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Role of Toll-like Receptor 9 in Fibroblastic Reticular Cell-based Therapy for Intra-abdominal Sepsis

Award Number: R01AI152044
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Summary Sepsis is now the leading cause of death in US hospitals and there are currently no effective pharmacological treatments for sepsis. Stromal cell-based therapies have shown efficacy in treating sepsis in experimental models and have been approved for use in multiple countries for various immune dysregulation diseases. Fibroblastic reticular cells (FRCs) are a subpopulation of stromal cells existing in all lymphoid organs including fat associated lymphoid cluster (FALC) in adipose tissue. We have shown that TLR9 signaling suppresses chemokine production in FRCs. Adoptive transfer of Tlr9-deficient FRCs decreased mortality, bacterial load, and systemic inflammation compared with wild type (WT) FRCs after cecal ligation and puncture (CLP). Here, we identified two distinct subsets of FRCs (Ly6Chi and Ly6Clo) in mesenteric FALCs at baseline and after CLP. Importantly, the Ly6Chi FRC subset express similar top marker genes as the CD55+ stromal cell subset that was previously described in both mouse and human subcutaneous adipose tissue. Ly6Chi FRCs are enriched in the innate immune response-related genes after CLP, whereas Ly6Clo FRCs are enriched in the humoral immune response-related genes. Furthermore, we found that both Ly6Chi and Ly6Clo FRCs from Tlr9-/- mice increased gene expression associated with inflammation, proliferation, and extracellular matrix remodeling compared with WT FRCs at baseline and after CLP. Based on these findings, we hypothesize that TLR9 plays critical roles in regulating the biology of distinct FRC subsets, and that modulation of TLR9 signaling in a subset-specific manner may improve the efficacy of FRC-based therapy in sepsis. We will test our hypothesis by pursuing two specific aims: Aim 1: To determine the mechanisms of TLR9-mediated regulation of FRC biology in mouse and human adipose FRC subsets. We will take advantage of single cell technologies (single cell RNA-sequencing and Mass cytometry) combined with the FRC-specific Tlr9-/- mice to determine the role of TLR9 in gene expression, cell fate, and immunoregulatory functions in individual FRC subset in vivo and in vitro. We will also validate the findings from mouse FRCs in human adipose FRCs. Aim 2: To determine the impact of TLR9 inhibition preconditioning on FRC therapy in intra-abdominal sepsis. We will determine the therapeutic efficacy of TLR9 inhibition preconditioned FRC subsets in two clinically relevant intra-abdominal sepsis models: (1) CLP-induced polymicrobial peritonitis; and (2) intra-abdominal infection of a human strain of Escherichia coli. We will also use an LPS-induced peritonitis model to determine the mechanisms underlying the beneficial effects of FRC-based therapy and the impact of TLR9 on individual FRC subset therapies. Our study will advance understanding of the diversity and biology of FRC subsets as well as the regulation of TLR9 in these distinct subsets, which will discover new strategies to modify selective FRC subsets to improve efficacy of FRC-based therapy for sepsis and other immune dysregulation diseases.


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 = $383,297 )
2024	2024	FEINSTEIN INSTITUTES FOR MEDICAL RESEARCH, THE	350 COMMUNITY DR	MANHASSET	NY	11030	NASSAU	USA	Allergy and Infectious Diseases Research	000	7	2/12/2024	NON-COMPETING CONTINUATION	$383,297
														Subtotal = $383,297

Issue Date FY: 2023 ( Subtotal = $226,915 )
2023	2023	FEINSTEIN INSTITUTES FOR MEDICAL RESEARCH, THE	350 COMMUNITY DR	MANHASSET	NY	11030	NASSAU	USA	Allergy and Infectious Diseases Research	003	6	12/21/2022	NON-COMPETING CONTINUATION	$434,478
2023	2022	FEINSTEIN INSTITUTES FOR MEDICAL RESEARCH, THE	350 COMMUNITY DR	MANHASSET	NY	11030	NASSAU	USA	Allergy and Infectious Diseases Research	000	5	10/27/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$193,270
2023	2022	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Allergy and Infectious Diseases Research	001	4	10/28/2022	NON-COMPETING CONTINUATION	-$180,000
2023	2022	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Allergy and Infectious Diseases Research	005	4	5/15/2023	NON-COMPETING CONTINUATION	-$210,237
2023	2022	FEINSTEIN INSTITUTES FOR MEDICAL RESEARCH, THE	350 COMMUNITY DR	MANHASSET	NY	11030	NASSAU	USA	Allergy and Infectious Diseases Research	002	5	11/3/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2023	2021	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Allergy and Infectious Diseases Research	004	3	5/15/2023	NON-COMPETING CONTINUATION	-$10,596
														Subtotal = $226,915

Issue Date FY: 2022 ( Subtotal = $390,237 )
2022	2022	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Allergy and Infectious Diseases Research	000	4	1/20/2022	NON-COMPETING CONTINUATION	$390,237
														Subtotal = $390,237

Issue Date FY: 2021 ( Subtotal = $383,914 )
2021	2021	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Allergy and Infectious Diseases Research	002	3	2/18/2021	NON-COMPETING CONTINUATION	$376,771
2021	2020	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	1	12/16/2020	NEW	-$252,561
2021	2020	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Allergy and Infectious Diseases Research	004	2	3/5/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$28,220
2021	2020	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Allergy and Infectious Diseases Research	001	2	12/16/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$259,704
2021	2020	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	003	1	3/5/2021	NEW	-$28,220
														Subtotal = $383,914

Issue Date FY: 2020 ( Subtotal = $405,956 )
2020	2020	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	1	2/24/2020	NEW	$405,956
														Subtotal = $405,956

Grand Total All Awards = $1,790,319

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Role of Toll-like Receptor 9 in Fibroblastic Reticular Cell-based Therapy for Intra-abdominal Sepsis

Award Number: R01AI152044

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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