# Characterization of a sensor domain for cytoplasmic nucleic acid in the antiviral factor, SAMD9

> **NIH NIH F31** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2024 · $38,314

## Abstract

Project Summary
Monkeypox virus (mpox) is an emerging zoonosis with an oropharynx route of transmission that causes oral pathology in
approximately 70% of infected individuals. Studies suggest that transmissibility of mpox has increased, and with the waning
of poxvirus immunity in younger generations, there is a need to understand host immune responses against mpox. The
closely related vaccinia virus (VACV) and mpox can enter nearly all cell types and replicate exclusively in the cytoplasm,
making intracellular factors critical host barriers. Sterile Alpha Motif Domain-containing 9 (SAMD9) is a self-regulating
cytosolic host restriction factor for poxviruses. SAMD9 is ubiquitously expressed across several cell types within the oral
mucosa, making it a host barrier for oral mpox transmission. Understanding the mechanism of how SAMD9 regulates mpox
replication is essential in developing effective antiviral strategies to mitigate oral pathology in infected individuals.
While SAMD9 is predicted to function like a pathogen recognition receptor (PRR), the mechanism by which SAMD9 senses
viral infection and is activated to mitigate viral replication remains unknown. SAMD9 is predicted to have a TPR/OB
domain that serves as a sensor domain. The early phase of VACV infection, during which double-stranded DNA enters the
cytoplasm, is sufficient for SAMD9 activation. This proposal addresses the hypothesis that the TPR/OB is a sensor domain
that recognizes cytosolic nucleic acid to induce SAMD9 activation. The physiological and structural basis for SAMD9
activation will be investigated using VACV as a model for mpox infection. First, antiviral experiments will be conducted to
pinpoint the stage of infection during which SAMD9 is activated. This will be verified with in vitro biochemical studies that
test what nucleic acid type activates SAMD9 outside the context of infection. Next, biochemical experiments using
recombinant TPR/OB protein will determine what type of nucleic acid binds to this domain, and the physiological basis for
this binding activity will be investigated with antiviral assays and in vitro assays.
This proposal seeks to elucidate the danger signals and sensor domain involved in activating SAMD9 to induce its antiviral
activity. The proposed work is significant, as it will uncover the mechanism behind how SAMD9 can protect against viral
infection and identify the stage of poxvirus infection during which it is activated. The proposal has the potential impact of
helping to develop effective antiviral strategies against future mpox outbreaks and will open new areas of investigation
between SAMD9 and other viruses of the oral cavity. This project is innovative in that it will help to establish SAMD9 as a
novel pathogen recognition receptor for cytosolic nucleic acid. Completion of the proposed work will provide me with the
necessary knowledge and technical skills to become an independent investigator in the field of virus-host interactions.

## Key facts

- **NIH application ID:** 10999180
- **Project number:** 1F31AI186499-01
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** Marisol Morales
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $38,314
- **Award type:** 1
- **Project period:** 2024-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10999180

## Citation

> US National Institutes of Health, RePORTER application 10999180, Characterization of a sensor domain for cytoplasmic nucleic acid in the antiviral factor, SAMD9 (1F31AI186499-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10999180. Licensed CC0.

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