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Systematic Analysis of Morphogenesis, Commensalism, and Virulence in a Leading Human Fungal Pathogen

Award Number: R01AI127375
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: 08/01/2017
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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Systematic Analysis of Morphogenesis, Commensalism, and Virulence in a Leading Human Fungal Pathogen - SUMMARY/ABSTRACT Fungal pathogens pose a devastating threat to human health, infecting billions of people worldwide and causing more than 1.5 million deaths each year. Candida albicans is one of the most pervasive fungal pathogens, killing almost 40% of people suffering from bloodstream infections. Treating these infections is extremely difficult, as fungi are closely related to humans and there are very few drugs that kill the fungus without host toxicity. With the emergence of drug resistance, the development of new therapeutic strategies is now crucial. To address this important clinical need and identify new antifungal drug targets, it is critical to uncover mechanisms that enable C. albicans to cause life-threatening human disease. We are one of the first academic labs to obtain a powerful functional genomics resource that we are uniquely positioned to expand to allow us to test the function of almost every gene in the C. albicans genome. This resource includes a collection of conditional expression strains that covers ~40% of the genome where one allele of a target gene is deleted in the diploid pathogen, and expression of the remaining wild-type allele is governed by the tetracycline-repressible promoter. During the prior funding period we: developed a pipeline to expand the resource to genome scale, optimized a functional genomics platform for massively parallel analysis of fungal virulence traits using next generation sequencing with pooled assays to quantify the relative proportion of each strain, which are uniquely marked with molecular barcodes; optimized high-resolution image analysis of cellular morphology and structures; and developed assays for identifying genes important for commensalism, virulence, and interaction with host immune cells. Our efficient high-throughput analyses established the power of systematic genetic analysis to uncover new biological insights that could not have been predicted based on current paradigms and enabled focused, hypothesis-driven dissection of key mechanisms governing host- pathogen interactions. Our studies will provide the first global analysis of C. albicans morphogenesis, commensalism, and virulence, and will reveal fundamental biological mechanisms that could not be predicted without a systematic genetic approach. Our studies will: 1) complete the collection of tetracycline-repressible conditional expression strains to cover non-essential genes, since genes required for pathogen viability in vitro provide little insight into host adaptation or virulence; 2) identify novel regulators of key virulence traits such as morphogenesis; and 3) identify determinants of C. albicans host adaptation and virulence on a genome scale. Our comprehensive strain resources and compendium of phenotypic profiles will be made available to the community, advancing the field with a publicly accessible database and interpretive machine learning model to maximize insight. This work will provide the most comprehensive functional genomics resource for any fungal pathogen and will reveal genes governing host adaptation, revealing new strategies to cripple fungal pathogens.


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: 2025 ( Subtotal = $611,446 )
2025	2025	THE GOVERNING COUNCIL OF THE UNIVERSITY OF TORONTO	27 KING'S COLLEGE CIR	TORONTO	ON			CAN	Allergy and Infectious Diseases Research	000	8	8/15/2025	NON-COMPETING CONTINUATION	$611,446
														Subtotal = $611,446

Issue Date FY: 2024 ( Subtotal = $615,726 )
2024	2024	THE GOVERNING COUNCIL OF THE UNIVERSITY OF TORONTO	27 KING'S COLLEGE CIR	TORONTO	ON			CAN	Allergy and Infectious Diseases Research	002	7	7/29/2024	NON-COMPETING CONTINUATION	$615,726
2024	2022	THE GOVERNING COUNCIL OF THE UNIVERSITY OF TORONTO	27 KING'S COLLEGE CIR	TORONTO	ON			CAN	Allergy and Infectious Diseases Research	001	5	2/6/2024	COMPETING CONTINUATION	$196
2024	2020	THE GOVERNING COUNCIL OF THE UNIVERSITY OF TORONTO	27 KING'S COLLEGE CIR	TORONTO	ON			CAN	Allergy and Infectious Diseases Research	000	4	2/6/2024	NON-COMPETING CONTINUATION	-$196
														Subtotal = $615,726

Issue Date FY: 2023 ( Subtotal = $614,985 )
2023	2023	GOVERNING COUNCIL OF THE UNIVERSITY OF TORONTO	27 KING'S COLLEGE CIR	TORONTO	ON			CAN	Allergy and Infectious Diseases Research	000	6	8/3/2023	NON-COMPETING CONTINUATION	$614,985
														Subtotal = $614,985

Issue Date FY: 2022 ( Subtotal = $603,000 )
2022	2022	GOVERNING COUNCIL OF THE UNIVERSITY OF TORONTO	27 KING'S COLLEGE CIR	TORONTO	ON			CAN	Allergy and Infectious Diseases Research	000	5	9/23/2022	COMPETING CONTINUATION	$603,000
														Subtotal = $603,000

Issue Date FY: 2020 ( Subtotal = $545,004 )
2020	2020	GOVERNING COUNCIL OF THE UNIVERSITY OF TORONTO	27 KING'S COLLEGE CIR	TORONTO	ON	M5S 1A1		CAN	Allergy and Infectious Diseases Research	000	4	7/13/2020	NON-COMPETING CONTINUATION	$545,004
														Subtotal = $545,004

Issue Date FY: 2019 ( Subtotal = $545,099 )
2019	2019	GOVERNING COUNCIL OF THE UNIVERSITY OF TORONTO	27 KING'S COLLEGE CIR	TORONTO	ON	M5S 1A1		CAN	Allergy and Infectious Diseases Research	000	3	7/30/2019	NON-COMPETING CONTINUATION	$545,099
														Subtotal = $545,099

Issue Date FY: 2018 ( Subtotal = $570,554 )
2018	2018	GOVERNING COUNCIL OF THE UNIVERSITY OF TORONTO	27 KING'S COLLEGE CIR	TORONTO	ON	M5S 1A1		CAN	Allergy and Infectious Diseases Research	000	2	7/26/2018	NON-COMPETING CONTINUATION	$570,554
														Subtotal = $570,554

Issue Date FY: 2017 ( Subtotal = $591,721 )
2017	2017	UNIVERSITY OF TORONTO	27 KING'S COLLEGE CIR	TORONTO	ON	M5S 1A1		CAN	Allergy and Infectious Diseases Research	000	1	7/31/2017	NEW	$591,721
														Subtotal = $591,721

Grand Total All Awards = $4,697,535

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Systematic Analysis of Morphogenesis, Commensalism, and Virulence in a Leading Human Fungal Pathogen

Award Number: R01AI127375

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: 08/01/2017

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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