Characterization of Resolved, Localized, and Progressing Infections at the Maternal-Fetal Interface in a Nonhuman Primate Model
- 1University of Washington
Abstract
Background: Inflammation and infection are responsible for the majority of early preterm births. Host innate immune responses at the maternal-fetal interface that contribute to sterile intra-amniotic inflammation (SIAI), bacterial clearance, or invasive infection remain poorly understood. Group B Streptococcus (Streptococcus agalactiae) is a leading cause of preterm birth, stillbirth, and invasive neonatal disease. Objective: To determine the host innate immune factors and transcriptional profiles that characterize the persistence versus resolution of a Group B Streptococcus infection at the maternal-fetal interface in a nonhuman primate (pigtail macaque, Macaca nemestrina) model. We hypothesized that a highly inflammatory profile, associated with interleukin-1 signaling, is linked to progression, whereas a mild or non-inflammatory signature is associated with infection resolution. Study Design: In a chronically catheterized pregnant pigtail macaque model, Group B Streptococcus was inoculated into the choriodecidual space. Infections were classified as progressing (invasive into the amniotic fluid), localized (bacteria persisting at the inoculation site), or resolved (minimal to no bacteria detected). Temporal and spatial RNA and protein profiles in the chorioamniotic membranes and decidua and in the myometrium were assessed by histopathology, multiplex protein assays, total RNA-sequencing, Nanostring nCounter, and spatial transcriptomics (digital spatial profiling). Differential gene expression was analyzed with limma using moderated t-tests and by gene set enrichment analysis. Results: A GBS infection at the maternal-fetal interface produced three infection outcomes: progressing infections that disseminated into the amniotic fluid (AF, N=5), low-titer localized infections remaining at the inoculation site (N=6), and resolved infections (N=5), compared with saline controls (N=3). Preterm labor occurred frequently regardless of infection outcome (40-80%). In resolved infections, SIAI occurred in the AF and lymphocytes infiltrated the myometrium. Total RNA-Seq of the chorioamniotic membranes demonstrated that 99 genes separated progressing from resolved infections, 98 of them were upregulated and dominated by IL-1 signaling and granulocyte recruitment (i.e., IL1B, CXCL8, TLR2, CLEC4A). Histone deacetylase 10 (HDAC10) was the only significantly downregulated gene in the progressing versus resolved contrast (p<0.05). An exploratory spatial transcriptomics experiment localized the progressing inflammatory response to the chorion. In the myometrium, zinc and RING finger 3 (ZNRF3) was significantly downregulated in localized versus control and resolved versus control and was also the only differentially expressed gene. Downregulated WNT signaling and upregulated lymphocyte-mediated immunity gene sets in the myometrium were a signature of resolved infections. Conclusion: A GBS infection at the maternal-fetal interface can result in a spectrum of progressing, localized and resolved outcomes. An early IL-1 and granulocyte response in the chorion layer of the chorioamniotic membranes marks bacterial dissemination, with loss of HDAC10 suggesting epigenetic regulation within the membranes with progressing infections. In the myometrium, ZNRF3 and downregulation of WNT signaling persisted even after infection resolution, reflecting an infectious exposure. Unexpectedly, resolved infections were associated with SIAI and a myometrial inflammatory response, offering a possible explanation for preterm labor associated with SIAI.
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BibTeX
@misc{manuel2026characterization,
title = {{Characterization of Resolved, Localized, and Progressing Infections at the Maternal-Fetal Interface in a Nonhuman Primate Model}},
author = {G. Manuel and C. Coler and J. Munson and J. Cornelius and T. Duell and T. Kim and A. Vo and A. Orvis and M. Coleman and K. Murphy and H. Zhao and S. Sun and S. Chima and V. Sindhu and H. Huang and A. Li and M. Li and C. English and A. Baldessari and B. Del Rosario and O. Cervantes and R. Kapur and L. Rajagopal and K. Adams Waldorf},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.15.751503},
url = {https://www.biorxiv.org/content/10.64898/2026.09.15.751503v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Characterization of Resolved, Localized, and Progressing Infections at the Maternal-Fetal Interface in a Nonhuman Primate Model
AU - G. Manuel
AU - C. Coler
AU - J. Munson
AU - J. Cornelius
AU - T. Duell
AU - T. Kim
AU - A. Vo
AU - A. Orvis
AU - M. Coleman
AU - K. Murphy
AU - H. Zhao
AU - S. Sun
AU - S. Chima
AU - V. Sindhu
AU - H. Huang
AU - A. Li
AU - M. Li
AU - C. English
AU - A. Baldessari
AU - B. Del Rosario
AU - O. Cervantes
AU - R. Kapur
AU - L. Rajagopal
AU - K. Adams Waldorf
PY - 2026
DA - 2026/09/15
PB - bioRxiv
DO - 10.64898/2026.09.15.751503
UR - https://www.biorxiv.org/content/10.64898/2026.09.15.751503v1
AB - Background: Inflammation and infection are responsible for the majority of early preterm births. Host innate immune responses at the maternal-fetal interface that contribute to sterile intra-amniotic inflammation (SIAI), bacterial clearance, or invasive infection remain poorly understood. Group B Streptococcus (Streptococcus agalactiae) is a leading cause of preterm birth, stillbirth, and invasive neonatal disease. Objective: To determine the host innate immune factors and transcriptional profiles that characterize the persistence versus resolution of a Group B Streptococcus infection at the maternal-fetal interface in a nonhuman primate (pigtail macaque, Macaca nemestrina) model. We hypothesized that a highly inflammatory profile, associated with interleukin-1 signaling, is linked to progression, whereas a mild or non-inflammatory signature is associated with infection resolution. Study Design: In a chronically catheterized pregnant pigtail macaque model, Group B Streptococcus was inoculated into the choriodecidual space. Infections were classified as progressing (invasive into the amniotic fluid), localized (bacteria persisting at the inoculation site), or resolved (minimal to no bacteria detected). Temporal and spatial RNA and protein profiles in the chorioamniotic membranes and decidua and in the myometrium were assessed by histopathology, multiplex protein assays, total RNA-sequencing, Nanostring nCounter, and spatial transcriptomics (digital spatial profiling). Differential gene expression was analyzed with limma using moderated t-tests and by gene set enrichment analysis. Results: A GBS infection at the maternal-fetal interface produced three infection outcomes: progressing infections that disseminated into the amniotic fluid (AF, N=5), low-titer localized infections remaining at the inoculation site (N=6), and resolved infections (N=5), compared with saline controls (N=3). Preterm labor occurred frequently regardless of infection outcome (40-80%). In resolved infections, SIAI occurred in the AF and lymphocytes infiltrated the myometrium. Total RNA-Seq of the chorioamniotic membranes demonstrated that 99 genes separated progressing from resolved infections, 98 of them were upregulated and dominated by IL-1 signaling and granulocyte recruitment (i.e., IL1B, CXCL8, TLR2, CLEC4A). Histone deacetylase 10 (HDAC10) was the only significantly downregulated gene in the progressing versus resolved contrast (p<0.05). An exploratory spatial transcriptomics experiment localized the progressing inflammatory response to the chorion. In the myometrium, zinc and RING finger 3 (ZNRF3) was significantly downregulated in localized versus control and resolved versus control and was also the only differentially expressed gene. Downregulated WNT signaling and upregulated lymphocyte-mediated immunity gene sets in the myometrium were a signature of resolved infections. Conclusion: A GBS infection at the maternal-fetal interface can result in a spectrum of progressing, localized and resolved outcomes. An early IL-1 and granulocyte response in the chorion layer of the chorioamniotic membranes marks bacterial dissemination, with loss of HDAC10 suggesting epigenetic regulation within the membranes with progressing infections. In the myometrium, ZNRF3 and downregulation of WNT signaling persisted even after infection resolution, reflecting an infectious exposure. Unexpectedly, resolved infections were associated with SIAI and a myometrial inflammatory response, offering a possible explanation for preterm labor associated with SIAI.
ER -