# Features of PMN Senescence that Lead to Susceptibility to Pneumococcal Infection

> **NIH NIH R21** · TUFTS UNIVERSITY BOSTON · 2021 · $255,291

## Abstract

PROJECT ABSTRACT/SUMMARY
Immunosenescence, the age-related decline in immune function, is manifested by an increase in susceptibility
to many infectious diseases, including serious Streptococcus pneumoniae (pneumococcus) infection. Acute
pulmonary inflammation is characteristic of pneumococcal lung infection and may exacerbate tissue damage
and disease progression. The elderly suffer from `Inflammaging', the age-dependent increase in basal and
induced levels of proinflammatory cytokines. Further, polymorphonuclear leukocytes (PMNs) from elderly
individuals display defects in several activities, such as chemotaxis, opsonophagocytic killing, and ROS
production. Using a model of intratracheal challenge of wild-type mice, which recapitulates the susceptibility to
pneumococcal infection among the elderly, our preliminary data suggests that PMN dysfunction may be a
primary cause of the increased susceptibility to pneumococcal pneumonia. Furthermore, adoptive transfer of
PMNs from young mice into aged mice conferred resistance to pneumococcal lung challenge, indicating that
young PMNs possess defense functions that are lacking in aged PMNs. Comparing the gene expression of
uninfected or pneumococcus-exposed PMNs from young and aged mice (by our collaborator Dr. Bou Ghanem)
revealed age-dependent expression differences. However, the precise PMN dysfunction leading to age-
dependent susceptibility remains unknown and is a focus of this proposal. Here we propose to identify the
specific PMN functions that diminish with age and result in the susceptibility to pneumococcal lung infection, as
well as systematically test the degree to which age-associated, PMN-mediated susceptibility is due to a
diminished defense and/or an enhanced disease-promoting activity. By pinpointing the key host defenses that
degrade with age and result in invasive pneumococcal disease, these studies will not only facilitate precisely
targeted interventions against a major infectious agent, but also provide insight into the aging innate immune
system that may lead to novel therapies against other infections that disproportionately afflict the elderly. In
addition, taking a high-risk, high-reward approach, we seek to treat PMNs derived from HoxB8 progenitor cell
lines with low levels of inflammatory cytokines found in the bloodstream of the aged host to confer on these
PMNs an aged phenotypic profile with respect to PMN activities and RNA expression. Our Aims are (1)
Characterize PMN functions that diminish upon aging and recapitulation these defects in PMNs derived from
immortalized myeloid progenitors. (2) Assess the degree to which aged PMNs not only fail to defend against
infection but also actively promote pneumococcal disease, thus contributing to age-associated susceptibility to
S. pneumoniae.

## Key facts

- **NIH application ID:** 10152199
- **Project number:** 1R21AG071268-01
- **Recipient organization:** TUFTS UNIVERSITY BOSTON
- **Principal Investigator:** JOHN M LEONG
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $255,291
- **Award type:** 1
- **Project period:** 2021-03-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10152199

## Citation

> US National Institutes of Health, RePORTER application 10152199, Features of PMN Senescence that Lead to Susceptibility to Pneumococcal Infection (1R21AG071268-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10152199. Licensed CC0.

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