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TOLLIP Deficiency, Immune Dysregulation, and Tuberculosis Susceptibility

Award Number: R01AI136921
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: 03/01/2018
PERIOD OF PERFORMANCE END DATE: 02/29/2024

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TOLLIP Deficiency, Immune Dysregulation, and Tuberculosis Susceptibility - Project Summary/Abstract Over one million people died from tuberculosis (TB) in 2016. Improved understanding of the host factors that influence TB infection and TB disease severity is needed to improve TB treatments and vaccines. Multiple lines of evidence show that excess inflammation worsens outcomes from M. tuberculosis (Mtb) infection. After Mtb infection, macrophages and dendritic cells initiate the immune response, leading to mycobacterial killing, granuloma formation, and T cell activation. The Toll-Interacting Protein (TOLLIP) mediates the immune response to Mtb by dampening several innate immune pathways, including TLR and IL-1 signaling pathways. Our long-term goal is to determine the molecular and cellular mechanisms that influence vaccine immunity and susceptibility to TB. Discovery of innate immune factors, including TOLLIP, that influence vaccine development may influence vaccine design. The objective of this grant is to characterize the role of TOLLIP in influencing T memory differentiation and persistence in the context of chronic TB or BCG exposure. The central hypothesis is that TOLLIP deficiency – a phenotype we have discovered exists in multiple population -- amplifies the innate immune response to Mtb in a deleterious fashion, weakening Mtb- specific T cell responses and increasing TB susceptibility. The rationale is that identification of innate immune factors that influence T cell immunity in a nuanced fashion provides a novel path toward rational vaccine design. Our specific aims will test the following hypotheses: 1) TOLLIP deficiency in macrophages is caused by alterations in the TOLLIP transcriptional complex and influences multiple signaling pathways within the macrophage; 2) TOLLIP deficiency increases DC activation, which leads to increased T cell differentiation but reduced vaccine effectiveness in humans, and 3) TOLLIP deficiency impairs lung-specific immunity, particularly in the formation and persistence of resident memory T cells and exhausted T cells in knockout mice. This contribution is significant because it will establish that TOLLIP regulates the innate immune response and improves host defense against M. tuberculosis; this proposal may lead to improved vaccine adjuvants and host-directed therapeutics to Mtb. The proposed work is innovative because we investigate the mechanisms and effects of a functionally active variant of TOLLIP in humans and combine with a knockout mouse model of infection, using novel tools to investigate an understudied, critical immune regulator. Insight into immunoregulatory genes like TOLLIP is impactful because they may offer new targets for modifying the immune response.


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 = -$77,925 )
2024	2022	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Allergy and Infectious Diseases Research	001	5	8/28/2024	SUPPLEMENT FOR EXPANSION	-$1,293
2024	2022	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Allergy and Infectious Diseases Research	000	5	8/28/2024	NON-COMPETING CONTINUATION	-$76,632
														Subtotal = -$77,925

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Allergy and Infectious Diseases Research	000	5	11/2/2022	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $458,608 )
2022	2022	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Allergy and Infectious Diseases Research	000	5	3/1/2022	NON-COMPETING CONTINUATION	$451,000
2022	2022	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Allergy and Infectious Diseases Research	001	5	3/3/2022	SUPPLEMENT FOR EXPANSION	$7,608
														Subtotal = $458,608

Issue Date FY: 2021 ( Subtotal = $544,556 )
2021	2021	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Allergy and Infectious Diseases Research	000	4	1/29/2021	NON-COMPETING CONTINUATION	$544,556
														Subtotal = $544,556

Issue Date FY: 2020 ( Subtotal = $534,655 )
2020	2020	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Allergy and Infectious Diseases Research	000	3	2/18/2020	NON-COMPETING CONTINUATION	$451,000
2020	2020	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Allergy and Infectious Diseases Research	001	3	4/9/2020	SUPPLEMENT FOR EXPANSION	$83,655
														Subtotal = $534,655

Issue Date FY: 2019 ( Subtotal = $450,667 )
2019	2019	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Allergy and Infectious Diseases Research	000	2	2/13/2019	NON-COMPETING CONTINUATION	$450,667
														Subtotal = $450,667

Issue Date FY: 2018 ( Subtotal = $469,000 )
2018	2018	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Allergy and Infectious Diseases Research	000	1	2/27/2018	NEW	$469,000
														Subtotal = $469,000

Grand Total All Awards = $2,379,561

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TOLLIP Deficiency, Immune Dysregulation, and Tuberculosis Susceptibility

Award Number: R01AI136921

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: 03/01/2018

PERIOD OF PERFORMANCE END DATE: 02/29/2024

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