# Bioactivities of pneumococcal cell wall in neuropathogenesis

> **NIH NIH R01** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2024 · $455,000

## Abstract

Using the pneumococcus as a model, our lab has revealed many features of the biochemical basis of
the inflammatory response to bacteria in the brain. The important discovery of this application is the
opening of a new area of pathogenesis at the maternal/fetal interface that will inform newly discovered
cell wall/TLR2 effects as a morphogen in the brain. We have determined that cell wall, a universal
pathogen associated molecular pattern, circulates in the bloodstream of pregnant mice and traverses the
placenta to the fetal brain. The response of fetal neurons is not the well characterized inflammation and
neuronal death of the postnatal setting but the exact opposite: neuroproliferation without inflammation.
This response involves two new activities of cell wall: 1) induction of cell proliferation via TLR2 without
inflammatory signaling, and 2) remodeling of embryonic brain anatomy and changes in postnatal
behavior. We will further determine the relevance of these findings to the human brain using organoids.
 An understanding of the details of this new biology, to be investigated in this application, represents
both novel bacterial pathogenesis and an avenue of high potential for tangible medical impact. Using
single cell spatial RNASeq and knock out animal models, we propose to identify the signaling cascade
initiated by cell wall to modulate brain structure, including determining the links between TLR2/6, the
signaling node of the neuronal cilium and the neuronal transcription factor FoxG1. This will connect
innate immune receptors to nuclear transcription factors for the first time and define a new activity of
TLRs as morphogens. The involvement of the LANDO autophagy pathway will be characterized as a cell
wall trafficking/removal pathway associated with defects in cognitive function.

## Key facts

- **NIH application ID:** 10767911
- **Project number:** 5R01AI128756-08
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** Elaine I Tuomanen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $455,000
- **Award type:** 5
- **Project period:** 2016-11-04 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10767911

## Citation

> US National Institutes of Health, RePORTER application 10767911, Bioactivities of pneumococcal cell wall in neuropathogenesis (5R01AI128756-08). Retrieved via AI Analytics 2026-05-30 from https://api.ai-analytics.org/grant/nih/10767911. Licensed CC0.

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