Monday, June 30, 2025 6/30/2025

Context dependent amino acid availability and sensing determines humoral immunity

Award Number: R01AI162678
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/10/2022
PERIOD OF PERFORMANCE END DATE: 01/31/2027

Group Awards By:

View Award Description

Context dependent amino acid availability and sensing determines humoral immunity - Project Summary Amino acids are crucial nutrients that are also important to support immunity. Yet, we have limited understanding with regard to how immune challenges modulate amino acid availability, and how immune cells sense amino acid and transduce the signals to execute immune reponses. Rag-GTPase has recently been identified as a key amino acid sensor that mostly transduce signals from amino acids to mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) in non-hematopoietic cells. However, Rag-GTPase also modulates transcription factor TFEB, a member of the microphthalmia (MiT/TFE) family of HLH-leucine zipper transcription factors, whose functions in B cells remain unknown. Moreover, Rag-GTPase independent mTORC1 activation has been identified. How Rag-GTPase and mTORC1 coordinates to regulate humoral immunity has not been addressed. We compared the functions of Rag-GTPase and mTORC1 in B cell response in vivo using genetic knockout models. Our data showed that while both Rag-GTPase and mTORC1 are required for systemic immune challenges, Rag-GTPase, but not mTORC1, is critical for humoral immune response towards respiratory influenza infection. This divergent requirement between Rag-GTPase and mTORC1 is associated with differential amino acid availability between systemic immunization and airway influenza infection. Furthermore, we showed that Rag-GTPase suppresses TFEB and promotes autophagy, which is associated with ERK activation, but largely independent of mTORC1. Thus, we hypothesize that reduced availability of specific amino acids during respiratory viral infection renders B cells dependent on Rag- GTPase-TFEB pathway, for GC reaction and anti-influenza antibody production. In Aim 1, we will first test whether the respiratory route of live virus immune challenge is the determining factor for Rag-GTPase dependent, but mTORC1 independent, humoral immunity. Second, we will further investigate the temporal and spatial dynamics of amino acid availability during immune challenges. Finally, we will test whether dietary amino acid intervention can improve humoral immunity against respiratory viral infection. In Aim 2, we will utilize complementary loss-of-function and gain-of-function approaches to elucidate the downstream signaling mechanisms by which Rag-GTPase promotes GC reaction and humoral immunity. We will further characterize the Rag-GTPase interactome in B cells using unbiased proteomics approach. Our study will define a novel Rag-GTPase-ERK-TFEB signaling axis that respond to amino acid availability to promote B cell activation and antibody production against airway viral infection.


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 = $456,703 )
2025	2025	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Allergy and Infectious Diseases Research	000	4	1/17/2025	NON-COMPETING CONTINUATION	$456,703
														Subtotal = $456,703

Issue Date FY: 2024 ( Subtotal = $470,828 )
2024	2024	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Allergy and Infectious Diseases Research	000	3	12/5/2023	NON-COMPETING CONTINUATION	$423,745
2024	2024	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Allergy and Infectious Diseases Research	001	3	5/24/2024	NON-COMPETING CONTINUATION	$47,083
														Subtotal = $470,828

Issue Date FY: 2023 ( Subtotal = $470,828 )
2023	2023	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Allergy and Infectious Diseases Research	000	2	1/26/2023	NON-COMPETING CONTINUATION	$470,828
														Subtotal = $470,828

Issue Date FY: 2022 ( Subtotal = $470,828 )
2022	2022	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Allergy and Infectious Diseases Research	000	1	2/10/2022	NEW	$470,828
														Subtotal = $470,828

Grand Total All Awards = $1,869,187

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Context dependent amino acid availability and sensing determines humoral immunity

Award Number: R01AI162678

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/10/2022

PERIOD OF PERFORMANCE END DATE: 01/31/2027

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer