# Altered hyaluronan deposition by bronchial epithelial cells contributes to inflammation during respiratory syncytial virus infection

> **NIH NIH R03** · SEATTLE CHILDREN'S HOSPITAL · 2022 · $94,250

## Abstract

PROJECT SUMMARY / ABSTRACT
Lower respiratory tract infections commonly caused by respiratory syncytial virus (RSV) are a leading cause of
hospitalizations and mortality worldwide in young children. Despite many years of study, the mainstay of
treatment remains supportive care and currently no RSV specific treatment or vaccine is available. The cells
that line the airways, otherwise known as bronchial epithelial cells (BECs), are the primary target for RSV
infection. Infection of the BECs with RSV leads to subsequent BEC damage, obstruction of the lower airways
with cellular debris and mucous, and the establishment of airway inflammation by recruitment of immune cells
such as neutrophils into the peribronchial space. Recent studies from our laboratory have demonstrated that
RSV infection of stromal cells such as lung fibroblasts leads to the establishment of an extracellular matrix
(ECM) that is enriched with hyaluronan (HA) which promotes the accumulation and activation of leukocytes in
ex vivo cell culture models. Furthermore, we found that the increased HA accumulation following RSV infection
was more closely associated with the fibroblast cell layer and displayed greater modification with heavy chains
(HC) which has been described in other studies to enhance the ECM’s ability to become sticky for
inflammatory cells and promotes the inflammatory response in the lung. The formation of HC-HA is the result
of the enzymatic activity of tumor necrosis factor stimulated gene 6 (TSG-6), which is not normally expressed
in healthy lung tissue, but is induced in response to injury. In our previous work with lung fibroblasts, we have
shown that TSG-6 is upregulated during RSV infection and blocking its induction with siRNA decreased the
amount of HC-HA that was formed and decreased the accumulation of leukocytes. Despite being the primary
target of RSV infection, no studies exist that have evaluated the effects of RSV infection on BEC production of
HA or TSG-6 induced HC-HA formation despite the important role that HC-HA plays in promoting lung
inflammation. Our laboratory both has expertise in the characterization of HA matrices and access to primary
human BECs from well-characterized pediatric donors placing our group in a unique position to evaluate the
contribution of BEC derived HC-HA to the inflammatory response following RSV infection. We hypothesize that
RSV infection of BECs leads to increased production and accumulation of HA which will in turn promote the
accumulation and activation of neutrophils in an ex vivo human cell culture model system. Additionally, we will
test the hypothesis that RSV infection of BECs will induce the expression of TSG-6 thereby promoting the
formation of HC-HA and further drive the accumulation and activation of neutrophils in our model system. We
will pharmacologically block the formation of HC-HA enriched ECMs and also block the induction of TSG-6
during RSV infection in order to establish whether the increased accu...

## Key facts

- **NIH application ID:** 10418432
- **Project number:** 1R03HL156916-01A1
- **Recipient organization:** SEATTLE CHILDREN'S HOSPITAL
- **Principal Investigator:** STEPHEN R REEVES
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $94,250
- **Award type:** 1
- **Project period:** 2022-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10418432

## Citation

> US National Institutes of Health, RePORTER application 10418432, Altered hyaluronan deposition by bronchial epithelial cells contributes to inflammation during respiratory syncytial virus infection (1R03HL156916-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10418432. Licensed CC0.

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