Interferon-λ signaling to maternal dendritic cells protects against congenital Zika virus infection
Interferon-λ (IFN-λ, type III IFN) mediates antiviral immunity at anatomic barriers, including the maternal-fetal interface. To investigate the effects of IFN-λ during congenital Zika virus (ZIKV) infection, we infected mice lacking the IFN-αβ receptor (Ifnar1−/−) or both the IFN-αβ and IFN-λ receptors (Ifnar1−/−Ifnlr1−/−) at embryonic day 9 and found that loss of maternal IFN-λ signaling resulted in greater transplacental transmission, highlighting a protective effect of IFN-λ at the maternal-fetal interface. To investigate the spatial relationship between ZIKV infection and antiviral responses, we used HiPlex RNAscope on the entire gravid uterus and found that IFN-λ was expressed more proximal to the site of ZIKV infection in Ifnar1−/− dams compared to Ifnar1−/−Ifnlr1−/− dams. We performed immunophenotyping of the placenta and uterus by flow cytometry and found a decrease in dendritic cells and natural killer (NK) cells in the uterus of Ifnar1−/−Ifnlr1−/− dams compared to Ifnar1−/− dams, but NK cell depletion did not affect fetal infection. Using conditional knockout mice, we identified maternal dendritic cells as the key IFN-λ–responsive cell type mediating protection against ZIKV congenital infection. Together, our data support a model in which IFN-λ signaling to maternal dendritic cells increases dendritic cell accumulation in the uterus, which facilitates a protective antiviral response that restricts ZIKV congenital infection.
Authors
- Joel Rivera-Cardona (ORCID: https://orcid.org/0000-0002-2630-6740)
- Michelle S. Itano (ORCID: https://orcid.org/0000-0001-6853-1228)
- Rebecca L. Casazza (ORCID: https://orcid.org/0000-0002-8271-6947)
- Margaret R. Dedloff (ORCID: https://orcid.org/0000-0002-0175-116X)
- Jennifer Ashley Ezzell (ORCID: https://orcid.org/0000-0002-5142-4685)
- Tessa‐Jonne F. Ropp (ORCID: https://orcid.org/0000-0001-9831-0557)
- Helen M. Lazear (ORCID: https://orcid.org/0000-0002-8649-4579)
- Celeste R. Robles (ORCID: https://orcid.org/0000-0002-4854-7676)
- Thomas R. Reinhardt (ORCID: https://orcid.org/0009-0003-4749-8213)
Institutions
- University of North Carolina at Chapel Hill (US)
Publication Details
- Journal
- UNC Libraries
- Published
- 2026-10-30
- DOI
- https://doi.org/10.17615/ath2-h107
- Primary Topic
- interferon and immune responses
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Howard Hughes Medical Institute
- Burroughs Wellcome Fund
- Bill and Melinda Gates Foundation
- John Templeton Foundation
- Paul G. Allen Family Foundation
- Morris Animal Foundation
- Blue Cross and Blue Shield of Florida Foundation
- Leakey Foundation
- National Geographic Society
- Natural Science Foundation of Jilin Province
- Fondation Brain Canada
- Japan Agency for Medical Research and Development
- Wellcome Trust
- Environmental Restoration and Conservation Agency
- Ministerio de Ciencia, Innovación y Universidades
- Fulbright Norway
- Ministerio de Educación y Ciencias
- Michael Smith Health Research BC
- British Heart Foundation
- European Commission
- Commonwealth Scientific and Industrial Research Organisation
- Indian Council of Medical Research
- Deutsche Forschungsgemeinschaft
- Institut National de la Santé et de la Recherche Médicale
- Japan Science and Technology Corporation
- Ministry of Education, Culture, Sports, Science and Technology
- Canada Research Chairs
- National Natural Science Foundation of China
- Ministry of Education of the People's Republic of China
- Austrian Science Fund
- Ministry of Science and Technology of the People's Republic of China
- Consejo Nacional de Investigaciones Científicas y Técnicas
- Fudan University
- Shanghai Municipal Education Commission
- Conselho Nacional de Desenvolvimento Científico e Tecnológico
- Iran National Science Foundation
- Stavros Niarchos Foundation
- Natural Science Foundation of Jiangxi Province
- China Scholarship Council
- Ministerio de Ciencia e Innovación
- Universitetet i Bergen
- Shionogi
- Deutsche Krebshilfe
- Yildiz Teknik Üniversitesi
- Comisión Interministerial de Ciencia y Tecnología
- Universität zu Köln
- Japan Diabetes Society
- Canada First Research Excellence Fund
- Centro de Investigación Biomédica en Red-Fisiopatología de la Obesidad y Nutrición
- Fundación Palarq
- Peder Sather Center for Advanced Study
- Taipei Medical University-Shuang Ho Hospital, Ministry of Health and Welfare
- Canadian Institutes of Health Research
- Natural Sciences and Engineering Research Council of Canada
- Engineering and Physical Sciences Research Council
- Economic and Social Research Council
- National Health and Medical Research Council
- Japan Science and Technology Agency
- Freiburg Institute for Advanced Studies, Albert-Ludwigs-Universität Freiburg
- Instituto de Salud Carlos III
- Agencia Estatal de Investigación
- Key Technologies Research and Development Program
- National Key Research and Development Program of China
- Agricultural Science and Technology Innovation Program
- National Major Science and Technology Projects of China
- National Defense Science and Technology Innovation Fund of the Chinese Academy of Sciences
- Henan Provincial Science and Technology Research Project
- Science and Technology Innovation Talents in Universities of Henan Province
- NIHR Cambridge Biomedical Research Centre
- National Heart, Lung, and Blood Institute
- National Institute of General Medical Sciences
- National Institute of Allergy and Infectious Diseases
- National Institute of Neurological Disorders and Stroke
- National Institute of Arthritis and Musculoskeletal and Skin Diseases
- National Institute of Biomedical Imaging and Bioengineering
- National Institute of Dental and Craniofacial Research
- Jonsson Comprehensive Cancer Center
- School of Medicine, University of North Carolina at Chapel Hill