516 - Spatially Resolved Immune Landscape of the Placenta During Congenital Cytomegalovirus Infection

Publication Number: 3497.516

Elise Sintim-Aboagye, Mayo Clinic Alix School of Medicine, Rochester, MN, United States; Indrani Mukherjee, University of Miami Leonard M. Miller School of Medicine, Miami, FL, United States; Will Sherman, Mayo Clinic Department of Quantitative Health Science, Rochester, MN, United States; Huy Quach, Mayo Clinic, Rochester, MN, United States; Neil Ferland, University of Miami, Miami Beach, FL, United States; Katelyn T. Nguyen, University of Miami, Miami, FL, United States; Kamila Otrubova, STGAG, Steckborn, Thurgau, Switzerland; Namisha Verma, University hospitals Plymouth NHS trust, Plymouth, England, United Kingdom; Dawn Littlefield, University of Miami Leonard M. Miller School of Medicine, Miami, FL, United States; Sohan Punia, Baylor Scott White McLane Children's Medical Center, Troy, TX, United States; Erica L. Johnson, Morehouse School of Medicine, Atlanta, GA, United States; Mark Blackstad, University of Minnesota, Minneapolis, MN, United States; Mark R.. Schleiss, University of Minnesota Masonic Children's Hospital, Minneapolis, MN, United States; Clive Gray, Stellenbosch University, Cape Town, Western Cape, South Africa; Elizabeth Ann Enninga, Mayo Clinic, Rochester, MN, United States; Rana Chakraborty, Miller School of Medicine, Miami, FL, United States

Background: Human placentae play a critical role in vertical transmission, as both trophoblasts and placental immune cells are permissive to cytomegalovirus (CMV) infection. CMV remains the primary infectious cause of congenital birth defects globally. While only a subset of infants with congenital CMV (cCMV) exhibit overt clinical symptoms, those affected frequently experience lasting outcomes such as sensorineural hearing loss, visual impairment, and neurodevelopmental delays. However, the mechanisms that drive symptomatic disease are still unknown.

Objective: In this study, we aimed to spatially characterize changes in gene and protein expression within placental immune cells and trophoblasts during cCMV infection.

Design/Methods: Placental tissue from CMV-affected and CMV unaffected pregnancies were retrieved from the Mayo Clinic tissue repository. Immune cells were
identified by CD45 positivity and cytotrophoblasts (CTBs) identified by CK7. The cell-specific genome and proteome of these tissues was identified using the NanoString™ immune cell and cell death panels. Data was analyzed by NanoString™ GeoMx technology.

Results: Our analyses revealed upregulated expression of immune activation markers and related signaling cascades across trophoblasts and placental immune populations. In contrast, pathways supporting tissue repair and remodeling were markedly suppressed, accompanied by elevated pro-apoptotic transcripts and proteins associated with cell death processes. Spatial profiling further demonstrated that immune compartments within CMV+ tissue were enriched for pathways governing immune cell proliferation, differentiation, lymphopoiesis, and T cell maturation.

Conclusion(s): Findings from our study delineate spatially distinct immune and trophoblastic responses to CMV infection, offering mechanistic insights into CMV-induced placental dysregulation with identification of potential molecular targets for therapeutic intervention.