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Determining the role of NLRP3 on the placement and protective potential of CD73+ BRMs post influenza infection

Award Number: R21AI149271
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 Little is known about antigen (Ag) specific memory B (BMEM) cells, in the context of a public health relevant pathogen. Our studies clearly resolve the subsets of non-circulating, influenza specific, resident memory B cells (BRM) in the lung. BRM establishment relied on early CD40 signaling and maintained a CD73 (ectoenzyme)+ and CD73- population, whereas the lymph node (LN) showed a decline in the CD73- population. This raised the question of the inherent differences in formation and function of CD73+ and CD73- BRMs. CD73 is a marker of germinal center (GC) emigrants in the LN and memory cells in the LN reside in niches close to macrophages that capture and transfer antigen and T cells which can provide help; therefore, we hypothesized that the CD73+BRMs will home to areas of organized lymphoid structures in the lung and be dependent on T cell help. Our RNASeq data shows NLRP3 (NOD-like receptor protein 3), an innate danger sensing complex, to be the most upregulated gene in CD73+BRMs. To our knowledge NLRP3 activity is not associated with B cell differentiation, which makes this finding novel and may inaugurate studies into innate like functions in B cells during adaptive responses. NLRP3 activity produces interleukin B (IL-1B) and IL-1B is a well-known up regulator of interleukin 6 (IL-6), which promotes GCs and plasma cell differentiation. As our CD73+BRMs may have higher NLRP3 expression, we hypothesize that NLRP3 will be active during recall and produce GCs and ASCs, while the CD73-BRMs may be sentinels in the lung which spontaneously convert to ASCs, in response to the returning virus. To test these hypotheses, we ask the following: 1) Are CD73+ and CD73- BRM cells dependent on GCs? If so, GC-specific blockade should reduce CD73+ BRMs in the lung and produce low affinity BCRs. 2) Do CD73+ BRMs preferentially reside in iBALT? If so, using histology, we should observe them congregating in the iBALT while the CD73-BRMs are scattered in the parenchyma. 3) Do CD73+ and CD73- BRM cells respond differently in functional assays? We will answer this question by performing in vitro assays for BRM differentiation to ASCs, using cytokine cocktails and sorted T cells. 4) Does the NLRP3 complex become activated in BRMs upon viral challenge? If so, using NLRP3 inflammasome reporter mice, we expect that CD73+ BRM cells, but not CD73- BRM cells to increase NLRP3 activity. 5) Does NLRP3 regulate the formation or function of BRMs? If so, B cell specific NLRP3 deficiency should alter the proportions of CD73+ and CD73-BRMs and their protective function with observable differences in morbidity and mortality. The findings from this study despite the outcome will be extremely important to allow for the resolution of a target population and potential molecular targets for an effective 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: 2023 ( Subtotal = -$156,877 )
2023	2021	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Allergy and Infectious Diseases Research	000	2	6/20/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$156,877
														Subtotal = -$156,877

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Allergy and Infectious Diseases Research	001	2	11/11/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$154,162
2022	2020	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	1	11/11/2021	NEW	-$154,162
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $202,725 )
2021	2021	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Allergy and Infectious Diseases Research	001	2	7/15/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$202,725
2021	2020	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	1	7/15/2021	NEW	$0
														Subtotal = $202,725

Issue Date FY: 2020 ( Subtotal = $222,750 )
2020	2020	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Allergy and Infectious Diseases Research	001	1	8/24/2020	NEW	$0
2020	2020	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	1	2/25/2020	NEW	$222,750
														Subtotal = $222,750

Grand Total All Awards = $268,598

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Determining the role of NLRP3 on the placement and protective potential of CD73+ BRMs post influenza infection

Award Number: R21AI149271

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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