# Alveolar Heparan Sulfate Shedding Involvement in Bacterial Superinfections

> **NIH NIH F31** · UNIVERSITY OF COLORADO DENVER · 2022 · $27,462

## Abstract

PROJECT SUMMARY/ABSTRACT:
Viral pneumonias are increasingly recognized as major causes of respiratory failure. The severity of a viral
pneumonia is substantially worsened by bacterial coinfection, commonly caused by community- or hospital-
acquired pathogens such as methicillin-resistant Staphylococcus aureus (MRSA). Despite this significance,
how an antecedent viral infection (such as influenza) invites secondary bacterial pneumonia remains
understudied.
The Schmidt laboratory has recently demonstrated that at peak influenza lung injury, MRSA responds to the
injured lung microenvironment to increase the expression of pore-forming toxins (PFTs) implicated in severe
pneumonia pathogenesis. These toxins are regulated by bacterial two-component systems which help MRSA
respond to environmental cues. In preliminary studies, MRSA deficient in SaeRS, a two-component system
previously implicated in pneumonia, induced less lung injury (in comparison to wild-type MRSA) when
administered to mice recovering from antecedent influenza infection. These results highlight SaeRS
importance in sensing the injured lung microenvironment and causing lung injury.
Simultaneous with induction of MRSA toxin expression, influenza infection induces massive shedding of the
alveolar epithelial glycocalyx, a heparan sulfate (HS) rich layer of glycosaminoglycans lining the airspace
surface. Using state-of-the-art glycomic techniques, we found that shed HS polysaccharides are full-length and
highly-sulfated, indicating sufficient charge density to drive electrostatic binding to pathogen proteins in the
airspace. HS oligosaccharides with high affinity to PFTs was observed to increase lung epithelial and
neutrophil cell death. Based upon these preliminary studies, MRSA is hypothesized to sense the post-viral,
injured lung microenvironment via SaeRS, leading to the induction of pathogenic PFT expression. In
addition, airspace HS fragments, shed from the epithelial surface as a consequence of viral lung injury,
is proposed to directly enhance PFT cytolytic activity, further contributing to increased host cell death.
To explore these hypotheses, state-of-the-art techniques will be utilized to determine 1) how the MRSA
transcriptome and proteome temporally changes in response to bronchoalveolar lavage fluid (representing the
injured lung microenvironment) collected from influenza-infected mice at various points after influenza
infection, and 2) if shed HS oligosaccharides increase PFT oligomerization and thus cytolytic pore assembly.
Techniques in glycosaminoglycan and in vivo lung injury quantification, and MRSA RNA, protein purification
will be learned. These studies promise not only to identify airspace HS fragments as a potential mediator of
(and predictive biomarker for) bacterial superinfection, but also will provide a key training opportunity during my
PhD to develop unique expertise in host glycobiology and pathogen behavior.

## Key facts

- **NIH application ID:** 10465500
- **Project number:** 1F31HL160080-01A1
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Christophe J Langouet-Astrie
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $27,462
- **Award type:** 1
- **Project period:** 2022-03-16 → 2022-12-08

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10465500

## Citation

> US National Institutes of Health, RePORTER application 10465500, Alveolar Heparan Sulfate Shedding Involvement in Bacterial Superinfections (1F31HL160080-01A1). Retrieved via AI Analytics 2026-06-24 from https://api.ai-analytics.org/grant/nih/10465500. Licensed CC0.

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