# Role of ADAM9 in viral RNA sensing and antiviral innate immunity

> **NIH NIH R21** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2024 · $206,742

## Abstract

Project Abstract
 Picornavirus infections are a leading cause of viral encephalitis and myocarditis in humans. These viral
infections can cause substantial inflammatory changes in the brain and heart and lead to significant morbidity
and mortality. The immune system detects picornavirus infections, and other single-stranded RNA (ssRNA)
viruses, via DEAD/H-box (DDX) helicases that sense cytosolic viral ssRNA and initiate the protective interferon
(IFN) response. Two DDX helicases critical in this process are retinoic acid-inducible gene I (RIG-I) and
melanoma differentiation-associated gene 5 (MDA5). Both RIG-I and MDA5 are members of the RIG-I-like
receptor (RLR) family of RNA-sensing helicases. RIG-I is known to sense negative-sense ssRNA (–ssRNA)
viruses (e.g., Sendai virus or vesicular stomatitis virus), while MDA5 is the major sensor for RNA from
picornaviruses and other positive-sense ssRNA (+ssRNA) viruses including SARS-CoV2 and other
coronaviruses. How MDA5 is activated and regulated is currently not well known, which is in striking contrast to
RIG-I for which the activating mechanisms have been elucidated in detail.
 To study the pathogenesis of myocarditis and encephalitis, researchers have used a prototypical
member of the picornavirus family, encephalomyocarditis virus (EMCV). Using EMCV, we demonstrated an
important role for the A disintegrin and metalloproteinase protein (ADAM9) in viral pathogenesis. We
discovered that mice lacking ADAM9 rapidly succumb to EMCV infection without mounting the characteristic
IFN response seen in wild-type mice. Our data indicate a novel role for ADAM9 in viral RNA-induced IFN
production through the DDX helicase MDA5.
 In EMCV infection, MDA5 is the sensor that recognizes viral RNA and initiates a signaling cascade that
leads to activation of the mitochondrial antiviral signaling (MAVS) pathway and subsequent IFN production.
IFN production is triggered when the viral genome interacts with nucleic acid sensors in the host cell to activate
downstream pathways. The host IFN response is crucial to protect the host by limiting virus replication. We
hypothesize that ADAM9’s role in viral-induced IFN production is mediated through the MDA5-MAVS pathway.
 The role of ADAM9 in regulating the IFN response to diverse RNA viruses, including picornaviruses and
coronaviruses, will be defined in terms of its effects on the ability of MDA5 to interact with viral RNA and its
effect on protein-protein interactions and post-translational modifications of MAVS pathway adapters and
effector proteins. Through these experiments, we will define new pathways of IFN activation and better define
the pathogenesis of RNA viruses in an animal model system for studying encephalitis and myocarditis.

## Key facts

- **NIH application ID:** 10854969
- **Project number:** 5R21AI174534-02
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Michaela Ulrike Gack
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $206,742
- **Award type:** 5
- **Project period:** 2023-06-02 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10854969

## Citation

> US National Institutes of Health, RePORTER application 10854969, Role of ADAM9 in viral RNA sensing and antiviral innate immunity (5R21AI174534-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10854969. Licensed CC0.

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