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Defective Zn Homeostasis impairs host defense against pneumococcal pneumonia

Award Number: R01HL156952
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/22/2021
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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Defective Zn Homeostasis impairs host defense against pneumococcal pneumonia - 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 worldwide. We envision that this will also lend itself to new approaches to treat or prevent other harmful pathogens.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $0 )
2026	2025	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	4215 EMILE ST	OMAHA	NE	68105	DOUGLAS	USA	Lung Diseases Research	000	4	11/17/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $383,750 )
2025	2025	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Lung Diseases Research	000	4	12/5/2024	NON-COMPETING CONTINUATION	$383,750
														Subtotal = $383,750

Issue Date FY: 2024 ( Subtotal = $383,750 )
2024	2024	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Lung Diseases Research	001	3	6/26/2024	NON-COMPETING CONTINUATION	$38,375
2024	2024	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Lung Diseases Research	000	3	11/6/2023	NON-COMPETING CONTINUATION	$345,375
														Subtotal = $383,750

Issue Date FY: 2023 ( Subtotal = $383,750 )
2023	2023	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Lung Diseases Research	000	2	12/12/2022	NON-COMPETING CONTINUATION	$345,375
2023	2023	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Lung Diseases Research	001	2	3/6/2023	NON-COMPETING CONTINUATION	$38,375
														Subtotal = $383,750

Issue Date FY: 2022 ( Subtotal = $383,020 )
2022	2022	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Lung Diseases Research	000	1	12/22/2021	NEW	$383,020
														Subtotal = $383,020

Grand Total All Awards = $1,534,270

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Defective Zn Homeostasis impairs host defense against pneumococcal pneumonia

Award Number: R01HL156952

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 12/22/2021

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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