# Defective Zn Homeostasis impairs host defense against pneumococcal pneumonia

> **NIH NIH R01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2024 · $383,750

## Abstract

Community acquired pneumonia (CAP) is a leading cause of morbidity and mortality worldwide. Streptococcus
pneumoniae (pneumococcus) remains the most common cause of CAP in the U.S. The incidence of CAP
continues to rise contributing to increased hospitalization and mortality. A major cause of CAP is decline in
immune function in vulnerable populations. Zinc (Zn) is required for proper immune function and insufficient
dietary intake is highly prevalent within vulnerable populations. Zn deficient subjects are more susceptible to
pathogens and have a higher incidence of pneumonia whereas Zn supplementation reduces the incidence of
pneumonia. The long-term goal of this project is to determine the role of the human zinc transporter ZIP8 and
dietary Zn intake in the host immune response to pneumococcal pneumonia. Our group was the first to reveal
that ZIP8 is required for myeloid cell activation following exposure to bacteria. This is relevant because a relative
deficit of Zn, either by dietary restriction or deficits in ZIP8-mediated Zn transport, in the setting of the host
response to bacterial invasion in the lung leads to immune dysfunction, increased lung damage, and higher
mortality (see preliminary data). We hypothesize that ZIP8 plays a pivotal role in lung macrophages and dendritic
cells by maintaining favorable balance of both the innate and adaptive immune response. Accordingly, defective
Zn intake or ZIP8 function prohibits the ability of Zn to facilitate normal immune function and host defense. If
proven correct, this will have important implications on pneumonia pathogenesis and increase our capacity to
predict disease susceptibility and prevent morbidity and mortality. Guided by strong preliminary evidence, this
hypothesis will be tested by pursuing three specific aims that will: 1) Determine the impact of ZIP8 loss on the
lung myeloid landscape in vivo and its impact on pathogen clearance and host survival; 2) Determine
how ZIP8 impacts Macrophage and DC function; and 3) Determine the impact of Zn supplementation on
pneumococcal pneumonia in vivo in the setting of Zn dyshomeostasis. To accomplish our goals we have
assembled a strong and experienced team that will pursue novel studies in two novel knockout mouse models
and a model of dietary Zn restriction that will explore the role of the zinc transporter protein ZIP8 in maintaining
myeloid cell-driven immune balance in the setting pneumococcal pneumonia. At the successful completion of
this study, we will better understand the interplay between Zn homeostasis and ZIP8 in the context of
pneumococcal infection in the lung. This is expected to have a positive impact because it will reveal previously
unidentified molecular pathways that are instrumental in host defense. Further, we have the potential to identify
novel micronutrient and genetic surveillance as well as treatment strategies that will improve our ability to prevent
pneumococcal pneumonia in the most vulnerable populations worl...

## Key facts

- **NIH application ID:** 10753542
- **Project number:** 5R01HL156952-03
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** DAREN Lee KNOELL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $383,750
- **Award type:** 5
- **Project period:** 2021-12-22 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10753542

## Citation

> US National Institutes of Health, RePORTER application 10753542, Defective Zn Homeostasis impairs host defense against pneumococcal pneumonia (5R01HL156952-03). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10753542. Licensed CC0.

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