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Molecular pathogenesis of Blastomycosis

Award Number: R01AI035681
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: 01/01/1995
PERIOD OF PERFORMANCE END DATE: 12/31/2021

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Molecular pathogenesis of Blastomycosis - DESCRIPTION (provided by applicant): This R01 renewal dissects the role and action of a fungal product that inactivates innate immunity. Even in healthy hosts, the systemic mycoses produce immune disturbances and progressive disease. This finding implies that the fungi disable immune responses, but little is known about the molecular bases. This knowledge gap limits development of new therapies. We've developed Blastomyces dermatitidis and murine infection into an excellent model to unravel such enigmas. We have reported that CCR2+ inflammatory monocytes promote fungal vaccine immunity, yet host mediators retard their influx into the lung upon vaccination at this site. We focus here on a yeast product that undercuts these cells and innate immunity, facilitating progressive infection. We propose that dipeptidyl peptitidase IVA (DPP4A) blunts innate lung immunity. DPP4A is an oligopepti- dase that cleaves protein after a 2-position proline at the N-terminus. Mammalian DPP4 (CD26) inactivates cytokine/chemokine, tempering immunity. While such activity is unreported in microbes, DPP4 is conserved in bacteria, parasites and fungi, and DPP4 inhibitors are being used to treat diabetes, heart disease & Alzheimer's. We have preliminary data that fungal DPP4A blunts innate immunity and that silencing or deleting DPP4A attenuates B. dermatitidis in a GM-CSF & CCR2 dependent manner. We hypothesize that DPP4A inactivates GM-CSF & CCL2 (recruits CCR2+ cells) and digests the lung extracellular matrix that displays chemokine, and that these events blunt influx/function of CCR2+ monocytes, macrophages and neutrophils. We aim to: 1. Define DPP4A action on GM-CSF and its effect on macrophages and neutrophils. Fungal DPP4A will be studied for action on GM-CSF and inactivation of the cytokine. Mice infected with DPP4A-plus or -minus yeast will be used to study whether & how DPP4A-clipped GM-CSF disables leukocytes and assess drug inhibitor or cytokine therapy. 2. Delineate DPP4A action on CCL2 and the impact on CCR2+ inflammatory monocytes. Fungal DPP4A will be studied for inactivation of C-C chemokine, and the ensuing impact on CCR2+ monocyte recruitment and function to define the mechanics that underpin failed influx and function of the cells during innate resistance to fungal infection. 3. Analyze DPP4A action on cell matrix and the impact on CCR2+ cell migration. Fungal DPP4A will be studied for action on collagen I & the glycosaminoglycan heparin, ECM elements that display chemokine to leukocytes. CCR2+ GFP reporter mice/cells will be used to assay how DPP4A action on ECM alters cell migration in vitro and in vivo. Our work tackles a prevailing knowledge gap: the basis for disease progression during systemic mycosis. It breaks new ground by exposing yeast mimicry of a host tactic that tempers innate immunity by regulating 2 key mediators: GM-CSF & CCR2+ cells. The actions can be targeted with drug inhibitors or immune therapy.


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: 2023 ( Subtotal = -$2,140 )
2023	2019	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	000	24	11/10/2022	NON-COMPETING CONTINUATION	-$2,140
														Subtotal = -$2,140

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2019	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	000	24	12/3/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $494,393 )
2019	2019	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	000	24	12/19/2018	NON-COMPETING CONTINUATION	$494,393
														Subtotal = $494,393

Issue Date FY: 2018 ( Subtotal = $543,035 )
2018	2018	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	000	23	12/13/2017	NON-COMPETING CONTINUATION	$543,035
														Subtotal = $543,035

Issue Date FY: 2017 ( Subtotal = $582,368 )
2017	2017	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	000	22	12/9/2016	NON-COMPETING CONTINUATION	$582,368
														Subtotal = $582,368

Issue Date FY: 2016 ( Subtotal = $614,018 )
2016	2016	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	000	21	11/24/2015	NON-COMPETING CONTINUATION	$576,980
2016	2016	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	001	21	5/24/2016	SUPPLEMENT FOR EXPANSION	$37,038
														Subtotal = $614,018

Issue Date FY: 2015 ( Subtotal = $494,393 )
2015	2015	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	000	20	12/24/2014	COMPETING CONTINUATION	$494,393
														Subtotal = $494,393

Issue Date FY: 2004 ( Subtotal = $359,071 )
2004	2004	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	750 UNIVERSITY AVENUE	MADISON	WI	53706	DANE	USA	Microbiology and Infectious Diseases Research	000	10	11/24/2003	COMPETING CONTINUATION	$359,071
														Subtotal = $359,071

Issue Date FY: 2003 ( Subtotal = $304,134 )
2003	2003	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	750 UNIVERSITY AVENUE	MADISON	WI	53706	DANE	USA	Microbiology and Infectious Diseases Research	000	9		NON-COMPETING CONTINUATION	$304,134
														Subtotal = $304,134

Issue Date FY: 2002 ( Subtotal = $295,452 )
2002	2002	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	750 UNIVERSITY AVENUE	MADISON	WI	53706	DANE	USA	Microbiology and Infectious Diseases Research	000	8	12/21/2001	NON-COMPETING CONTINUATION	$295,452
														Subtotal = $295,452

Issue Date FY: 2001 ( Subtotal = $281,602 )
2001	2001	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	750 UNIVERSITY AVENUE	MADISON	WI	53706	DANE	USA	Microbiology and Infectious Diseases Research	000	7	1/12/2001	NON-COMPETING CONTINUATION	$281,602
														Subtotal = $281,602

Issue Date FY: 2000 ( Subtotal = $268,940 )
2000	2000	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 NORTH PARK STREET	MADISON	WI	53715	DANE	USA	Microbiology and Infectious Diseases Research	000	6	1/27/2000	NON-COMPETING CONTINUATION	$268,940
														Subtotal = $268,940

Issue Date FY: 1999 ( Subtotal = $184,643 )
1999	1999	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 NORTH PARK STREET	MADISON	WI	53715	DANE	USA	Microbiology and Infectious Diseases Research	000	5	11/20/1998	COMPETING CONTINUATION	$184,643
														Subtotal = $184,643

Issue Date FY: 1998 ( Subtotal = $148,070 )
1998	1998	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 NORTH PARK STREET	MADISON	WI	53715	DANE	USA	Microbiology and Infectious Diseases Research	000	4	12/8/1997	NON-COMPETING CONTINUATION	$148,070
														Subtotal = $148,070

Grand Total All Awards = $4,567,979

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Molecular pathogenesis of Blastomycosis

Award Number: R01AI035681

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: 01/01/1995

PERIOD OF PERFORMANCE END DATE: 12/31/2021

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