Influenza A virus infection induces immune dysregulation in the placenta and fetus without vertical transmission in nonhuman primates
12 affiliations
- 1Department of Global Health, University of Washington, Seattle, WA, USA.
- 2Department of Obstetrics and Gynecology, University of Washington, Seattle, WA, USA.
- 3Case Western Reserve School of Medicine, Cleveland, OH, USA.
- 4School of Medicine, University of Washington, Seattle, WA, USA.
- 5Department of Psychiatry, University of Washington, Seattle, WA, USA.
- 6Department of Lab Medicine and Pathology, University of Washington, Seattle, WA, USA.
- 7Department of Pathology, Seattle Children’s Hospital, Seattle, WA, USA.
- 8Washington National Biomedical Research Center, Seattle, WA, USA.
- 9Department of Microbiology, University of Washington, Seattle, WA, USA.
- 10Oregon Health & Science University, Portland, OR, USA.
- 11Center for Global Infectious Disease Research, Seattle Children’s Research Institute, Seattle, WA, USA.
- 12Department of Pediatrics, University of Washington, Seattle, WA.
Abstract
Influenza A virus (IAV) infection during pregnancy is associated with stillbirth and preterm birth, but the degree to which IAV alters placental and fetal immunity is poorly understood. The objective of our study was to determine the immunologic impact of maternal IAV infection on the placenta and fetus in a pigtail macaque ( Macaca nemestrina ) model. Pregnant pigtail macaques were inoculated with 10 7 plaque forming units (PFU) of IAV [A/California/07/2009 (H1N1)] and underwent necropsy 5 days post-infection (N=11). Results were compared to uninfected historical controls (N=16). IAV inoculation induced maternal pneumonia in all cases. Stillbirth occurred in 18% (2/11) of IAV-infected pregnancies, but not in controls. While vertical transmission was not observed, low-level IAV viral RNA was detected in two placentas. In the placenta, maternal IAV infection was associated with increased IL-1β, IL-18, and IFN-β levels, and an upregulated type I interferon (IFN) transcriptional response. IAV infection was also associated with significantly higher frequencies of intermediate and non-classical monocytes, plasmacytoid dendritic cells, CD4⁺ T cells, and NKT cells in the fetus (lung, lymph node, blood). Although placental immune and transcriptional perturbations were rarely correlated with maternal IAV disease indicators (e.g., maternal lung viral load/IFN-α/IFN-β/IL-6), there were consistent and significant correlations between these metrics and perturbed immune cell populations in the fetus (CD4+ and CD8+ T cells, plasmacytoid dendritic cells, monocyte sub-populations). Maternal IAV infection disrupted both placental and fetal immune environments, but only fetal immune alterations correlated with maternal lung disease severity. One Sentence Summary Maternal influenza A virus infection in pregnant pigtail macaques dysregulates placental and fetal immunity, with disease severity correlating strongly with fetal, but not placental, immune perturbations.
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BibTeX
@article{cervantes2026influenza,
title = {{Influenza A virus infection induces immune dysregulation in the placenta and fetus without vertical transmission in nonhuman primates}},
author = {Orlando Cervantes and Sidney Sun and Hazel Huang and Briana Del Rosario and Hong Zhao and Amanda Li and Andrew Vo and Gygeria Manuel and Roslyn Van Abel and Jeff Munson and John Cornelius and Raj P. Kapur and Miranda Li and Edmunda Li and Hanning Li and Alexandra Christodoulou and Melissa Berg and Britni Curtis and Elizabeth Miller and Shannon Ruff and Brenna Menz and Solomon Wangari and Audrey Germond and Audrey Baldessari and Chris English and W. McIntyre Durning and Thomas B. Lewis and Megan N. Fredericks and Mara Maughan and Austyn Orvis and Michelle Coleman and Lakshmi Rajagopal and Deborah H. Fuller and Kristina M. Adams Waldorf},
journal = {Science Advances},
year = {2026},
month = oct,
doi = {10.1126/sciadv.aee9861},
url = {https://www.science.org/doi/10.1126/sciadv.aee9861},
note = {CC BY},
}
RIS
TY - JOUR
TI - Influenza A virus infection induces immune dysregulation in the placenta and fetus without vertical transmission in nonhuman primates
AU - Orlando Cervantes
AU - Sidney Sun
AU - Hazel Huang
AU - Briana Del Rosario
AU - Hong Zhao
AU - Amanda Li
AU - Andrew Vo
AU - Gygeria Manuel
AU - Roslyn Van Abel
AU - Jeff Munson
AU - John Cornelius
AU - Raj P. Kapur
AU - Miranda Li
AU - Edmunda Li
AU - Hanning Li
AU - Alexandra Christodoulou
AU - Melissa Berg
AU - Britni Curtis
AU - Elizabeth Miller
AU - Shannon Ruff
AU - Brenna Menz
AU - Solomon Wangari
AU - Audrey Germond
AU - Audrey Baldessari
AU - Chris English
AU - W. McIntyre Durning
AU - Thomas B. Lewis
AU - Megan N. Fredericks
AU - Mara Maughan
AU - Austyn Orvis
AU - Michelle Coleman
AU - Lakshmi Rajagopal
AU - Deborah H. Fuller
AU - Kristina M. Adams Waldorf
PY - 2026
DA - 2026/10/09
JO - Science Advances
DO - 10.1126/sciadv.aee9861
UR - https://www.science.org/doi/10.1126/sciadv.aee9861
AB - Influenza A virus (IAV) infection during pregnancy is associated with stillbirth and preterm birth, but the degree to which IAV alters placental and fetal immunity is poorly understood. The objective of our study was to determine the immunologic impact of maternal IAV infection on the placenta and fetus in a pigtail macaque ( Macaca nemestrina ) model. Pregnant pigtail macaques were inoculated with 10 7 plaque forming units (PFU) of IAV [A/California/07/2009 (H1N1)] and underwent necropsy 5 days post-infection (N=11). Results were compared to uninfected historical controls (N=16). IAV inoculation induced maternal pneumonia in all cases. Stillbirth occurred in 18% (2/11) of IAV-infected pregnancies, but not in controls. While vertical transmission was not observed, low-level IAV viral RNA was detected in two placentas. In the placenta, maternal IAV infection was associated with increased IL-1β, IL-18, and IFN-β levels, and an upregulated type I interferon (IFN) transcriptional response. IAV infection was also associated with significantly higher frequencies of intermediate and non-classical monocytes, plasmacytoid dendritic cells, CD4⁺ T cells, and NKT cells in the fetus (lung, lymph node, blood). Although placental immune and transcriptional perturbations were rarely correlated with maternal IAV disease indicators (e.g., maternal lung viral load/IFN-α/IFN-β/IL-6), there were consistent and significant correlations between these metrics and perturbed immune cell populations in the fetus (CD4+ and CD8+ T cells, plasmacytoid dendritic cells, monocyte sub-populations). Maternal IAV infection disrupted both placental and fetal immune environments, but only fetal immune alterations correlated with maternal lung disease severity. One Sentence Summary Maternal influenza A virus infection in pregnant pigtail macaques dysregulates placental and fetal immunity, with disease severity correlating strongly with fetal, but not placental, immune perturbations.
SN - 2375-2548
ER -