# PARP9-DTX3L Control Of Viral Infection and Airway Disease

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2020 · $608,777

## Abstract

Abstract
A major goal of this proposal is to define the role of the airway epithelial cells in the immune response to
respiratory viral infection and to extend this information to better control acute viral illness and prevent post-
viral airway disease. Based on new insights into the issue of how airway epithelial cells mediate host defense
against respiratory viruses, we will develop the hypothesis that the proper quality and quantity of interferon
(IFN) signaling in airway epithelial cells is critical for controlling acute viral illness and post-viral airway disease.
Studies of transgenic mice and transduced human cell lines further revealed that IFN signaling is limited by a
PARP9-DTX3L complex with distinct domains for interaction with STAT1 and for activity as an E3 ubiquitin
ligase that acted on host histone H2BJ to promote IFN-stimulated gene (ISG) expression and on viral 3C
protease to degrade these proteases via the immunoproteasome. Thus, PARP9-DTX3L acts on host and
pathogen to achieve a double layer of immunity within a safe reserve in the IFN signaling pathway and
specially controls viruses like human rhinovirus (HRV) that require viral 3C protease for replication. We
therefore hypothesize that airway epithelial cell PARP9-DTX3L specially regulates the severity of infection due
to HRV and other picornaviruses like human enterovirus-D68 (HEV-D68) that might be more severe in patients
with airway disease and/or linked to exacerbation or progression of airway disease. We also propose that the
novel dual-mechanism for PARP9-DTX3L to safely harness IFN signaling reserve provides a roadmap to
protect against respiratory viral infection and post-viral airway disease. Indeed, we used our findings to develop
small-molecule IFN-signal enhancer (SMISE) compounds to enable the antiviral benefit of PARP9-DTX3L
expression. To further develop these insights and translate them to practice, we have the following Specific
Aims:
1. In human cell and molecular models, determine the role of PARP9-DTX3L in IFN signaling and control of
respiratory picornaviruses in primary-culture human airway epithelial cells and recombinant human proteins.
This Aim will also pursue the mechanism for PARP9-DTX3L activities and a structural biology approach to
enhancing these actions.
2. In mouse cell and in vivo models, define the role of PARP9-DTX3L in IFN signaling and control of respiratory
picornaviruses and post-viral airway disease using cell-specific transgenic, knock-out, and knock-in mice and
airway epithelial cells from these mice. This Aim will develop new models of picornavirus infection and pursue
the mechanism for PARP9-DTX3L activities in IFN signaling and SMISE effect.
Together, the results will provide the first proof-of-concept for the role of PARP9-DTX3L in controlling
respiratory picornavirus infection in vitro and in vivo and will advance the basis for developing an effective
antiviral compound for this type of infection.

## Key facts

- **NIH application ID:** 9844054
- **Project number:** 5R01AI130591-04
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Michael J Holtzman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $608,777
- **Award type:** 5
- **Project period:** 2017-02-21 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9844054

## Citation

> US National Institutes of Health, RePORTER application 9844054, PARP9-DTX3L Control Of Viral Infection and Airway Disease (5R01AI130591-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9844054. Licensed CC0.

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