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Immunity against fungal infections

Award Number: R01AI153522
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: 01/15/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Immunity against fungal infections - PROJECT SUMMARY Despite the global rise in fungal infections, including those by endemic sp ., there is no licensed fungal vaccine available. This is mainly due to poor understanding of mechanisms of vaccine immunity, and lack of a functional phenotypic marker associated with vaccine efficacy. Opportunistic fungal infections, including those caused by dimorphic fungi, Histoplasma, Coccidiodes and Blastomyces, are rising at an alarming rate in such at-risk individuals. A major limitation in the development of tailored fungal vaccines for the at-risk population is poor understanding of requisite elements of CD8+ T cell responses to mediate vaccine-immunity. Recent advances in the understanding of immune correlates against fungal infections has helped in advancing vaccinology in parallel. T-cell derived IL-17A, IFNγ, GM-CSF, IL-22, and TNFα are primarily involved in protection against fungi. Identification of potential targets on host cells can provide novel efficacious vaccine platforms, including for immunocompromised. We have established a mouse model of CD4+ T cell lymphopenia, where CD8+ T cells can be stimulated to produce protective cytokines IL-17A (Tc17) and IFNγ (Tc1) to execute a sterilizing immunity against lethal pulmonary fungal infection. We have shown that vaccine-elicited antifungal CD8+ T cells persisted as long-term functional memory. In this proposal, we present seminal findings: 1. GM-CSF+ Tc17 cells bolster vaccine-immunity without pathology; 2. Anti-fungal CD8+ T cells preferentially express O-glycosylated Sialophorin; and 3. Sialophorin is required for differentiation and expansion of CD8+ T cells. Therefore, our central hypotheses are that (1) Sialophorin acts as a co-stimulator for CD8+ T cell responses, (2) retention of Sialophorin is essential for memory CD8+ T-cell homeostasis and recall responses, (3) Sialophorin signaling potentiates cross-presentation to augment CD8+ T cell responses. Our specific aims are to: 1. Determine and dissect the role of Sialophorin for CD8+ T-cell fungal vaccine responses. We will decipher and delineate the cell- intrinsic role of Sialophorin for vaccine-induced Tc17 and Tc1 cell responses using adoptive transfer and bone- marrow chimera experiments, and using TCRα KO, congenic and crosses of Sialophorin KO mice. 2. Elucidate the role of Sialophorin for memory T cell homeostasis and recall responses during fungal pneumonia. We will define the role of Sialophorin for vaccine-induced memory CD8+ T-cell homeostasis, recall responses, and vaccine-immunity. We will use bone marrow chimera, adoptive transfers, CRISPR-Cas9 gene-editing, in vivo stimulation, and E-selectin blocking to delineate the role of Sialophorin on memory CD8+ T-cell responses. 3. Dissect the role of Sialophorin on dendritic cells for CD8+ T-cell fungal vaccine responses. We will identify the role of CD43 on antigen-presenting cells for activation of CD8+ T cells following vaccination . Our findings will uncover the functional role of Sialophorin for fungal CD8+ T-cell responses and immunity to guide in the design of novel vaccine platforms and test the efficacy of vaccines.


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 ILLINOIS	506 S WRIGHT ST	URBANA	IL	61801	CHAMPAIGN	USA	Allergy and Infectious Diseases Research	000	5	10/7/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $440,103 )
2025	2025	UNIVERSITY OF ILLINOIS	506 S WRIGHT ST	URBANA	IL	61801	CHAMPAIGN	USA	Allergy and Infectious Diseases Research	000	5	1/13/2025	NON-COMPETING CONTINUATION	$440,103
														Subtotal = $440,103

Issue Date FY: 2024 ( Subtotal = $453,714 )
2024	2024	UNIVERSITY OF ILLINOIS	506 S WRIGHT ST	URBANA	IL	61801	CHAMPAIGN	USA	Allergy and Infectious Diseases Research	001	4	5/21/2024	NON-COMPETING CONTINUATION	$45,371
2024	2024	UNIVERSITY OF ILLINOIS	506 S WRIGHT ST	URBANA	IL	61801	CHAMPAIGN	USA	Allergy and Infectious Diseases Research	000	4	12/1/2023	NON-COMPETING CONTINUATION	$408,343
														Subtotal = $453,714

Issue Date FY: 2023 ( Subtotal = $453,714 )
2023	2023	UNIVERSITY OF ILLINOIS	506 S WRIGHT ST	URBANA	IL	61801	CHAMPAIGN	USA	Allergy and Infectious Diseases Research	000	3	12/15/2022	NON-COMPETING CONTINUATION	$453,714
														Subtotal = $453,714

Issue Date FY: 2022 ( Subtotal = $455,863 )
2022	2022	UNIVERSITY OF ILLINOIS	352 HENRY ADMINISTRATION BLDG	URBANA	IL	61801	CHAMPAIGN	USA	Allergy and Infectious Diseases Research	000	2	12/7/2021	NON-COMPETING CONTINUATION	$455,863
														Subtotal = $455,863

Issue Date FY: 2021 ( Subtotal = $466,116 )
2021	2021	UNIVERSITY OF ILLINOIS	364 HENRY ADMINISTRATION BLDG	URBANA	IL	61801	CHAMPAIGN	USA	Allergy and Infectious Diseases Research	000	1	1/15/2021	NEW	$466,116
														Subtotal = $466,116

Grand Total All Awards = $2,269,510

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Immunity against fungal infections

Award Number: R01AI153522

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: 01/15/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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