# Elucidating the role of RXRA in the myeloid lineage in post-infectious basal ganglia encephalitis

> **NIH NIH R21** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2022 · $441,853

## Abstract

PROJECT SUMMARY
Childhood infections with Streptococcus pyogenes (Group A Streptococcus; GAS) are associated with basal
ganglia encephalitis (BGE) sequelae that present with either movement [Sydenham’s chorea (SC)] or psychiatric
[Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections (PANDAS)]
symptoms. Human and animal studies have shown that aberrant cellular (Th17 lymphocytes) and humoral
(autoantibodies) adaptive immune responses, generated normally to fight recurrent S. pyogenes infections,
target the brain and elicit neurovascular damage, antibody entry into the brain, neuroinflammation (microglial
activation and macrophage infiltration) and neural circuit dysfunction. However, not all children develop post-
infectious BGE despite frequent GAS infections suggesting the presence of genetic risk factors that predispose
them to develop disease. Through whole-exome sequencing of genomic DNA from 82 patients and 146 controls
followed by bioinformatics analysis, we have identified candidate genetic variants in ~20 genes that are likely
associated with disease risk for post-infectious BGE. One of the top BGE risk genes, RXRA (encoding for
Retinoid X Receptor Alpha), is a key regulator of both innate and adaptive immune responses. We have found
that Rxra mRNA and proteins levels are upregulated in activated microglia and infiltrating macrophages in the
brain after recurrent intranasal GAS infections in mice. Here, we will test the hypothesis that RXRA, identified by
whole-exome sequencing, regulates several innate immune responses in the myeloid lineage (microglia and
macrophages) ranging from activation, antigen presentation, cytokine production and phagocytosis, that are
critical for both neurovascular damage and neuronal circuit dysfunction in the brain after recurrent GAS
infections. We have generated mice lacking Rxra function in the myeloid lineage (microglia and macrophages).
For our first objective, we will test the requirement of Rxra in microglial/macrophages for their activation, antigen
presentation, cytokine production and phagocytosis in vivo using PET imaging, single cell RNA sequencing and
validation in our mouse model for post-infectious BGE. In parallel, we will perform in vitro studies with the human
microglia cells, carrying the nonsense mutations in the RXRA gene identified in SC/PANDAS/PANS patients, to
test activation and phagocytic ability following GAS exposure. For our second objective, we will examine the
consequences of eliminating Rxra function in the myeloid cell for neurovascular damage (i.e. blood-brain barrier
dysfunction), elimination of excitatory synapses and neuronal circuitry dysfunction using single cell RNA
sequencing studies, pathological, physiological and behavioral assays after recurrent intranasal GAS infections
in control or myeloid-specific Rxra deficient mice. These proof-of-principle studies have the potential to uncover
novel mechanisms of disease pathogenesis and ...

## Key facts

- **NIH application ID:** 10574727
- **Project number:** 1R21NS130265-01
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Dritan Agalliu
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $441,853
- **Award type:** 1
- **Project period:** 2022-09-15 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10574727

## Citation

> US National Institutes of Health, RePORTER application 10574727, Elucidating the role of RXRA in the myeloid lineage in post-infectious basal ganglia encephalitis (1R21NS130265-01). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/10574727. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*