NIH grant: Noncanonical DNA Virus Sensing via an IKK-alpha-Driven Interferon Signaling Cascade (1R21AI199683-01)

retained text

NIH grant 1R21AI199683-01: Noncanonical DNA Virus Sensing via an IKK-alpha-Driven Interferon Signaling Cascade
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: DAVID JESSE SANCHEZ. Award: $200600.
Start: 2026-08-07T00:00:00.
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.

document fetched 2026-08-16 06:34