# Impact of Heightened UPR Activation on Inflammasome Responses to Influenza and Secondary Streptococcus pneumoniae Infection in Aged Lung

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2022 · $372,900

## Abstract

Project Summary
With an aging population and pulmonary infections becoming an increasingly significant cause of morbidity and
mortality, there is an urgent need to investigate molecular pathways underlying these impairments and devise
new therapeutics that can stimulate innate immune responses within this population. Our results demonstrate
aged hosts have impaired inflammasome activation, decreased gene expression of several key components of
the NLRP3 signaling pathway, reduced caspase-1 activity, and diminished IL1β production in response to in
vitro and in vivo infection with influenza or S. pneumoniae. Using in vitro and in vivo aging murine models of
primary influenza and secondary S. pneumoniae infection, we will employ cellular and molecular techniques to
test our overall hypothesis that the NLRP3 inflammasome is necessary for survival and age associated
impairments in ER and mitochondrial Ca2+ homeostasis result in impaired activation of the NLRP3
inflammasome in aged lung; thereby, resulting in increased pathogenesis, tissue injury, and pneumonic edema
in the elderly lung. To test this hypothesis, we will examine the role of the unfolded protein response (UPR) on
inflammasome activity in response to influenza (Aim 1) and the impact of overly heightened pathogenic
mediated UPR on inflammasome activation in response to secondary S. pneumoniae infection (Aim 2).
Summary and impact: As pulmonary pneumococcal infections remain a substantial cause of morbidity and
mortality in the elderly, even in an era of routine adult vaccination, there is a pressing need to identify
mechanistic pathways that regulate innate immune responses and investigate novel therapeutics and
treatment strategies that reduce serious disease and improve clinical outcomes. By establishing and dissecting
a pivotal mechanistic link between UPR activation and inflammasome signaling in aged lung, this research
proposal has high potential to elucidate innovative regulatory pathways and expand current understanding of
age associated changes in ER homeostasis. Therapeutic strategies designed to target defects in innate
signaling in the aged host will aid in circumventing emergent strains of antibiotic resistant bacteria and may be
utilized for treatment against a wide variety of pathogenic stimuli. Completion of the proposed aims will further
define the role of the NLRP3 inflammasome as an important innate signaling pathway during influenza and
secondary S. pneumoniae infections as well as yield new therapeutics that can be readily tested in primary
human cells and evaluated in additional model systems.

## Key facts

- **NIH application ID:** 10401901
- **Project number:** 5R01AG056699-05
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Heather Winona Stout Delgado
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $372,900
- **Award type:** 5
- **Project period:** 2018-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10401901

## Citation

> US National Institutes of Health, RePORTER application 10401901, Impact of Heightened UPR Activation on Inflammasome Responses to Influenza and Secondary Streptococcus pneumoniae Infection in Aged Lung (5R01AG056699-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10401901. Licensed CC0.

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