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Complex haploinsufficiency based genetic analysis of C. albicans pathogenesis

Award Number: R01AI133409
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: 12/01/2017
PERIOD OF PERFORMANCE END DATE: 11/30/2023

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Complex haploinsufficiency based genetic analysis of C. albicans pathogenesis - PROJECT SUMMARY Candida albicans is an important opportunistic pathogen for people living with HIV/AIDS and primarily causes mucosal diseases such as oropharyngeal candidiasis (OPC) and esophageal candidiasis (EC). In the era of antiretroviral therapy (ART), C. albicans remains the most common fungal pathogen affecting those with HIV/AIDS and OPC is one of the most common infections in HIV patients with mild-to-moderate immunosuppression (CD4 counts 200-500). The pathogenesis of OPC can be separated into two stages: 1) C. albicans adhesion/biofilm formation on the mucosal surface and 2) hyphae-mediated invasion of the epithelium and submucosal stroma with concomitant inflammation and tissue damage. Thus, OPC pathogenesis is dependent on three of the most important mediators of C. albicans virulence: adhesion, biofilm formation, and filamentation. Although each of these factors has been studied using specific C. albicans mutants, no systematic large-scale genetic analysis of OPC pathogenesis has been undertaken. The goal of this application is to define and characterize the transcriptional networks that underlay the ability of C. albicans to cause oral disease. Recently, we have pioneered the use of complex haploinsufficiency (CHI)-based genetic interaction analysis to understand the function of complex genetic networks. Here, we propose to use CHI analysis to test the hypothesis that Cbk1 represents a master regulator of transcriptional processes critical for OPC pathogenesis (Aim 1). In addition to this intra-pathway analysis, we will perform the first large-scale genetic screens for, and CHI analyses of, TF networks required for murine oral candidiasis (Aim 2) and in vivo filamentation (Aim 3). The screen in Aim 3 will utilize our novel intra-vital imaging assay to quantitatively differentiate between yeast and filamentous cells in the sub-epithelial stroma of mice. This screen will not only be the first in vivo C. albicans filamentation screen but also will allow us to distinguish TFs required for the invasion stage of OPC from TFs required for the adhesion/biofilm formation stage.


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: 2024 ( Subtotal = -$14 )
2024	2022	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Allergy and Infectious Diseases Research	000	5	7/18/2024	NON-COMPETING CONTINUATION	-$14
														Subtotal = -$14

Issue Date FY: 2022 ( Subtotal = $415,075 )
2022	2022	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Allergy and Infectious Diseases Research	000	5	11/3/2021	NON-COMPETING CONTINUATION	$415,075
														Subtotal = $415,075

Issue Date FY: 2021 ( Subtotal = $414,829 )
2021	2021	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Allergy and Infectious Diseases Research	000	4	11/10/2020	NON-COMPETING CONTINUATION	$414,829
														Subtotal = $414,829

Issue Date FY: 2020 ( Subtotal = $540,362 )
2020	2020	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Allergy and Infectious Diseases Research	000	3	11/27/2019	NON-COMPETING CONTINUATION	$540,362
														Subtotal = $540,362

Issue Date FY: 2019 ( Subtotal = $571,858 )
2019	2019	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Allergy and Infectious Diseases Research	000	2	11/29/2018	NON-COMPETING CONTINUATION	$571,858
														Subtotal = $571,858

Issue Date FY: 2018 ( Subtotal = $517,953 )
2018	2018	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Allergy and Infectious Diseases Research	000	1	12/1/2017	NEW	$517,953
														Subtotal = $517,953

Grand Total All Awards = $2,460,063

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Complex haploinsufficiency based genetic analysis of C. albicans pathogenesis

Award Number: R01AI133409

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: 12/01/2017

PERIOD OF PERFORMANCE END DATE: 11/30/2023

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