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Noncanonical DNA Virus Sensing via an IKK-alpha-Driven Interferon Signaling Cascade

Award Number: R21AI199683
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: 08/07/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2028

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Noncanonical DNA Virus Sensing via an IKK-alpha-Driven Interferon Signaling Cascade - Project Summary/Abstract Innate immune recognition of viral DNA is a cornerstone of antiviral defense, primarily mediated through the cGAS–STING–TBK1–IRF3 signaling axis. This canonical pathway leads to type I interferon (IFN-I) production and restricts viral replication. However, gammaherpesviruses such as murine gammaherpesvirus 68 (MHV- 68), Epstein–Barr virus (EBV), and Kaposi’s sarcoma-associated herpesvirus (KSHV) have evolved mechanisms to subvert these pathways, raising the question of how IFN-I is still produced in infected cells. Our preliminary data reveal a surprising finding: robust IFN-I responses to MHV-68 infection persist in cells lacking both TBK1 and IKKi, but are completely dependent on the kinase IKKα. This observation suggests a previously unrecognized, noncanonical DNA-sensing pathway that bypasses TBK1/IKKi and instead utilizes IKKα, which is traditionally associated with TLR7/9–MyD88 signaling in plasmacytoid dendritic cells, to drive IFN-I responses in broader cell types. This R21 proposal seeks to uncover the molecular basis of this alternate antiviral signaling axis. We hypothesize that viral DNA is sensed by conventional receptors, but signals downstream through IKKα rather than TBK1, leading to IFN-I activation. We will employ a combination of knockout mouse cells, RNA- sequencing, biochemical interaction studies, and reporter assays to map the upstream sensors, define the critical transcription factors, and determine how gammaherpesvirus DNA engages with this pathway. The discovery of an IKKα-dependent IFN pathway in non-immune cells would shift the current paradigm in antiviral innate immunity by demonstrating that antiviral IFN responses can be maintained even when canonical pathways are blocked by viruses. This could explain how hosts retain immune surveillance under viral pressure and point to novel strategies that exploit this “backup” system to bolster immunity against persistent viruses. By revealing new mechanistic insights into immune redundancy and pathway plasticity, this work will advance our understanding of host–virus interactions during DNA viral infection.


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 = $200,600 )
2026	2026	WESTERN UNIVERSITY OF HEALTH SCIENCES	309 E 2ND ST	POMONA	CA	91766	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	1	8/7/2026	NEW	$200,600
														Subtotal = $200,600

Grand Total All Awards = $200,600

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Noncanonical DNA Virus Sensing via an IKK-alpha-Driven Interferon Signaling Cascade

Award Number: R21AI199683

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: 08/07/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2028

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