# Molecular Interrogation of the Host-Pathogen Interface in Idiopathic Subglottic Stensosis

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2022 · $382,500

## Abstract

Project Summary/Abstract
Idiopathic subglottic stenosis (iSGS) is an unexplained mucosal fibroinflammatory disease of the
upper airway that occurs almost exclusively in adult, Caucasian women. Patients require urgent
surgery to prevent death from airway obstruction. Novel therapies aimed at halting the
progressive airway fibrosis are critical to reduce the burden of this disease. Given its rarity, the
geographical dispersal of affected patients has previously limited investigations to define the basic
biology of the disease. Our recent publications reveal microbial dysbiosis in iSGS airway scar,
along with inflammatory pathway activation. Leveraging a 1000-patient international iSGS cohort
led by this proposal’s PI (iSGS1000), this project is designed to understand the pathogenesis of
iSGS by answering the question: Is iSGS related to an active infection, or does bacteria
trigger a self-reactive immune response. Our proposal utilizes independent but interrelated
approaches to address this question. In Aim 1 we will apply cutting edge molecular immunology
and bioinformatic techniques to sort infiltrating CD8+ T cells from airway scar, directly sequence
individual T cell receptors (TCR) via RNAseq, then clone high frequency TCRs into an in vitro
model system to map antigen specificity. This will allow us to investigate the hypothesis that CD8+
T cells in the mucosa of iSGS airway scar demonstrate a clonal response directed at a bacterial
antigen. Then in Aim 2 we will utilize whole genome sequencing (WGS) of the bacteria in iSGS
airway scar to confirm a unique bacterial association with iSGS. Precise molecular
characterization of the bacteria with metatranscriptomic analysis will provide new information on
genetic features impacting pathogenicity. In Aim 3 we will investigate how current treatments for
iSGS impact both the local microbiome as well as host immunity. Taken together our independent
but interrelated approaches will help define how host and pathogen collide to produce pathogenic
tissue fibrosis in iSGS.

## Key facts

- **NIH application ID:** 10375532
- **Project number:** 5R01HL146401-04
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Alexander Gelbard
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $382,500
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10375532

## Citation

> US National Institutes of Health, RePORTER application 10375532, Molecular Interrogation of the Host-Pathogen Interface in Idiopathic Subglottic Stensosis (5R01HL146401-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10375532. Licensed CC0.

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