# New insight into innate immune regulation through mechanistic studies of a novel oligoadenylate synthetase-like (OASL) gain-of-function variant

> **NIH NIH R21** · EMORY UNIVERSITY · 2024 · $223,450

## Abstract

ABSTRACT
Inborn errors of immunity (IEI; or primary immunodeficiencies) comprise a large, heterogeneous group of
inherited genetic defects that manifest as acute sensitivity to infection or recurring infection, autoimmunity,
autoinflammation, allergies, or malignancy. Even in the case of exceptionally rare IEIs, studies of the impact(s)
of these genetic defects can offer an unparalleled opportunity to gain deeper insight into the molecular and
cellular mechanisms of fundamental immune system function. Through our established connection to a multi-
national clinical monitoring network, we identified an unprecedented IEI arising from a single heterozygous
missense mutation in the gene encoding the innate immune protein and double-stranded (ds)RNA sensor
oligoadenylate synthetase-like (OASL) which results in a glutamic acid to lysin amino acid substitution at a
critical site in the protein structure. This new IEI was identified in a patient with a post-infectious bronchiolitis
obliterans triggered by adenovirus (a double-stranded (ds)DNA-virus). This finding and our preliminary
investigations implicate OASL gain-of-function and dysregulation of currently uncharacterized connections
between innate immune networks sensing dsRNA (via retinoic acid-inducible gene I; RIG-I) and dsDNA (via
cyclic GMP-AMP synthase; cGAS) as the basis of this novel IEI. However, the nature of the protein defect and
how it leads to aberrant, disease-causing OASL activity is currently unknown. In this exploratory research
program, we will test our current working model in which the E237K amino acid substitution changes OASL
structure and/ or dynamics in a manner that shifts the balance of OASL innate immune signaling via altered
interaction with its binding partners (e.g. dsRNA or cGAS) or altered regulation of their activity (e.g. cGAS
activation by dsDNA). The aims of this proposal will address the following two overarching questions: Aim 1–
How does the OASL-E273K substitution alter OASL protein structure and dynamics? Aim 2–What is the effect
of the OASL-E273K substitution on OASL’s interaction with dsRNA and with cGAS, and on cGAS activation by
dsDNA? We will use a powerful combination of approaches to address these questions, including computational,
e.g. classical and accelerated molecular dynamics simulations coupled with protein residue pathway analyses,
and experimental approaches, e.g. hydrogen-deuterium exchange coupled to mass spectrometry, X-ray
crystallographic structure determination, and defined in vitro binding and enzyme activity assays. Collectively,
this exploratory project will establish the necessary foundation for detailed future studies that promise to
significantly deepen our understanding of OASL’s function(s) as a point of innate immune pathway crosstalk in
a cellular context and during infection, as well as the molecular basis of the novel OASL IEI we have identified.

## Key facts

- **NIH application ID:** 10811188
- **Project number:** 1R21AI175846-01A1
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Graeme L Conn
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $223,450
- **Award type:** 1
- **Project period:** 2024-06-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10811188

## Citation

> US National Institutes of Health, RePORTER application 10811188, New insight into innate immune regulation through mechanistic studies of a novel oligoadenylate synthetase-like (OASL) gain-of-function variant (1R21AI175846-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10811188. Licensed CC0.

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