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Mechanisms for Human TLR8 induced pregnancy loss in a mouse model of SLE

Award Number: R21AI156019
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: 06/18/2021
PERIOD OF PERFORMANCE END DATE: 05/31/2024

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Mechanisms for Human TLR8 induced pregnancy loss in a mouse model of SLE - Systemic lupus erythematosus (SLE) is a multisystem, autoimmune disease that causes a significant decrease in quality of life and early mortality. Genetic studies have identified activation of the innate immune system, with excess production of Type I interferons as a major causative pathway. RNA-sensing Toll-like receptors are crucial protective receptors of the innate immune system but are also implicated in autoimmunity because they can recognize nucleic acids released from damaged cells and within nucleic acid containing immune complexes. Functional polymorphisms of the endosomal RNA-recognizing innate receptors TLR7 and TLR8 predispose to SLE and excess mouse TLR7 and human TLR8 accelerate lupus in mouse models. Human TLR8 differs in its function from TLR7 because it recognizes different ligands and is expressed on different immune cell subsets. TLR8 is not an RNA sensor in mice because of a 5 amino acid deletion that attenuates its RNA-binding site. We therefore bred a human TLR8 BAC transgene (huTLR8) into mice in which a mild lupus phenotype is conferred by the susceptibility locus Sle1. Expression of the transgene is physiologically regulated such that huTLR8 is expressed at high levels in myeloid DCs and monocytes but at 50-100-fold lower levels in lymphocytes. We found that huTLR8 induces an anti- phospholipid like syndrome in Sle1 mice that leads to spontaneous placental inflammation, fetal resorptions and late-term pregnancy loss in up to 60% of female dams. In this proposal we will test the mechanism for huTLR8 mediated pregnancy loss by addressing the role of huTLR8 as a sensor of RNA in placental trophoblasts and immune cells. In Aim 1 we will examine the role of autoantibodies in placental injury in mice with or without huTLR8 expression and determine whether huTLR8 expression in B cells results in the production of autoantibodies with enhanced pathogenicity. In Aim 2 we will determine the timing and characteristics of placental injury, the contribution of huTLR8 in maternal vs. fetal cells to injury and whether placental trophoblasts activated by anti-phospholipid antibodies release huTLR8 ligands that enhance local inflammation. In Aim 3 we will determine whether myeloid cells from huTLR8tg mice are intrinsically more pro-inflammatory than those of their wild-type counterparts and therefore amplify the effector response to antibody mediated placental injury. These experiments should allow us to distinguish the role of huTLR8 in maternal cells, trophoblasts and immune cell subsets in the induction of placental damage that leads to pregnancy loss. Our studies will inform us whether specific huTLR8 antagonists or antagonists of huTLR8 ligands should be tested for their ability to prevent or treat placental injury.


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 = $0 )
2025	2022	THE FEINSTEIN INSTITUTES FOR MEDICAL RESEARCH	350 COMMUNITY DR	MANHASSET	NY	11030	NASSAU	USA	Allergy and Infectious Diseases Research	000	2	1/23/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $254,354 )
2022	2022	FEINSTEIN INSTITUTES FOR MEDICAL RESEARCH, THE	350 COMMUNITY DR	MANHASSET	NY	11030	NASSAU	USA	Allergy and Infectious Diseases Research	000	2	5/11/2022	NON-COMPETING CONTINUATION	$254,354
														Subtotal = $254,354

Issue Date FY: 2021 ( Subtotal = $229,354 )
2021	2021	FEINSTEIN INSTITUTES FOR MEDICAL RESEARCH, THE	350 COMMUNITY DR	MANHASSET	NY	11030	NASSAU	USA	Allergy and Infectious Diseases Research	000	1	6/17/2021	NEW	$229,354
														Subtotal = $229,354

Grand Total All Awards = $483,708

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Mechanisms for Human TLR8 induced pregnancy loss in a mouse model of SLE

Award Number: R21AI156019

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: 06/18/2021

PERIOD OF PERFORMANCE END DATE: 05/31/2024

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