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Elucidating the role of type I interferon signaling and macrophage-derived inflammation in the juvenile host with viral pneumonia

Award Number: R01HL168672
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary: Viral respiratory infections are a leading cause of hospitalization in children. In the absence of co-morbidities, children are much more likely than adults to require hospitalization for most respiratory viruses, including influenza A virus (IAV). Age-related changes in innate immune signaling over the first few years of life likely impact the course of viral respiratory infections, but the mechanisms driving viral-induced respiratory failure in children are unknown. Viral load has not been associated with severity of illness in children with IAV pneumonia, so failure to control viral replication is not likely the primary driver of severe illness in children. We have found that juvenile mice recruit more monocyte-derived alveolar macrophages and have increased activation of the NLRP3 inflammasome compared to adult mice late in IAV infection. This was associated with increased production of type I interferon (IFN) in juvenile mice, despite equal viral burden. Importantly, inhibition of macrophage recruitment decreased type I IFN levels and improved survival in juvenile IAV infection. These data suggest that age-related differences in type I IFN production in response to IAV infection promote the recruitment of inflammatory macrophages and contribute to mortality in juvenile mice. In preliminary data, we now show that genetic deletion or pharmacologic inhibition of the type I IFN receptor, IFNAR1, on recruited macrophages improves survival in IAV-infected juvenile mice. Therefore, we hypothesize that children fail to recover from IAV infection due to increased type I IFN signaling and macrophage recruitment to the lungs. We further hypothesize that recruited macrophages maintain an injurious inflammatory phenotype in the juvenile lung due to age-related differences in the lung microenvironment. We will test these hypotheses in the following specific aims: Aim 1: Determine whether age-related differences in the microenvironment of the juvenile lung promote an inflammatory phenotype in recruited macrophages. Aim 2: Determine whether inhibition of type I IFN signaling in recruited macrophages decreases lung injury and improves outcomes in juvenile viral pneumonia. Aim 3: Determine whether increased type I IFN signaling in epithelial cells contributes to severity of illness in juvenile viral pneumonia. Completion of these aims will identify mechanisms driving viral-induced respiratory failure in the juvenile host and explore the potential benefit of targeting IFNAR1 signaling in macrophages to minimize lung injury caused by viral respiratory infections in children. Using age-appropriate mouse models of IAV pneumonia and multidimensional phenotyping of children with viral-induced respiratory failure, we are positioned to define key determinants of disease severity in children with IAV pneumonia that will support the rationale design of new treatment strategies to minimize lung injury and optimize recovery.


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: 2024 ( Subtotal = $620,028 )
2024	2024	ANN & ROBERT H LURIE CHILDRENS HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Lung Diseases Research	000	2	2/1/2024	NON-COMPETING CONTINUATION	$569,413
2024	2024	ANN & ROBERT H LURIE CHILDRENS HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Lung Diseases Research	001	2	6/18/2024	NON-COMPETING CONTINUATION	$50,615
														Subtotal = $620,028

Issue Date FY: 2023 ( Subtotal = $646,431 )
2023	2023	ANN & ROBERT H LURIE CHILDRENS HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Lung Diseases Research	000	1	5/5/2023	NEW	$646,431
														Subtotal = $646,431

Grand Total All Awards = $1,266,459

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Elucidating the role of type I interferon signaling and macrophage-derived inflammation in the juvenile host with viral pneumonia

Award Number: R01HL168672

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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