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IL-4-activated macrophages: Contribution to allergic lung inflammation linked to viral infection

Award Number: R01AI143845
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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SUMMARY It is now recognized that infection of genetically susceptible individuals with certain respiratory viruses, including human rhinovirus (HRV) and respiratory syncytial virus (RSV), during infancy or early childhood leads to an increased risk of subsequent development of allergic asthma. Survivors of preterm birth, with and without the complication bronchopulmonary dysplasia (BPD), exhibit increased susceptibility to viral infection and greater risk of developing childhood-onset asthma than term infants. In addition, infection of children with allergic asthma with these viruses can severely exacerbate ongoing disease. Despite the recognition of this relationship, the mechanism linking viral infection and susceptibility to and severity of allergic lung inflammation is not known representing a critical unmet need. We have shown that viral infection induces the IL-4Ra-dependent, alternative activation of macrophages (Mf) referred to as “M2” in lungs of mice that remain long after virus is cleared (~90 days after infection). Fur- thermore, we showed that allergens induce M2 in the lung and that M2 actively mediate enhanced allergic in- flammation. Adoptive transfer of highly purified Mf that express IL-4Ra into IL-4Ra-/- mice resulted in the differ- entiation of M2 in the lung that mitigated virus-induced pro-inflammatory pathology, as part of their repair func- tion. However, they produced Th2-promoting cytokines and actively promoted allergen-induced, Th2-driven al- lergic inflammation associated with asthma. Recent studies demonstrated that M2 Mf polarization is associated with normal alveolar development, and increased M2 polarization protected against hyperoxia-induced lung in- jury in neonatal mice. Based on our recent publications and additional preliminary data described in this appli- cation, we propose the novel hypothesis that enhanced responsiveness to allergen exposure that occurs after viral infection of young mice is in part mediated by long-lived M2. We further propose that virus-induced exacer- bation of ongoing allergic disease is mediated by M2. To test this hypothesis, we will complete the following specific aims: 1) to determine the mechanism for M2 maintenance between virus and allergen exposure; 2) to analyze the specific role of Mfs on the virus-induced enhanced responses to allergen and virus-induced exac- erbation; and 3) to characterize the contribution M2 to enhanced susceptibility of neonates to virus-induced inception of allergic inflammation in vivo. This project will benefit from the expertise and oversight of the 3 PIs. At the conclusion of these studies, we expect to have determined the mechanism by which viral infection leads to development of long-lived M2 that enhance the development of asthma later in life. They will determine whether alterations in lung M2 formation during lung maturation lead to virus-enhanced asthma, thus providing a potential therapeutic target.


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: 2025 ( Subtotal = $0 )
2025	2023	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	5	11/15/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $610,630 )
2023	2023	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	5	12/12/2022	NON-COMPETING CONTINUATION	$610,630
														Subtotal = $610,630

Issue Date FY: 2022 ( Subtotal = $610,630 )
2022	2022	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	4	11/29/2021	NON-COMPETING CONTINUATION	$610,630
														Subtotal = $610,630

Issue Date FY: 2021 ( Subtotal = $610,630 )
2021	2021	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	3	12/18/2020	NON-COMPETING CONTINUATION	$610,630
														Subtotal = $610,630

Issue Date FY: 2020 ( Subtotal = $610,630 )
2020	2020	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	2	12/19/2019	NON-COMPETING CONTINUATION	$610,630
														Subtotal = $610,630

Issue Date FY: 2019 ( Subtotal = $610,630 )
2019	2019	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	1	1/2/2019	NEW	$610,630
														Subtotal = $610,630

Grand Total All Awards = $3,053,150

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IL-4-activated macrophages: Contribution to allergic lung inflammation linked to viral infection

Award Number: R01AI143845

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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