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Targeting professional APCs using Fasciola hepatica FABP to suppresses inflammation

Award Number: SC1AI155439
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: 08/01/2020
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Targeting professional APCs using Fasciola hepatica FABP to suppresses inflammation - ABSTRACT The growing use of `helminth-therapy' in the last decade to prevent or ameliorate inflammatory diseases is a promising and novel approach. Fasciola hepatica, one of the most globally prevalent parasitic helminths of domestic animals, is particularly adept at controlling the immune response of its host. At early stages of infection the parasite induces a dominant Th2/T-regulatory-type immune response coincidental with suppression of Th1 responses. Recent studies have demonstrated that F. hepatica infection attenuates the clinical signs of murine experimental autoimmune encephalomyelitis [1] and prevents the development of Type-1 diabetes in a non-obese diabetic mouse model [2]. However, the immunoregulation associated to F. hepatica lacks specificity and results in a compromised immune system unable to respond effectively to bystander infections [3, 4]. A better alternative for drug development would be to identify parasite molecules with immune-modulatory capacity and to characterize their precise mechanism of action. Fatty acid binding proteins (FABPs) are proteins that play an important role in the parasite's lipid metabolism and have been recently categorized as anti-oxidant molecules [5]. We have demonstrated that a recombinant 14.5kDa protein belonging to the fatty acid binding protein (Fh15) is able to significantly suppress the cytokine storm when is applied therapeutically 1h after exposure to lethal doses of LPS, which suggest that Fh15 could act as a TLR4-antagonist. Moreover, we also found that Fh15-treatment increased accumulation of large and small peritoneal MΦs (LPMs and SPMs) into the peritoneal cavity (PerC) compared to the of septic mice [6]. Moreover, we also demonstrated by proximity ligation assay (PLA) that the native F. hepatica FABP variant (Fh12) binds to the human CD14-coreceptor [7], which has been associated to the activation-signaling cascade of various TLRs [8-11]. Because TLR4 is directly involved in the inflammatory responses during sepsis and ulcerative colitis (UC), this role for Fh15 could have a significant impact on human health [12, 13]. Our central hypothesis is that the suppression of pro-inflammatory cytokines induced by injection (i.p.) with Fh15 is enough to prevent the high mortality in mice exposed to a lethal dose of LPS and to prevent or ameliorate the intestinal inflammation in a DSS-induced mouse model of UC. Both therapeutic effects will be directly associated with the production of M2-type MΦs in the PerC of animals and the induction of tolerogenic properties of DCs, which will be critically dependent on CD14. The proposed research is conceptually innovative because it is the first time that a protein of the F. hepatica FABP family, specifically Fh15, is investigated as an anti-inflammatory molecule and there are no reported works on MΦs and DCs in relation to Fh15 exposure in vivo or in vitro. Understanding how Fh15 modulate and interact with MΦs and DCs at early stages of innate immunity could contribute to the development of anti-inflammatory drugs against sepsis and other inflammatory diseases. The specific aims are: 1) Determine the capacity of Fh15 to suppress the pathologic effects of septic shock and ulcerous colitis (UC) in the mouse model and, 2) Determine whether Fh15 induces the tolerogenic properties of DCs and identify mechanism- underlying immunosuppression caused by Fh15. The proposed studies significantly will advance anti- inflammatory drug development based on helminth-antigen derived therapy by providing a well-defined F. hepatica molecule as drug target mechanism of action.


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: 2026 ( Subtotal = -$766 )
2026	2023	UNIVERSITY OF PUERTO RICO MEDICAL SCIENCES CAMPUS	B622 MAIN BUILDING FLR 6	SAN JUAN	PR	00935	SAN JUAN	USA	Allergy and Infectious Diseases Research	000	4	2/19/2026	NON-COMPETING CONTINUATION	-$766
														Subtotal = -$766

Issue Date FY: 2023 ( Subtotal = $375,000 )
2023	2023	UNIVERSITY OF PUERTO RICO MEDICAL SCIENCES CAMPUS	B622 MAIN BUILDING FLR 6	SAN JUAN	PR	00935	SAN JUAN	USA	Allergy and Infectious Diseases Research	000	4	6/22/2023	NON-COMPETING CONTINUATION	$375,000
														Subtotal = $375,000

Issue Date FY: 2022 ( Subtotal = $371,223 )
2022	2022	UNIVERSITY OF PUERTO RICO MEDICAL SCIENCES CAMPUS	MAIN BLDG FLR 6 B-622	SAN JUAN	PR	00935	SAN JUAN	USA	Allergy and Infectious Diseases Research	000	3	7/22/2022	NON-COMPETING CONTINUATION	$371,223
														Subtotal = $371,223

Issue Date FY: 2021 ( Subtotal = $360,136 )
2021	2021	UNIVERSITY OF PUERTO RICO MEDICAL SCIENCES CAMPUS	MAIN BLDG FLR 6 B-622	SAN JUAN	PR	00935	SAN JUAN	USA	Allergy and Infectious Diseases Research	000	2	7/20/2021	NON-COMPETING CONTINUATION	$360,136
														Subtotal = $360,136

Issue Date FY: 2020 ( Subtotal = $360,250 )
2020	2020	UNIVERSITY OF PUERTO RICO MEDICAL SCIENCES CAMPUS	MAIN BLDG FLR 6 B-622	SAN JUAN	PR	00935	SAN JUAN	USA	Allergy and Infectious Diseases Research	000	1	7/28/2020	NEW	$360,250
														Subtotal = $360,250

Grand Total All Awards = $1,465,843

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Targeting professional APCs using Fasciola hepatica FABP to suppresses inflammation

Award Number: SC1AI155439

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: 08/01/2020

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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