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The role of caspase-3 mediated cleavage of VPS4A in restricting HSV-1

Award Number: F30AI188981
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 03/06/2025
PERIOD OF PERFORMANCE END DATE: 06/30/2029

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The role of caspase-3 mediated cleavage of VPS4A in restricting HSV-1 - PROJECT SUMMARY/ABSTRACT Caspases are critical initiators and executioners of programmed cell death (PCD) pathways. While these pathways function in antiviral defense, little is known about the mechanisms by which caspases and PCD pathways restrict virus replication. This is particularly true in mucosal barrier tissues, such as the oral cavity which is the entry site of numerous human pathogens including herpes simplex virus 1 (HSV-1). Recently, we found that oral epithelial keratinocytes undergo a pro-inflammatory cell death process known as pyroptosis when treated with activators of the tumor necrosis factor receptor (TNFR)-dependent extrinsic PCD pathway. In addition, activation of this extrinsic PCD pathway inhibited the replication of a HSV-1 mutant lacking the viral protein ICP6 (HSV-1 ∆ICP6), which has previously been shown to be unable to inhibit extrinsic cell death in other cell types. TNFR-mediated restriction of HSV-1 ∆ICP6 in keratinocytes was blocked with the addition of a pan-caspase inhibitor, implicating a role for caspases in inhibiting this viral mutant. Thus, oral keratinocytes represent a robust biologically relevant system to study the mechanisms by which caspases restrict virus replication. We found that several caspases, including caspase-3 and -8, were activated in normal oral keratinocytes where the TNFR-dependent extrinsic PCD pathway was activated. Further, we found that restriction of HSV-1 ∆ICP6 under these conditions occurs at a late step in the viral replication cycle (e.g., egress). Additional investigation revealed that caspase-3 activation in oral keratinocytes promotes cleavage of a pool of vacuolar protein sorting 4A (VPS4A), a component of the endosomal sorting complex required for transport (ESCRT)-III pathway. VPS4A is an AAA-ATPase known to function in HSV-1 egress. Thus, the central hypothesis of this proposal is that extrinsic cell death activation results in caspase-3-mediated cleavage of VPS4A, resulting in the formation of a dominant negative protein that inhibits HSV-1 egress. We will investigate this hypothesis with two distinct aims. In Aim 1, we will define the mechanism and functional consequences of VPS4A cleavage on HSV-1 replication. In Aim 2, we will determine the mechanism by which TNFR-mediated extrinsic cell death activation restricts HSV-1 ∆ICP6. Completion of these aims will lead to a better understanding of the molecular mechanisms by which caspases restrict HSV-1 and fill an important gap in the field regarding how these proteases function in antiviral defense at barrier tissues.


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 = $40,599 )
2026	2026	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Allergy and Infectious Diseases Research	001	2	4/24/2026	NON-COMPETING CONTINUATION	$576
2026	2026	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Allergy and Infectious Diseases Research	000	2	2/19/2026	NON-COMPETING CONTINUATION	$40,023
														Subtotal = $40,599

Issue Date FY: 2025 ( Subtotal = $37,023 )
2025	2025	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Allergy and Infectious Diseases Research	001	1	4/14/2025	NEW	$0
2025	2025	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Allergy and Infectious Diseases Research	002	1	4/21/2025	NEW	$0
2025	2025	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Allergy and Infectious Diseases Research	000	1	11/5/2024	NEW	$36,459
2025	2025	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Allergy and Infectious Diseases Research	003	1	7/31/2025	NEW	$564
														Subtotal = $37,023

Grand Total All Awards = $77,622

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The role of caspase-3 mediated cleavage of VPS4A in restricting HSV-1

Award Number: F30AI188981

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 03/06/2025

PERIOD OF PERFORMANCE END DATE: 06/30/2029

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