# 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 · 2021 · $372,900

## Abstract

Project Summary
While influenza and pneumococcal infections are historically responsible for significant morbidity and mortality,
a pandemic of respiratory disease by a novel coronavirus (SARS-CoV-2), resulting in the development of
coronavirus disease 2019 (COVID-19), has been shown to develop in severe illness, with the highest morbidity
and mortality occurring in older persons (> 65 years of age). We believe that the experiments in this Competitive
Revision will expand upon our current findings in the influenza model and will provide a deeper understanding
into how molecular and cellular pathways in the aged lung contribute to coronavirus pathogenesis. Based upon
our preliminary findings gained by our parent R01, we hypothesize that dysregulated immune activation, in
response to increased mitochondrial dysfunction and ROS production, results in overzealous pro-inflammatory
signaling in response to an infectious viral agent, such as influenza or coronavirus. By establishing and dissecting
a pivotal mechanistic link between cellular response pathways and inflammatory signaling in aged lung during
viral infection, this research proposal has high potential to elucidate innovative regulatory pathways, expand our
current understanding of age associated changes in mitochondrial homeostasis, and devise therapeutic
strategies to improve morbidity and mortality in response to pathogenic stimuli. We are currently requesting two
years of support to complete all of the experiments detailed in the Competitive Revision: Year 1 will focus on
completion of Specific Aim 1 and Year 2 will focus on completion of Specific Aim 2.
Summary and impact: Improve our understanding the balance between beneficial and harmful
inflammation. It has been well established that inflammatory responses are tightly regulated, however the
balance between harmful and beneficial responses to coronavirus has not been fully elucidated. Work entailed
in the current proposal will examine the impact of location and magnitude of inflammatory cell infiltration and
cytokine production on the development of pneumonia and ARDS in aged lung in response to coronavirus.
Highlight similarities and differences between influenza and coronavirus, with a focus on the role of a
pro-inflammatory immune response on disease pathogenesis in aged lung. At present, very little is known
regarding the similarities and differences in pathogenesis of influenza and coronavirus. Heightened pro-
inflammatory host immune responses, rather than viral virulence, can contribute to multi-organ tissue pathologies
occurring in response to CRS. This work will allow us to examine the initiation and progression of immune
responses in the aged lung during coronavirus infection and identify similarities and differences in host
responsiveness to influenza (work on influenza is described in the Parent R01).

## Key facts

- **NIH application ID:** 10161896
- **Project number:** 3R01AG056699-04S1
- **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:** 2021
- **Award amount:** $372,900
- **Award type:** 3
- **Project period:** 2018-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10161896

## Citation

> US National Institutes of Health, RePORTER application 10161896, Impact of Heightened UPR Activation on Inflammasome Responses to Influenza and Secondary Streptococcus pneumoniae Infection in Aged Lung (3R01AG056699-04S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10161896. Licensed CC0.

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