Saturday, November 23, 2024 11/23/2024

Elucidating Mechanisms of Mucosal Immune Protection Against Respiratory Syncytial Virus in Infants

Award Number: R01AI090059
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY/ABSTRACT: Respiratory syncytial virus (RSV) is the number one cause of lower respiratory tract viral infection in infants and is responsible for ~60,000 in-hospital deaths annually, with most deaths occurring in infants less than three months of age. Reinfections are common, and those who develop severe bronchiolitis are at further risk of developing chronic lung diseases such as asthma. Past efforts to prevent RSV infection in infants through vaccination with formalin-inactivated virus were disastrous resulting in 80% of vaccinees being hospitalized following community-acquired RSV infection. This has hampered RSV vaccine development for nearly 50 years. We, and other researchers, have used neonatal (i.e., <7d of age) mouse models of RSV infection to mimic the disease in human infants. Recently, we have shown that type I interferon (IFN-I) responses are deficient in neonatal mice, which is consistent with findings in human infants. As repeated infections are indicative of insufficient adaptive immunity, we assessed antibody responses and demonstrated that, congruent with deficiencies in IFN-I, neonatal mice and infants fail to produce RSV-specific IgA. We identified a mechanistic relationship between these components by demonstrating that IgA production requires IFNα in mice. This is especially important, because RSV-specific IgA responses correlate significantly with protection from disease and, in contrast to adults, infants and neonatal mice fail to mount such responses upon infection. IFNα administration in neonatal mice induced RSV-specific IgA production and decreased RSV disease severity. Importantly, neonatal B regulatory lymphocytes (nBregs) expressing IL10, but not IgA, have been observed in RSV-infected infants and neonatal mice in a time-frame consistent with decreased IFN-I levels. Together, these findings guide our hypothesis that failure to develop protective IgA responses in the respiratory mucosa is responsible for RSV severity. We will explore the validity of this hypothesis using unique sample sets from human infant RSV infection cohorts and age-relevant mouse models with three specific aims. Aim 1 will demonstrate that the inability of infants to induce mucosal RSV-specific IgA in response to RSV infection is responsible for enhanced disease severity. Aim 2 will determine whether failure to induce BAFF/APRIL hinders the development of IgA responses to RSV in infants. Aim 3 will establish that nBregs suppress RSV-specific IgA production in infants. The idea that age-dependent regulation of type I IFN regulates the development of protective IgA responses in the respiratory mucosa following RSV infection is novel. We will employ innovative methodologies including single-cell RNAseq (scRNASeq) on B-cell subsets in samples from RSV-infected infants and spatial transcriptomics in samples from RSV-infected neonatal mice to characterize Breg phenotypes, transcriptional programs, and local functions. Data derived from these studies will have a positive paradigm-shifting impact on the understanding of severe RSV disease and yield novel immunological targets to advance pediatric vaccine design.


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 = $575,767 )
2024	2024	LOUISIANA STATE UNIVERSITY	202 HIMES HALL	BATON ROUGE	LA	70803	EAST BATON ROUGE	USA	Allergy and Infectious Diseases Research	001	13	9/5/2024	NON-COMPETING CONTINUATION	$0
2024	2024	LOUISIANA STATE UNIVERSITY	202 HIMES HALL	BATON ROUGE	LA	70803	EAST BATON ROUGE	USA	Allergy and Infectious Diseases Research	000	13	8/1/2024	NON-COMPETING CONTINUATION	$575,767
														Subtotal = $575,767

Issue Date FY: 2023 ( Subtotal = $586,395 )
2023	2023	LOUISIANA STATE UNIVERSITY	202 HIMES HALL	BATON ROUGE	LA	70803	EAST BATON ROUGE	USA	Allergy and Infectious Diseases Research	001	12	8/11/2023	COMPETING CONTINUATION	$586,395
2023	2020	LOUISIANA STATE UNIVERSITY	202 HIMES HALL	BATON ROUGE	LA	70803	EAST BATON ROUGE	USA	Allergy and Infectious Diseases Research	000	11	11/8/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $586,395

Issue Date FY: 2020 ( Subtotal = $444,192 )
2020	2020	LOUISIANA STATE UNIVERSITY	202 HIMES HALL	BATON ROUGE	LA	70803	EAST BATON ROUGE	USA	Allergy and Infectious Diseases Research	000	11	7/13/2020	NON-COMPETING CONTINUATION	$444,192
2020	2020	LOUISIANA STATE UNIVERSITY	202 HIMES HALL	BATON ROUGE	LA	70803	EAST BATON ROUGE	USA	Allergy and Infectious Diseases Research	001	11	8/10/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $444,192

Issue Date FY: 2019 ( Subtotal = $468,288 )
2019	2019	LOUISIANA STATE UNIVERSITY	202 HIMES HALL	BATON ROUGE	LA	70803	EAST BATON ROUGE	USA	Allergy and Infectious Diseases Research	002	10	7/10/2019	NON-COMPETING CONTINUATION	$468,288
2019	2017	UNIVERSITY OF TENNESSEE	62 S DUNLAP STREET STE 103	MEMPHIS	TN	38103	SHELBY	USA	Allergy and Infectious Diseases Research	000	7	5/23/2019	NON-COMPETING CONTINUATION	-$876
2019	2017	LOUISIANA STATE UNIVERSITY	202 HIMES HALL	BATON ROUGE	LA	70803	EAST BATON ROUGE	USA	Allergy and Infectious Diseases Research	001	8	5/23/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$876
														Subtotal = $468,288

Issue Date FY: 2018 ( Subtotal = $463,800 )
2018	2018	LOUISIANA STATE UNIVERSITY	202 HIMES HALL	BATON ROUGE	LA	70803	EAST BATON ROUGE	USA	Allergy and Infectious Diseases Research	002	9	7/18/2018	NON-COMPETING CONTINUATION	$476,882
2018	2017	UNIVERSITY OF TENNESSEE	62 S DUNLAP STREET STE 103	MEMPHIS	TN	38103	SHELBY	USA	Allergy and Infectious Diseases Research	000	7	6/20/2018	NON-COMPETING CONTINUATION	-$504,994
2018	2017	UNIVERSITY OF TENNESSEE	62 S DUNLAP STREET STE 103	MEMPHIS	TN	38103	SHELBY	USA	Allergy and Infectious Diseases Research	003	7	7/25/2018	NON-COMPETING CONTINUATION	-$6,476
2018	2017	LOUISIANA STATE UNIVERSITY	202 HIMES HALL	BATON ROUGE	LA	70803	EAST BATON ROUGE	USA	Allergy and Infectious Diseases Research	001	8	6/20/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$491,912
2018	2017	LOUISIANA STATE UNIVERSITY	202 HIMES HALL	BATON ROUGE	LA	70803	EAST BATON ROUGE	USA	Allergy and Infectious Diseases Research	004	8	7/25/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$6,476
														Subtotal = $463,800

Issue Date FY: 2017 ( Subtotal = $554,769 )
2017	2017	UNIVERSITY OF TENNESSEE	62 S DUNLAP STREET STE 103	MEMPHIS	TN	38103	SHELBY	USA	Allergy and Infectious Diseases Research	002	7	7/22/2017	NON-COMPETING CONTINUATION	$554,769
2017	2016	UNIVERSITY OF TENNESSEE	62 S DUNLAP STREET STE 103	MEMPHIS	TN	38103	SHELBY	USA	Allergy and Infectious Diseases Research	001	6	1/26/2017	COMPETING CONTINUATION	$527
2017	2014	UNIVERSITY OF TENNESSEE	62 S DUNLAP STREET STE 103	MEMPHIS	TN	38103	SHELBY	USA	Allergy and Infectious Diseases Research	000	5	1/26/2017	NON-COMPETING CONTINUATION	-$527
														Subtotal = $554,769

Issue Date FY: 2016 ( Subtotal = $506,532 )
2016	2016	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Allergy and Infectious Diseases Research	000	6	7/7/2016	COMPETING CONTINUATION	$456,000
2016	2016	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Allergy and Infectious Diseases Research	001	6	8/8/2016	COMPETING CONTINUATION	$50,532
														Subtotal = $506,532

Issue Date FY: 2014 ( Subtotal = $375,000 )
2014	2014	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Allergy and Infectious Diseases Research	000	5	7/16/2014	NON-COMPETING CONTINUATION	$375,000
														Subtotal = $375,000

Issue Date FY: 2013 ( Subtotal = $367,700 )
2013	2013	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Allergy and Infectious Diseases Research	002	4	7/15/2013	NON-COMPETING CONTINUATION	$352,500
2013	2012	LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER	433 BOLIVAR STREET	NEW ORLEANS	LA	70112	ORLEANS	USA	Allergy and Infectious Diseases Research	000	2	6/12/2013	NON-COMPETING CONTINUATION	-$269,800
2013	2012	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Allergy and Infectious Diseases Research	001	3	6/12/2013	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$285,000
														Subtotal = $367,700

Issue Date FY: 2012 ( Subtotal = $352,445 )
2012	2012	LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER	433 BOLIVAR STREET	NEW ORLEANS	LA	70112	ORLEANS	USA	Allergy and Infectious Diseases Research	000	2	7/11/2012	NON-COMPETING CONTINUATION	$352,445
														Subtotal = $352,445

Issue Date FY: 2011 ( Subtotal = $352,519 )
2011	2011	LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER	433 BOLIVAR STREET	NEW ORLEANS	LA	70112	ORLEANS	USA	Allergy and Infectious Diseases Research	000	1	7/28/2011	NEW	$352,519
														Subtotal = $352,519

Grand Total All Awards = $5,047,407

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Elucidating Mechanisms of Mucosal Immune Protection Against Respiratory Syncytial Virus in Infants

Award Number: R01AI090059

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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