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Determining how Kaposi’s sarcoma-associated herpesvirus hijacks caspase function to inhibit anti-viral responses

Award Number: R01CA268976
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2021
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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Determining how Kaposi’s sarcoma-associated herpesvirus hijacks caspase function to inhibit anti-viral responses - Project summary. During lytic infection, the AIDS-associated tumor virus Kaposi’s sarcoma-associated herpesvirus (KSHV) blocks cells from activating the anti-viral type I interferon (IFN) responses. This block of the innate immune response facilitates efficient viral replication, which in turn contributes to development of Kaposi’s sarcoma. Thus, elucidating the mechanisms by which KSHV evades the host innate immune response may provide insights on how to target this and other KSHV-induced tumors. However, because of the complex and redundant nature of the type I IFN induction pathway, how KSHV blocks this early antiviral response is still incompletely understood. In a previous study, we found that the host protease caspase-8 is a major mediator of type I IFN inhibition by KSHV. KSHV reactivation from latency only triggers minimal type I IFN induction, but there is a much stronger transcriptional induction and secretion of type I IFNs when caspase-8 is also inhibited. This stronger IFN induction, in turn, reduces KSHV reactivation. These results indicate that caspase-8 activity is necessary to inhibit IFN induction, and thus promotes KSHV replication. This finding was surprising because caspase-8 activation is generally considered antiviral as it induces apoptotic cell death. However, we do not detect wide-spread cell death during reactivation from latency despite caspase-8 activation, suggesting that caspase-8 is hijacked and repurposed by KSHV to inhibit type I IFN responses. At present, the molecular mechanisms that lead to caspase-8 activity and the pathways that are targeted by caspase-8 to control type I IFN during KSHV infection remain unclear. We have new preliminary data suggesting that caspase-8 is activated by a pathogen sensing pathway, the Toll-like receptor (TLR) pathway, as a cellular response to infection. Caspase-8 then proceeds to inhibit a different pathogen sensing pathway, cGAS-mediated DNA sensing. Therefore, we hypothesize that KSHV is taking advantage of a TLR-mediated cellular response to infection that activates caspase-8. KSHV is then able to redirect this activity to inhibit DNA sensing instead of activating apoptosis. We will test this hypothesis and determine how caspase-8 is activated by TLR signaling in KSHV-infected cells without triggering cell death (Aim 1), and which host protein(s) are cleaved by caspase-8 to block cGAS-induced type I IFN responses (Aim 2). Moreover, we will also investigate whether and how caspase activity is connected to other previously described mechanisms of immune evasion by KSHV (Aim 3). As caspase-8 is a druggable target, understanding how caspase-8 is used by KSHV to regulate type I IFNs and promote its replication will reveal whether and how this enzyme could be exploited for KSHV therapy. This is important as there are no target therapies for this virus, and Kaposi’s sarcoma remains one of the leading types of cancers in sub-Saharan Africa and the second most common AIDS-associated malignancy in the US. This project will also uncover fundamental aspects of caspase signaling that may play a role in other diseases connected to IFN.


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 = $378,465 )
2026	2026	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Cancer Biology Research	000	5	1/14/2026	NON-COMPETING CONTINUATION	$340,619
2026	2026	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Cancer Biology Research	001	5	4/16/2026	NON-COMPETING CONTINUATION	$37,846
														Subtotal = $378,465

Issue Date FY: 2025 ( Subtotal = $361,435 )
2025	2025	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Cancer Biology Research	000	4	11/12/2024	NON-COMPETING CONTINUATION	$361,435
														Subtotal = $361,435

Issue Date FY: 2024 ( Subtotal = $352,662 )
2024	2024	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Cancer Biology Research	000	3	12/14/2023	NON-COMPETING CONTINUATION	$352,662
2024	2023	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Cancer Biology Research	002	2	12/21/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$145,391
2024	2022	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Cancer Biology Research	001	1	12/21/2023	NEW	-$145,391
														Subtotal = $352,662

Issue Date FY: 2023 ( Subtotal = $349,096 )
2023	2023	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Cancer Biology Research	001	2	12/8/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$349,096
2023	2022	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Cancer Biology Research	000	1	12/7/2022	NEW	$0
														Subtotal = $349,096

Issue Date FY: 2022 ( Subtotal = $377,634 )
2022	2022	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Cancer Biology Research	000	1	11/18/2021	NEW	$377,634
														Subtotal = $377,634

Grand Total All Awards = $1,819,292

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Determining how Kaposi’s sarcoma-associated herpesvirus hijacks caspase function to inhibit anti-viral responses

Award Number: R01CA268976

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2021

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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