Thursday, June 19, 2025 6/19/2025

LPS Signaling in Macrophages: The Roll of Toll

Award Number: R01AI032972
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: 07/01/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2023

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LPS Signaling in Macrophages: The Roll of Toll - The innate immune system is the first line of defense against pathogens. Innate immune cells lack the exquisite specificity of the adaptive immune system, yet in order to respond in a measured way, they must be able to tailor their activity to the specific pathogen. These cells have therefore evolved pattern recognition receptors (PRRs) that recognize conserved molecules characteristic of the microbe, which are not found within the host. The Toll-like receptors (TLRs) are the archetypal PRRs. The innate immune response to viruses occurs principally by inducing type I interferons (IFN). It has recently been appreciated that IFN also functions in the response to bacteria, although its role here is poorly defined. We have shown that 25-HC, an oxysterol which is derived enzymatically from cholesterol by Ch25h, has a role in regulating the inflammatory response and immunity. Ch25h is strongly induced by both TLR2-activation and by IFN, and we have further demonstrated that 25-HC reciprocally impacts both of these pathways: It amplifies and sustains a subset of the TLR-induced inflammatory genes while simultaneously suppressing expression of a subset of interferon- stimulated genes. Therefore, Ch25h is an immune modulator situated at the intersection of these two major pathways, the precise regulation of which is crucial to controlling viral and bacterial infections such as Listeria monocytogenes and Mycobacterium tuberculosis. We propose to identify the molecular mechanisms by which 25-HC impacts TLR and IFN responses and determine the role of these interactions in control of bacterial infections. We will first define the mechanism by which 25-HC amplifies TLR2 signaling in macrophages by examining the mechanism by which 25-HC suppresses IL-10 production and determining the role of 25-HC- mediated epigenetic regulation in altering expression of TLR2 induced genes. Next we will determine the mechanisms by which 25-HC regulates crosstalk between interferon and inflammatory signaling. Here we shall determine the mechanism by which 25-HC mediates the suppression of IFN-stimulated genes. We shall then determine the role of 25-HC in cross-regulation between innate immune pathways. Finally, we will determine the role of 25-HC in macrophage control of Listeria monocytogenes in vitro and in vivo.


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 = $0 )
2024	2020	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	31	3/21/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	31	6/23/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $986,460 )
2020	2020	SEATTLE CHILDREN'S HOSPITAL	4800 SAND PT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	31	6/5/2020	NON-COMPETING CONTINUATION	$986,460
														Subtotal = $986,460

Issue Date FY: 2019 ( Subtotal = $954,661 )
2019	2019	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	007	30	6/27/2019	NON-COMPETING CONTINUATION	$986,460
2019	2018	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	005	28	4/30/2019	NON-COMPETING CONTINUATION	-$58,582
2019	2018	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	002	28	1/10/2019	NON-COMPETING CONTINUATION	$48,153
2019	2018	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	001	29	12/7/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$857,558
2019	2018	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	28	12/7/2018	NON-COMPETING CONTINUATION	-$857,558
2019	2018	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	004	29	2/1/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2019	2018	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	003	29	1/10/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$79,952
2019	2018	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	006	29	4/30/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$58,582
														Subtotal = $954,661

Issue Date FY: 2018 ( Subtotal = $1,026,799 )
2018	2018	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	28	6/20/2018	NON-COMPETING CONTINUATION	$1,026,799
														Subtotal = $1,026,799

Issue Date FY: 2017 ( Subtotal = $990,128 )
2017	2017	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	001	27	6/28/2017	NON-COMPETING CONTINUATION	$990,128
2017	2015	INSTITUTE FOR SYSTEMS BIOLOGY	401 TERRY AVE N	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	25	2/17/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $990,128

Issue Date FY: 2016 ( Subtotal = $990,128 )
2016	2016	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N, STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	26	6/23/2016	COMPETING CONTINUATION	$990,128
														Subtotal = $990,128

Issue Date FY: 2015 ( Subtotal = $838,218 )
2015	2015	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N, STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	25	6/15/2015	NON-COMPETING CONTINUATION	$838,218
														Subtotal = $838,218

Issue Date FY: 2014 ( Subtotal = $838,218 )
2014	2014	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N, STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	24	6/26/2014	NON-COMPETING CONTINUATION	$838,218
														Subtotal = $838,218

Issue Date FY: 2013 ( Subtotal = $787,926 )
2013	2013	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N, STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	23	6/10/2013	NON-COMPETING CONTINUATION	$787,926
														Subtotal = $787,926

Issue Date FY: 2012 ( Subtotal = $838,218 )
2012	2012	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N, STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	22	6/18/2012	NON-COMPETING CONTINUATION	$838,218
														Subtotal = $838,218

Issue Date FY: 2011 ( Subtotal = $807,782 )
2011	2011	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N, STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	003	21	9/20/2011	COMPETING CONTINUATION	$0
2011	2011	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N, STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	001	21	7/6/2011	COMPETING CONTINUATION	$610,436
2011	2011	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N, STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	002	21	9/16/2011	COMPETING CONTINUATION	$197,346
2011	2010	INSTITUTE FOR SYSTEMS BIOLOGY	1441 N 34TH STREET	SEATTLE	WA	98103	KING	USA	Allergy and Infectious Diseases Research	000	20	6/30/2011	NON-COMPETING CONTINUATION	$0
														Subtotal = $807,782

Issue Date FY: 2010 ( Subtotal = $645,927 )
2010	2010	INSTITUTE FOR SYSTEMS BIOLOGY	1441 N 34TH STREET	SEATTLE	WA	98103	KING	USA	Allergy and Infectious Diseases Research	000	20	12/1/2009	NON-COMPETING CONTINUATION	$587,206
2010	2010	INSTITUTE FOR SYSTEMS BIOLOGY	1441 N 34TH STREET	SEATTLE	WA	98103	KING	USA	Allergy and Infectious Diseases Research	001	20	5/28/2010	NON-COMPETING CONTINUATION	$58,721
														Subtotal = $645,927

Issue Date FY: 2009 ( Subtotal = $633,450 )
2009	2009	INSTITUTE FOR SYSTEMS BIOLOGY	1441 N 34TH STREET	SEATTLE	WA	98103	KING	USA	Allergy and Infectious Diseases Research	001	19	6/8/2009	NON-COMPETING CONTINUATION	$63,344
2009	2009	INSTITUTE FOR SYSTEMS BIOLOGY	1441 N 34TH STREET	SEATTLE	WA	98103	KING	USA	Allergy and Infectious Diseases Research	000	19	11/26/2008	NON-COMPETING CONTINUATION	$570,106
														Subtotal = $633,450

Issue Date FY: 2008 ( Subtotal = $590,661 )
2008	2008	INSTITUTE FOR SYSTEMS BIOLOGY	1441 N 34TH STREET	SEATTLE	WA	98103	KING	USA	Allergy and Infectious Diseases Research	000	18	1/7/2008	NON-COMPETING CONTINUATION	$590,661
														Subtotal = $590,661

Issue Date FY: 2007 ( Subtotal = $628,944 )
2007	2007	INSTITUTE FOR SYSTEMS BIOLOGY	1441 N 34TH STREET	SEATTLE	WA	98103	KING	USA	Allergy and Infectious Diseases Research	000	17	1/16/2007	NON-COMPETING CONTINUATION	$628,944
														Subtotal = $628,944

Issue Date FY: 2006 ( Subtotal = $609,979 )
2006	2006	INSTITUTE FOR SYSTEMS BIOLOGY	1441 N 34TH STREET	SEATTLE	WA	98103	KING	USA	Allergy and Infectious Diseases Research	000	16	12/13/2005	COMPETING CONTINUATION	$609,979
														Subtotal = $609,979

Issue Date FY: 2004 ( Subtotal = $536,481 )
2004	2004	INSTITUTE FOR SYSTEMS BIOLOGY	4225 ROOSEVELT WAY NORTHEAST	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	15	5/27/2004	NON-COMPETING CONTINUATION	$536,481
														Subtotal = $536,481

Issue Date FY: 2003 ( Subtotal = $521,316 ) (Continued on the next page)
Grand Total All Awards = $15,282,402

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LPS Signaling in Macrophages: The Roll of Toll

Award Number: R01AI032972

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: 07/01/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2023

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