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Impact of RNAi and unisexual reproduction on Cryptococcus evolution, drug resistance, and pathogenesis

Award Number: R01AI039115
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: 05/01/1997
PERIOD OF PERFORMANCE END DATE: 04/30/2026

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Impact of RNAi and unisexual reproduction on Cryptococcus evolution, drug resistance, and pathogenesis - Abstract Cryptococcus neoformans and Cryptococcus gattii are globally distributed fungal pathogens that cause >220,000 life-threatening infections each year in immunocompromised and immunocompetent patients, leading to >180,000 deaths, >15% of all HIV/AIDS-related deaths, and >70% mortality in low-income countries. In studies supported by this award, the scope and functions of a- and - sexual reproduction on the evolution and pathogenesis of Cryptococcus were defined. Sexual reproduction governs population structure, enabling genetic exchange and promoting clonality, and results in the production of infectious spores. During this sustained funding period, significant advances were achieved characterizing the mechanisms and impact of sexual reproduction on these pathogens and their virulence: 1) discovery of roles of RNAi in controlling transposon movement and transgene silencing during mitosis and meiosis and characterization of the consequences of RNAi loss on genome structure and stability; 2) studies on generation and affect of aneuploidy on drug resistance, pathogenicity, and development, and engineering of a ploidy sensor to analyze genetic factors contributing to endoreplication during unisexual reproduction; 3) delineation of isolates causing the C. gattii outbreak in the Pacific Northwest and closely aligned hypermutator lineages, and 4) demonstration that unisexual reproduction generates genetic diversity de novo and enhances competitiveness for nutrients and mating partners. In the current proposal, we hypothesize 1) RNAi has been retained and lost in unique isolates and species, influencing genomic stability and driving evolution of drug resistance and pathogenesis, and 2) unisexual reproduction is a major force in evolution, global distribution, and impact of Cryptococcus pathogens. Our studies reveal unique facets of RNAi and sexual reproduction enabling us to propose new aims to test these hypotheses. Aim 1 focuses on RNAi in genome stability, elucidating components and mechanisms by which RNAi controls transposons and silences repetitive DNA sequences, and studying the short-term and long- term consequences of RNAi loss on drug resistance and pathogenesis in C. neoformans hypermutator clinical isolates and the RNAi-deficient C. deuterogattii outbreak species. Aim 2 will elucidate unisexual reproduction pathways and mechanisms involving 1) unisexual reproduction occurring in mixed mating-type populations and in strains with rearranged genomes as a model of speciation, 2) genetic and environmental factors that promote unisexual reproduction of global serotype A lineages and analysis of infectious spores in animal models, and 3) overcoming the Hill-Robertson effect to enable linkage of beneficial mutations and separation of detrimental and beneficial mutations to enhance fitness and pathogenesis. These studies will advance the understanding of how genome stability and unisexual reproduction drive pathogen evolution and population structure, development of drug resistance, and infectious spore production and virulence, with direct implications for infectious disease evolution, treatment, and prevention.


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 = $642,695 )
2025	2025	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Allergy and Infectious Diseases Research	000	28	7/16/2025	NON-COMPETING CONTINUATION	$642,695
														Subtotal = $642,695

Issue Date FY: 2024 ( Subtotal = $642,695 )
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Allergy and Infectious Diseases Research	000	27	4/30/2024	NON-COMPETING CONTINUATION	$642,695
														Subtotal = $642,695

Issue Date FY: 2023 ( Subtotal = $642,695 )
2023	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Allergy and Infectious Diseases Research	000	26	4/17/2023	NON-COMPETING CONTINUATION	$642,695
														Subtotal = $642,695

Issue Date FY: 2022 ( Subtotal = $679,110 )
2022	2022	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	001	25	4/11/2022	NON-COMPETING CONTINUATION	$642,748
2022	2021	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Allergy and Infectious Diseases Research	000	24	11/11/2021	COMPETING CONTINUATION	$36,362
														Subtotal = $679,110

Issue Date FY: 2021 ( Subtotal = $642,774 )
2021	2021	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	000	24	2/23/2021	COMPETING CONTINUATION	$642,774
														Subtotal = $642,774

Issue Date FY: 2010 ( Subtotal = $367,781 )
2010	2010	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	000	13	3/30/2010	NON-COMPETING CONTINUATION	$367,781
														Subtotal = $367,781

Issue Date FY: 2009 ( Subtotal = $371,495 )
2009	2009	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	000	12	3/19/2009	NON-COMPETING CONTINUATION	$371,495
														Subtotal = $371,495

Issue Date FY: 2008 ( Subtotal = $371,495 )
2008	2008	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	000	11	3/31/2008	NON-COMPETING CONTINUATION	$371,495
														Subtotal = $371,495

Issue Date FY: 2007 ( Subtotal = $378,488 )
2007	2007	DUKE UNIVERSITY	BOX 104135	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	000	10	4/12/2007	NON-COMPETING CONTINUATION	$378,488
														Subtotal = $378,488

Issue Date FY: 2006 ( Subtotal = $388,542 )
2006	2006	DUKE UNIVERSITY	POST OFFICE BOX 40005	DURHAM	NC	27706	DURHAM	USA	Allergy and Infectious Diseases Research	000	9	5/16/2006	COMPETING CONTINUATION	$388,542
														Subtotal = $388,542

Issue Date FY: 2005 ( Subtotal = $308,000 )
2005	2005	DUKE UNIVERSITY	POST OFFICE BOX 40005	DURHAM	NC	27706	DURHAM	USA	Microbiology and Infectious Diseases Research	000	8	1/20/2005	NON-COMPETING CONTINUATION	$308,000
														Subtotal = $308,000

Issue Date FY: 2004 ( Subtotal = $308,000 )
2004	2004	DUKE UNIVERSITY	POST OFFICE BOX 40005	DURHAM	NC	27706	DURHAM	USA	Microbiology and Infectious Diseases Research	000	7	1/16/2004	NON-COMPETING CONTINUATION	$308,000
														Subtotal = $308,000

Issue Date FY: 2003 ( Subtotal = $372,540 )
2003	2003	DUKE UNIVERSITY	POST OFFICE BOX 40005	DURHAM	NC	27706	DURHAM	USA	Microbiology and Infectious Diseases Research	000	6		NON-COMPETING CONTINUATION	$372,540
														Subtotal = $372,540

Issue Date FY: 2002 ( Subtotal = $368,986 )
2002	2002	DUKE UNIVERSITY	POST OFFICE BOX 40005	DURHAM	NC	27706	DURHAM	USA	Microbiology and Infectious Diseases Research	000	5	2/7/2002	NON-COMPETING CONTINUATION	$368,986
														Subtotal = $368,986

Issue Date FY: 2001 ( Subtotal = $338,509 )
2001	2001	DUKE UNIVERSITY	POST OFFICE BOX 40005	DURHAM	NC	27706	DURHAM	USA	Microbiology and Infectious Diseases Research	000	4	12/25/2000	COMPETING CONTINUATION	$308,000
2001	2001	DUKE UNIVERSITY	POST OFFICE BOX 40005	DURHAM	NC	27706	DURHAM	USA	Microbiology and Infectious Diseases Research	001	4	8/6/2001	SUPPLEMENT FOR EXPANSION	$30,509
														Subtotal = $338,509

Issue Date FY: 1999 ( Subtotal = $237,308 )
1999	1999	Duke University	OFFICE OF SPONSORED PROGRAMS	DURHAM	NC	27705	DURHAM	USA	Microbiology and Infectious Diseases Research	000	3	3/4/1999	NON-COMPETING CONTINUATION	$237,308
														Subtotal = $237,308

Issue Date FY: 1998 ( Subtotal = $230,398 )
1998	1998	Duke University	OFFICE OF SPONSORED PROGRAMS	DURHAM	NC	27705	DURHAM	USA	Microbiology and Infectious Diseases Research	000	2	3/2/1998	NON-COMPETING CONTINUATION	$230,398
														Subtotal = $230,398

Grand Total All Awards = $7,291,511

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Impact of RNAi and unisexual reproduction on Cryptococcus evolution, drug resistance, and pathogenesis

Award Number: R01AI039115

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: 05/01/1997

PERIOD OF PERFORMANCE END DATE: 04/30/2026

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