# Impact of versican deficiency on the innate immune response to influenza virus

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2020 · $616,343

## Abstract

PROJECT SUMMARY
 Our published work and preliminary data using mouse models and in vitro cell cultures show that
extracellular matrix (ECM) molecules such as versican accumulate in lungs following exposure to viruses
and bacteria. The creation of a specialized versican-enriched ECM coincides with invasion and retention
of leukocytes in lungs during the immune response to influenza virus. We have found that two cellular
sources synthesize versican in response to Toll-like receptor (TLR) agonists: macrophages and
fibroblasts. Studies identify two distinct signaling pathways directing versican synthesis in these two cell
types - the β-catenin/T-cell factor (TCF) pathway in stromal cells such as smooth muscle cells and
fibroblasts and the TLR/Trif/Type I interferon (IFN) receptor pathway in macrophages. However, the
cellular specificity of these signaling pathways is not known. Using two novel strains of genetically
engineered mice in which the versican gene is deleted in a cell- and time-specific manner, our published
and preliminary data shows that versican has a dramatic effect on leukocyte phenotype. When treated
with polyinosinic:polycytidylic acid (poly(I:C)), mice with a global deficiency in versican have decreased
recovery of leukocytes in bronchoalveolar (BAL) fluid suggesting that versican is pro-inflammatory and
required for leukocyte migration into lungs. In contrast, mice lacking versican in macrophages have
increased recovery of leukocytes in BAL fluid suggesting that macrophage-derived versican is anti-
inflammatory and suppresses leukocyte migration into lungs. Both strains of versican-deficient mice had
significantly decreased recovery of Type I IFNs and IL-10 in lung tissue or BAL fluid when compared to
controls. Our in vitro studies attribute this to decreased production of these anti-inflammatory cytokines by
versican-deficient macrophages. The differences observed in these novel versican-deficient mice are the
basis of our central hypothesis that the formation of a versican-enriched ECM by macrophages and
stromal cells provides critical contextual cues and extracellular-control of the innate immune response to
viral lung infection. We propose three aims to test this hypothesis. Aim 1 defines the role of versican
derived from macrophages and/or Type I IFN signaling in providing extracellular-control of the innate
immune response in lungs of mice exposed to influenza virus. Aim 2 determines if stromal cells and/or β-
catenin/TCF signaling promote the generation of a versican-enriched ECM that provides fine-control of
the innate immune response to influenza virus. Aim 3 identifies the mechanisms and signaling pathways
whereby macrophage- versus fibroblast-derived versican provide contextual extracellular-control of the
innate immune response. Understanding the contextual settings in which versican provides fine-control of
the innate immune response to influenza virus is critical for the design of therapeutic strategies for
improving...

## Key facts

- **NIH application ID:** 9821192
- **Project number:** 5R01AI136468-03
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** William A Altemeier
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $616,343
- **Award type:** 5
- **Project period:** 2017-12-12 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9821192

## Citation

> US National Institutes of Health, RePORTER application 9821192, Impact of versican deficiency on the innate immune response to influenza virus (5R01AI136468-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9821192. Licensed CC0.

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