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The role of ZBP1 in controlling HSV-1 pathogenesis

Award Number: R01AI189875
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/16/2026
PERIOD OF PERFORMANCE END DATE: 03/31/2031

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The role of ZBP1 in controlling HSV-1 pathogenesis - PROJECT SUMMARY Herpes simplex virus type 1 (HSV-1) is a highly prevalent human pathogen with worldwide prevalence levels of about 67%. The outcome of infection with HSV-1 can be asymptomatic, mild, or life-threatening. Our previous work has shown that HSV-1 activates Z-form nucleic acid Binding Protein 1 (ZBP1)-driven cell death, mediated by the receptor-interacting protein kinase (RIPK) 3. The mechanisms underlying the generation of ZBP1 ligands and the regulation of the ZBP1-signaling pathway during HSV-1 infections are unknown. Our preliminary studies have now demonstrated that HSV-1 generates both Z-DNA and Z-RNA (the left-handed dsDNA and dsRNA duplexes, respectively), of which Z-RNAs likely serve as essential ZBP1-activating ligands. We have also made the unanticipated discovery that ZBP1 requires the kinase RIPK1 to recruit and activate RIPK3 for the execution of downstream necroptosis in HSV-1-infected human cells. Importantly, we find that ZBP1-driven necroptosis is essential for limiting HSV-1 spread in a mouse model of transdermal infection. These findings allow us to put forward the hypothesis that ZBP1 senses Z-RNA species generated in HSV-1-infected cells, following which it triggers RIPK1/3-dependent cell death to restrict viral spread. This proposal will test these hypotheses by (1) identifying the Z-RNA ligands for ZBP1 are, and determining how these are formed during HSV-1 infections; (2) understanding how RIPK1 regulates ZBP1-driven RIPK3 activation; and (3) determining the role of ZBP1- activated cell death signaling (primarily necroptosis, but also apoptosis) in anti-HSV-1 host defense and pathogenesis in vivo. Together, these studies will provide pioneering insight into the mechanism, role, and function of ZBP1-initiated programmed cell death during HSV-1 infections.


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 = $660,723 )
2026	2026	LOUISIANA STATE UNIVERSITY	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Allergy and Infectious Diseases Research	000	1	4/17/2026	NEW	$660,723
														Subtotal = $660,723

Grand Total All Awards = $660,723

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The role of ZBP1 in controlling HSV-1 pathogenesis

Award Number: R01AI189875

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/16/2026

PERIOD OF PERFORMANCE END DATE: 03/31/2031

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