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 IL1? production in response to in vitro and in vivo infection with S. pneumoniae. Using in vitro and in vivo aging murine models of S. pneumoniae infection, we will employ cellular and molecular techniques to test our overall hypothesis that the NLRP3 inflammasome is necessary for protection against S. pneumoniae and age associated decreases in ER and mitochondrial Ca2+ homeostasis results in impaired activation of the NLRP3 inflammasome in aged lung; thereby, resulting in increased bacterial pathogenesis, tissue injury, and pneumonic edema in the elderly lung. To test this hypothesis, we will examine the impact of heightened ER stress and the unfolded protein response (UPR) on inflammasome activity (Aim 1) and the impact of aging on the maintenance of ER Ca2+ homeostasis and subsequent modulation of inflammasome activity (Aim 2) in aged lung during S. pneumoniae infection. 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. Despite the identification of factors that modulate the inflammasome, the impact of aging and age-enhanced levels of ER stress on the regulation of NLRP3 responses, specifically in response to pathogenic stimuli, has not been extensively studied. By establishing and dissecting a pivotal mechanistic link between ER stress regulation and inflammasome signaling in aged lung during S. pneumoniae infection, this research proposal has high potential to elucidate innovative regulatory pathways, 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 that continue to develop and may be utilized for treatment against a wide variety of pathogenic stimuli. Completion of the aims proposed in this R01 will further define the role of the NLRP3 inflammasome as an important innate signaling pathway during S. pneumoniae infections as well as yield new therapeutics that can be readily tested in primary human cells and evaluated in additional model systems.

Public Health Relevance

This proposal will investigate mechanistic pathways that underlie impaired immune responses to pathogenic stimuli in aged lung. Knowledge of signaling cascades and mechanisms utilized in lung as the host ages will aid in the design of therapeutics that reduce serious disease and improve clinical outcomes in the elderly.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG052530-04
Application #
9967921
Study Section
Aging Systems and Geriatrics Study Section (ASG)
Program Officer
Fuldner, Rebecca A
Project Start
2017-09-01
Project End
2022-05-31
Budget Start
2020-07-15
Budget End
2021-05-31
Support Year
4
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
Cho, Soo Jung; Plataki, Maria; Mitzel, Dana et al. (2018) Decreased NLRP3 inflammasome expression in aged lung may contribute to increased susceptibility to secondary Streptococcus pneumoniae infection. Exp Gerontol 105:40-46
Cho, Soo Jung; Rooney, Kristen; Choi, Augustine M K et al. (2018) NLRP3 inflammasome activation in aged macrophages is diminished during Streptococcus pneumoniae infection. Am J Physiol Lung Cell Mol Physiol 314:L372-L387