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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)

Group Awards By Issue Date FY or Funding FY:

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The impact of fungal pathogens on human health is devastating. They infect billions of people worldwide, and kill more than 1.5 million each year. The most vulnerable are people with reduced immune function, such as those with HIV or those undergoing immune suppressing treatments for cancer or organ transplants. One of the most pervasive fungal pathogens is Candida albicans, which kills 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 resource that will allow us to test the function of almost every gene in the C. albicans genome. This resource includes a collection of double barcoded heterozygous mutants covering ~90% of the genome, and a collection of strains covering ~40% of the genome where the expression of the remaining wild-type allele of a gene is governed by the tetracycline-repressible promoter. This resource provides an unprecedented opportunity to identify genes that control key virulence traits such as morphogenesis. It also enables the identification of determinants of commensalism and virulence, and to further elucidate the molecular mechanisms involved. We have optimized a functional genomics platform for massively parallel analysis of fungal virulence traits using next generation sequencing to quantify the relative proportion of each barcoded strain in pooled assays. We have also optimized high- resolution image analysis of cellular morphology and structures, and assays for identifying genes important for commensalism, virulence, and interaction with host immune cells. Our studies will provide the first global analysis of C. albicans morphogenesis, commensalism, and virulence. Our studies will: 1) develop a computational platform to predict C. albicans essential genes, and expand the collection of tetracycline-repressible conditional expression strains to cover most non-essential genes, since genes required for pathogen viability in vitro provide little insight into mechanisms of 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. This work will provide an expanded functional genomics resource to advance the field, and will leverage this resource to elucidate the genes and genetic networks governing morphogenesis and virulence. This will reveal new strategies to cripple fungal pathogens, and drug targets to improve clinical outcome.


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 = $0 )
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 = $0

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 = $3,470,363

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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)

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