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Molecular mechanisms of the DUX4-driven response to HCMV infection in trophoblasts

Award Number: K99AI201759
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Molecular mechanisms of the DUX4-driven response to HCMV infection in trophoblasts - PROJECT SUMMARY/ABSTRACT: Human cytomegalovirus (HCMV) is the leading infectious cause of congenital birth defects, affecting approximately 1 in 200 live births worldwide. Situated at the maternal-fetal interface (MFI), fetal placental trophoblasts form the primary barrier to congenital infection and have evolved specialized antiviral defenses to suit the unique immunological balance needed during pregnancy. In our recent publication, we report that the response to herpesvirus infections in trophoblasts is dominated by a transcriptional program controlled by the transcription factor DUX4 (Hatterschide et al., Journal of Experimental Medicine, 2025). Trophoblasts respond to HCMV and other herpesvirus infections with uniquely high levels of DUX4 and DUX4-stimulated genes (DSGs). Furthermore, we identified that many DSGs from unrelated gene families can inhibit herpesvirus replication, indicating a coordinated antiviral program with parallels to the interferon-stimulated gene response. However, due to limited models of HCMV and other herpesvirus infections at the maternal-fetal interface we currently have an incomplete understanding of 1) how this program is regulated, 2) how DSGs mediate antiviral activity, and 3) whether there are any detrimental consequences of this program to trophoblast physiology. I propose to use trophoblast organoids (TOs) to investigate the molecular mechanisms of the DUX4-drive response to HCMV infection in trophoblasts. TOs are a novel model that recapitulates many key aspects of the cellular and immunological complexity of the human placenta. The objectives of this proposal are to identify host- cell and viral factors that contribute to the unique regulation of the DUX4/DSG program in trophoblasts, identify the mechanism by which specific DSGs inhibit HCMV replication, and determine whether expression of DUX4 perturbs normal trophoblast function all while building upon the TO model to expand its utility in mechanistic studies. The specific aims of this proposal are to 1) identify the mechanisms by which HCMV induces DUX4 and DSGs in trophoblasts, 2) determine the mechanism by which LEUTX (a DSG) inhibits HCMV replication, and 3) define the consequences of DUX4 expression for trophoblast physiology. Aim 1 will test whether HCMV and HSV-1 immediate early genes are sufficient to induce DUX4 expression. It will also use single-nucleus multi-omics to define trophoblast subtype, gene expression, and chromatin accessibility patterns that enable uniquely high DUX4/DSG expression. Aim 2 will test whether LEUTX is sufficient to inhibit HCMV replication in TOs, identify the motifs and regions of LEUTX required for antiviral activity, and profile LEUTX transcriptional targets for antiviral activity. Aim 3 will assess whether DUX4 expression in trophoblasts impairs differentiation and if DUX4 expression in already differentiated cells dysregulates normal function. Training in key areas during the K99 phase of this award will leave me well situated to initiate the independent phase of my research career. Furthermore, completing the proposed aims will establish the basis for many additional projects that can be pursued by future trainees.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $143,897 )
2026	2026	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Allergy and Infectious Diseases Research	000	1	8/20/2026	NEW	$143,897
														Subtotal = $143,897

Grand Total All Awards = $143,897

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Molecular mechanisms of the DUX4-driven response to HCMV infection in trophoblasts

Award Number: K99AI201759

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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