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Genetic approaches to probe virulence and drug resistance in Candida auris

Award Number: R21AI178931
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: 11/24/2023
PERIOD OF PERFORMANCE END DATE: 10/31/2025

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Genetic approaches to probe virulence and drug resistance in Candida auris - Abstract Fungal infections have risen in frequency and severity over the last several decades, as the number of patients with increased susceptibility have also risen. Today, these infections are a serious clinical problem, and new species emerge to add to these challenges. Candida auris is one such species, having been first identified in a superficial infection in 2009. Subsequently, C. auris has been identified in four geographic foci on three continents, and spread throughout the world. A primary concern with C. auris is its resistance to antifungal drugs, with nearly all isolate resistance to azoles, and many to the polyenes and echinocandins. The rapidity with which this has happened is startling and has far outpaced research advances in this species. One advantage is that C. auris is a haploid species and this opens the door to powerful forward genetic approaches. To take advantage of this, we propose here to develop an insertional mutant library with thousands of mutants, which we will validate using two highly relevant genetic screens. To generate these mutants, we will use the bacterium Agrobacterium tumifaciens, which transfers an integrating vector (T-DNA) to a promiscuous range of host cells, including C. auris. We have adapted tools with which we propose to isolate ~5,000 mutants and array them in 96 well plates, then sequence each to identify the insertion site. Our primary goal is to develop this resource and make it available to the community. In doing so, we will validate this library with two screens that are particularly relevant to C. auris. In the first, we have developed an animal infection assay using the nematode model Caenorhabditis elegans that allows us to identify avirulent mutants. In other Candida species, this assay tracks murine virulence closely, and we have adapted it for C. auris. Our host strain, chosen for its virulence and transformation efficiency, is also highly fluconazole resistant and we will screen for insertions that increase susceptibility. At the conclusion of this project we expect to have (a) built a large mutant library of random insertional mutants which we will make available to the community, (b) generated two large datasets on virulence and drug resistance, (c) primed future mechanistic studies that will make substantial progress in improving the outcomes of patients, and (d) determined the applicability of the nematode model to a wide array of C. auris isolates..


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 = $191,279 )
2025	2025	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Allergy and Infectious Diseases Research	001	2	11/12/2024	NON-COMPETING CONTINUATION	$5,738
2025	2025	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Allergy and Infectious Diseases Research	000	2	11/6/2024	NON-COMPETING CONTINUATION	$185,541
														Subtotal = $191,279

Issue Date FY: 2024 ( Subtotal = $230,279 )
2024	2024	UNIVERSITY OF HEALTH SCIENCE CENTER	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Allergy and Infectious Diseases Research	000	1	11/24/2023	NEW	$207,251
2024	2024	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Allergy and Infectious Diseases Research	001	1	5/31/2024	NEW	$23,028
														Subtotal = $230,279

Grand Total All Awards = $421,558

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Genetic approaches to probe virulence and drug resistance in Candida auris

Award Number: R21AI178931

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: 11/24/2023

PERIOD OF PERFORMANCE END DATE: 10/31/2025

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