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Bidirectional paracrine signaling in the establishment of invasive aspergillosis

Award Number: R01AI150669
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: 03/01/2021
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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Bidirectional paracrine signaling in the establishment of invasive aspergillosis - ABSTRACT Invasive aspergillosis (IA) caused by Aspergillus fumigatus is characterized by uncontrolled filamentous hyphal growth deep into host tissues and is a fatal disease of immunocompromised patients with mortality rates as high as 90%. This high mortality rate indicates the critical need for improved antifungal therapeutic strategies. We have uncovered a bidirectional lipid signaling system between the fungus and host that mediates invasive hyphal growth and phagocyte activation. Based on strong preliminary data, this communication system consists of structurally similar fungal and host ligands (e.g. oxylipins) that are recognized by specific fungal and host G protein coupled receptors (GPCRs). The fungal and host oxylipins work in opposition to regulate fungal growth and leukocyte functionality. We hypothesize that fungal and host oxylipins are cross-Kingdom molecular analogs that signal through specific GPCR cascades, inducing penetrating hyphal growth and manipulating host defense responses to drive IA progression. Our data not only provide new insight into how eukaryotic pathogens and their hosts communicate with one another directly during disease but also provide a new foundation for experimental approaches to decipher, manipulate, and control this communication system in favor of the host. Accordingly, we will (1) Identify the oxylipins and their transcriptional cascades that regulate invasive branching growth and (2) Characterize the receptors by which fungus and host recognize each other’s oxylipins and the consequences of this recognition. GPCR are particularly propitious targets for therapeutic design (40% of current pharmaceuticals target GPCR). Thus, upon completion of this work, we anticipate that we will have delineated a new fungal-host ligand-receptor communication language amenable to therapeutic intervention to inhibit filamentous invasive growth during human disease.


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 = $0 )
2026	2025	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	000	5	12/16/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $457,852 )
2025	2025	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	000	5	2/13/2025	NON-COMPETING CONTINUATION	$457,852
														Subtotal = $457,852

Issue Date FY: 2024 ( Subtotal = $472,013 )
2024	2024	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	001	4	5/23/2024	NON-COMPETING CONTINUATION	$47,201
2024	2024	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	000	4	2/22/2024	NON-COMPETING CONTINUATION	$424,812
														Subtotal = $472,013

Issue Date FY: 2023 ( Subtotal = $472,013 )
2023	2023	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	000	3	2/15/2023	NON-COMPETING CONTINUATION	$472,013
														Subtotal = $472,013

Issue Date FY: 2022 ( Subtotal = $472,013 )
2022	2022	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	000	2	2/16/2022	NON-COMPETING CONTINUATION	$472,013
														Subtotal = $472,013

Issue Date FY: 2021 ( Subtotal = $838,527 )
2021	2021	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	000	1	2/24/2021	NEW	$496,373
2021	2021	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	001	1	6/28/2021	NEW	$342,154
														Subtotal = $838,527

Grand Total All Awards = $2,712,418

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Bidirectional paracrine signaling in the establishment of invasive aspergillosis

Award Number: R01AI150669

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: 03/01/2021

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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