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Evolution of heat tolerance and drug resistance in Cryptococcus

Award Number: DP2AI184725
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: 08/12/2024
PERIOD OF PERFORMANCE END DATE: 07/31/2029

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Evolution of heat tolerance and drug resistance in Cryptococcus - Project Summary Environmental microbes are affected by and evolve to succeed in the changing environments they inhabit. As a result, changes in the environment can select for microbes that are more or less capable of causing human infections. Cryptococcus is a genus of opportunistic fungal pathogens that cause approximately 200,000 deaths in HIV/AIDS individuals. Cryptococcus species grow in an environmental niche before causing “accidental” infections of mammals with no known return to the environment after infection or spread between hosts. Notably, the pathogens within the genus split from the nonpathogens approximately 100 million years ago, concurrent with the development of the ability to grow at human body temperature. In the proposed work, I will use the Cryptococcus genus to explore the genetic basis of two pathogenesis relevant traits that are changing in the environment because of human activities, with an eye towards using Cryptococcus as a model to understand how these changes in environment may alter other environmental fungi. Project 1 will focus on the transition to thermotolerance that occurred in the Cryptococcus genus. Elevated global temperatures as a result of climate change will likely select for environmental microbes that can grow at higher temperatures. I will employ high-throughput genetics approaches (TN-seq) to characterize genome-wide contributions to growth at various temperatures across the entire Cryptococcus genus, including both pathogens and nonpathogens. I will then use allele swap experiments to explore effects of sequence variation, lineage-specific gene content, and transcriptional reprogramming. Project 2 will focus on resistance to azole class drugs. Modern agricultural practices employ large amounts of azole drugs to control fungal plant pathogens. Environmental fungi are also commonly exposed to these drugs and thus are being selected for drug resistance. I will use a diploid complex trait genetics approach (RH-seq) that is based on TN-seq to explore the basis of azole drug resistance in a large (n=387) strain collection of environmental and clinical isolates from Africa. I will again use allele swap experiments to validate drug resistance mutations and test the contribution of epistasis to antifungal drug resistance. This work will reveal fundamental mechanisms underlying adaptation to high temperatures and antifungal drugs. It will also generate mutant libraries across an entire genus and mapping populations for a large number of C. neoformans isolates that can be used in future projects across the community. An expanded understanding of heat tolerance and of drug resistance may aid in the development of novel antifungal agents or more efficient use of the currently available drugs, leading to improved outcomes for treatment of invasive fungal diseases. Finally, a better understanding of how human activities lead to changes in environmental microbes can provide both predictions and potential guidance for intervention.


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 = $443,944 )
2025	2025	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 E CAMPUS RD RM 409	ATHENS	GA	30602	CLARKE	USA	Allergy and Infectious Diseases Research	000	2	7/31/2025	NON-COMPETING CONTINUATION	$443,944
														Subtotal = $443,944

Issue Date FY: 2024 ( Subtotal = $443,944 )
2024	2024	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 E CAMPUS RD RM 409	ATHENS	GA	30602	CLARKE	USA	Allergy and Infectious Diseases Research	000	1	8/12/2024	NEW	$443,944
														Subtotal = $443,944

Grand Total All Awards = $887,888

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Evolution of heat tolerance and drug resistance in Cryptococcus

Award Number: DP2AI184725

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: 08/12/2024

PERIOD OF PERFORMANCE END DATE: 07/31/2029

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