., Liu, X., Zhang, N., Shi, L., Qin, C.-F., & Xu, Z. (2016) · Cell Stem Cell · doi:10.1016/j.stem.2016.04.017 · Cited by 749 · see citing works
Persistence of Zika Virus in Body Fluids — Final Report
Paz‐Bailey, G., Rosenberg, E. S., Doyle, K., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1613108 · Cited by 487 · see citing works
Zika Virus Infects Human Placental Macrophages
Quicke, K. M., Bowen, J. R., Johnson, E. L., McDonald, C. E., Ma, H., O’Neal, J. T., Rajakumar, A., Wrammert, J., Rimawi, B. H., Pulendran, B., et al. (2016) · Cell Host & Microbe · doi:10.1016/j.chom.2016.05.015 · Cited by 473 · see citing works
Characterization of a Novel Murine Model to Study Zika Virus
Rossi, S. L., Tesh, R. B., Azar, S. R., Muruato, A. E., Hanley, K. A., Auguste, A. J., Langsjoen, R. M., Paessler, S., Vasilakis, N., & Weaver, S. C. (2016) · The American Society of Tropical Medicine and Hygiene · doi:10.4269/ajtmh.16-0111 · Cited by 458 · see citing works
Zika Virus: New Clinical Syndromes and Its Emergence in the Western Hemisphere
Lazear, H. M., & Diamond, M. (2016) · Journal of Virology · doi:10.1128/jvi.00252-16 · Cited by 451 · see citing works
Zika and the Risk of Microcephaly
Johansson, M. A., Mier-y-Terán-Romero, L., Reefhuis, J., et al. (2016) · New England Journal of Medicine · doi:10.1056/nejmp1605367 · Cited by 429 · see citing works
Congenital Zika Virus Infection
Melo, A., Aguiar, R. S., Amorim, M. M. R., Arruda, M. B., Melo, F. D. O., Ribeiro, S. T. C., Batista, A. G. M., Ferreira, T. A., dos Santos, M. P., Sampaio, V. V., et al. (2016) · JAMA Neurology · doi:10.1001/jamaneurol.2016.3720 · Cited by 400 · see citing works
Structural Basis of Zika Virus-Specific Antibody Protection
Zhao, H., Fernández, E., Dowd, K. A., Speer, S. D., Platt, D. J., Gorman, M. J., Govero, J., Nelson, C. A., Pierson, T. C., Diamond, M., et al. (2016) · Cell · doi:10.1016/j.cell.2016.07.020 · Cited by 377 · see citing works
Vaginal Exposure to Zika Virus during Pregnancy Leads to Fetal Brain Infection
Yockey, L. J., Varela, L., Rakib, T., Khoury-Hanold, W., Fink, S. L., Stutz, B., Szigeti‐Buck, K., van den Pol, A. N., Lindenbach, B. D., Horváth, T. L., et al. (2016) · Cell · doi:10.1016/j.cell.2016.08.004 · Cited by 358 · see citing works
Zika virus — reigniting the TORCH
Coyne, C. B., & Lazear, H. M. (2016) · Nature Reviews Microbiology · doi:10.1038/nrmicro.2016.125 · Cited by 355 · see citing works
Characterization of Lethal Zika Virus Infection in AG129 Mice
Aliota, M. T., Caine, E. A., Walker, E. C., Larkin, K. E., Camacho, E., & Osorio, J. E. (2016) · PLoS neglected tropical diseases · doi:10.1371/journal.pntd.0004682 · Cited by 322 · see citing works
Zika Virus Disease in Colombia — Preliminary Report
Pacheco, Ó., Beltrán, M., Nelson, C. A., Valencia, D., Tolosa, N., Farr, S. L., Padilla, A. V., Tong, V. T., Cuevas, E. L., Espinosa-Bode, A., et al. (2016) · New England Journal of Medicine · doi:10.1056/nejmoa1604037 · Cited by 305 · see citing works
Brasil, P., Calvet, G. A., Siqueira, A. M., Wakimoto, M. D., de Sequeira, P. C., Nobre, A. A., Quintana, M. D. S. B., de Mendonça, M. C. L., Lupi, O., de Souza, R. V., et al. (2016) · PLoS neglected tropical diseases · doi:10.1371/journal.pntd.0004636 · Cited by 298 · see citing works
Wu, K.-Y., Zuo, G.-L., Li, X.-F., Ye, Q., Deng, Y.-Q., Huang, X.-Y., Cao, W.-C., Qin, C.-F., & Luo, Z.-G. (2016) · Cell Research · doi:10.1038/cr.2016.58 · Cited by 283 · see citing works
Animal Models of Zika Virus Infection, Pathogenesis, and Immunity
Morrison, T. E., & Diamond, M. S. (2017) · Journal of Virology · doi:10.1128/jvi.00009-17 · Cited by 275 · see citing works
Vaccine Mediated Protection Against Zika Virus-Induced Congenital Disease
Richner, J. M., Jagger, B. W., Shan, C., Fontes, C. R., Dowd, K. A., Cao, B., Himansu, S., Caine, E. A., Nunes, B. T. D., Medeiros, D. B. A., et al. (2017) · Cell · doi:10.1016/j.cell.2017.06.040 · Cited by 267 · see citing works
Fetal brain lesions after subcutaneous inoculation of Zika virus in a pregnant nonhuman primate
Waldorf, K. M. A., Stencel-Baerenwald, J., Kapur, R. P., Studholme, C., Boldenow, E., Vornhagen, J., Baldessari, A. E., Dighe, M., Thiel, J., Merillat, S. A., et al. (2016) · Nature Medicine · doi:10.1038/nm.4193 · Cited by 258 · see citing works
Type I interferons instigate fetal demise after Zika virus infection
Yockey, L. J., Jurado, K. A., Arora, N., Millet, A., Rakib, T., Milano, K. M., Hastings, A. K., Fikrig, E., Kong, Y., Horváth, T. L., et al. (2018) · Science Immunology · doi:10.1126/sciimmunol.aao1680 · Cited by 253 · see citing works
Cardenas, I., Means, R. E., Aldo, P. B., Koga, K., Lang, S. M., Booth, C. J., Alejandro Manzur, Y., Enrique Oyarzún, E., Romero, R. J., & Mor, G. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.1000289 · Cited by 248 · see citing works
Mosquitoes Inoculate High Doses of West Nile Virus as They Probe and Feed on Live Hosts
Styer, L. M., Kent, K. A., Albright, R. G., Bennett, C. J., Kramer, L. D., & Bernard, K. A. (2007) · PLoS Pathogens · doi:10.1371/journal.ppat.0030132 · Cited by 240 · see citing works
Zika Virus Disrupts Neural Progenitor Development and Leads to Microcephaly in Mice
Li, C., Xu, D., Ye, Q., et al. (2016) · Cell stem cell · doi:10.1016/j.stem.2016.10.017 · Cited by 210 · see citing works
Zika virus infection in pregnant rhesus macaques causes placental dysfunction and immunopathology
Hirsch, A. J., Roberts, V. H. J., Grigsby, P. L., Haese, N. N., Schabel, M. C., Wang, X., Lo, J. O.-T., Liu, Z., Kroenke, C. D., Smith, J. L., et al. (2018) · Nature Communications · doi:10.1038/s41467-017-02499-9 · Cited by 203 · see citing works
Mosquito Bite Delivery of Dengue Virus Enhances Immunogenicity and Pathogenesis in Humanized Mice
Cox, J., Mota, J., Sukupolvi-Petty, S., et al. (2012) · Journal of Virology · doi:10.1128/jvi.00534-12 · Cited by 202 · see citing works
Zika Virus Persistence in the Central Nervous System and Lymph Nodes of Rhesus Monkeys
Aïd, M., Abbink, P., Larocca, R. A., Boyd, M. B., Nityanandam, R., Nanayakkara, O., Martinot, A. J., Moseley, E. T., Blass, E., Borducchi, E. N., et al. (2017) · Cell · doi:10.1016/j.cell.2017.04.008 · Cited by 201 · see citing works
Highly efficient maternal-fetal Zika virus transmission in pregnant rhesus macaques
Nguyen, S. M., Antony, K. M., Dudley, D. M., Kohn, S., Simmons, H. A., Wolfe, B., Salamat, M. S., Teixeira, L. B. C., Wiepz, G. J., Thoong, T. H., et al. (2017) · PLoS Pathogens · doi:10.1371/journal.ppat.1006378 · Cited by 201 · see citing works
Vermillion, M. S., Lei, J., Shabi, Y., Baxter, V. K., Crilly, N. P., McLane, M., Griffin, D. E., Pekosz, A. S., Klein, S. L., & Burd, I. D. (2017) · Nature Communications · doi:10.1038/ncomms14575 · Cited by 167 · see citing works
Gestational Stage and IFN-λ Signaling Regulate ZIKV Infection In Utero
Jagger, B. W., Miner, J. J., Cao, B., Arora, N., Smith, A. M., Kovács, A. D., Mysorekar, I. U., Coyne, C. B., & Diamond, M. (2017) · Cell Host & Microbe · doi:10.1016/j.chom.2017.08.012 · Cited by 155 · see citing works
Waldorf, K. M. A., Nelson, B. R., Stencel-Baerenwald, J., Studholme, C., Kapur, R. P., Armistead, B., Walker, C. L., Merillat, S. A., Vornhagen, J., Tisoncik-Go, J., et al. (2018) · Nature Medicine · doi:10.1038/nm.4485 · Cited by 147 · see citing works
Alvarado, G., & Schwartz, D. A. (2016) · Archives of Pathology & Laboratory Medicine · doi:10.5858/arpa.2016-0382-ra · Cited by 135 · see citing works
Xavier‐Neto, J., Carvalho, M. D. O., Pascoalino, B. S., Cardoso, A. C., Costa, Â. M. S., Pereira, A. H. M., Santos, L. N., Saito, Â., Marques, R. E., Smetana, J. H. C., et al. (2017) · PLoS neglected tropical diseases · doi:10.1371/journal.pntd.0005363 · Cited by 111 · see citing works
Modeling Zika Virus Infection in Pregnancy
Mysorekar, I. U., & Diamond, M. (2016) · New England Journal of Medicine · doi:10.1056/nejmcibr1605445 · Cited by 109 · see citing works
Halai, U., Nielsen‐Saines, K., Moreira, M. L., de Sequeira, P. C., Pereira, J. P., Zin, A., Cherry, J. D., Gabaglia, C. R., Gaw, S. L., Adachi, K., et al. (2017) · Clinical Infectious Diseases · doi:10.1093/cid/cix472 · Cited by 100 · see citing works
Dudley, D. M., Newman, C. M., Lalli, J. L., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-02222-8 · Cited by 98 · see citing works
Rb is critical in a mammalian tissue stem cell populationPreprint
Wenzel, P. L., Wu, L. L., de Bruin, A., Chong, J., Chen, W.-Y., Dureska, G., Sites, E., Pan, T., Sharma, A., Huang, K., et al. (2007) · Genes & Development · doi:10.1101/gad.1485307 · Cited by 89 · see citing works
The Origins and Emergence of Zika Virus, the Newest TORCH Infection: What's Old Is New Again
Schwartz, D. A. (2016) · Archives of Pathology & Laboratory Medicine · doi:10.5858/arpa.2016-0429-ed · Cited by 85 · see citing works
Huang, W., Abraham, R., Shim, B.-S., Choe, H., & Page, D. T. (2016) · Scientific Reports · doi:10.1038/srep34793 · Cited by 81 · see citing works
Zika virus: A new threat to human reproduction
Baud, D., Musso, D., Vouga, M., Alves, M. P., & Vulliémoz, N. R. (2016) · American Journal of Reproductive Immunology · doi:10.1111/aji.12614 · Cited by 48 · see citing works
Anderson, K. B., Thomas, S. J., & Endy, T. P. (2016) · Annals of Internal Medicine · doi:10.7326/m16-0617 · Cited by 44 · see citing works
Self-citationOverview on the Current Status of Zika Virus Pathogenesis and Animal Related Research
Pawitwar, S. S., Dhar, S., Tiwari, S., Ojha, C. R., Lapierre, J., Martins, K., Rodzinski, A., Parira, T., Paudel, I., Li, J., et al. (2017) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-017-9743-8 · Cited by 30 · see citing works
Congenital Zika virus infection
Alsufayanp, P. (2019) · Pediatrics & Therapeutics · Cited by 12 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
ICR suckling mouse model of Zika virus infection for disease modeling and drug validation
Wu, Y.-H., Tseng, C.-K., Lin, C.-K., Wei, C.-K., Lee, J.-C., & Young, K.-C. (2018) · PLoS Neglected Tropical Diseases · doi:10.1371/journal.pntd.0006848 · Cited by 35 · see citing works
- Authors
- Szaba, F. M., Tighe, M., Kummer, L. W., Lanzer, K. G., Ward, J. M., Lanthier, P., Kim, I.-J., Kuki, A., Blackman, M. A., Thomas, S. J., & Lin, J.-S.
- Affiliations
- Trudeau Institute (US)
- Global VetPathology (US)
- SUNY Upstate Medical University (US)
- Corresponding author
- Lin, Jr-Shiuan
- ORCID
- Venue
- PLoS Pathogens
- Publisher
- Public Library of Science (PLoS)
- Published
- 2018-04-10
- Volume
- 14
- Issue
- 4
- Pages
- e1006994
- ISSN
- 1553-7366 (ISSN-L)
- 1553-7374
- PMC
- PMC5909921
- OpenAlex
- W2797004612
- Cited by
- 97
- References
- 48
- Citations by year
- 2026: 9 · 2025: 7 · 2024: 4 · 2023: 5 · 2022: 13 · 2021: 16 · 2020: 9 · 2019: 25 · 2018: 9
- FWCI
- 14.04
- Type
- journal article
- Language
- en
- Update notices
- new_version (2018-04-20)
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS Pathogens (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- Trudeau Institute
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Mosquito-borne diseases and control
- Health Sciences › Medicine › Obstetrics and Gynecology › COVID-19 Impact on Reproduction
- Health Sciences › Medicine › Infectious Diseases › Viral Infections and Vectors
- Keywords
- Zika virus, pregnancy, placental pathology, intrauterine fetal death, congenital malformations, immunocompetent mice, type I interferon, placental blood vessels, vertical transmission
- MeSH terms
- Zika Virus Infection, Zika Virus, Animals, Disease Models, Animal, Female, Fetal Diseases, Mice, Inbred C57BL, Placenta Diseases, Pregnancy, Pregnancy Complications, Infectious, Pregnancy Outcome, RNA, Viral, Infectious Disease Transmission, Vertical, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
