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Structure, function, and evolution of the Cryptococcus MAT locus

Award Number: R01AI050113
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: 06/15/2002
PERIOD OF PERFORMANCE END DATE: 05/31/2025

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View Award Description

Structure, function, and evolution of the Cryptococcus MAT locus - The Cryptococcus genus spans a diverse group of fungal species from environmental saprophytes to common human pathogens. In fact, the Cryptococcus neoformans and Cryptococcus gattii species complexes cause >220,000 life-threatening infections each year in both 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, we defined the structure, function, and evolution of a large genomic region in Cryptococcus species that has co-evolved with pathogenesis, the fungal mating type (MAT) locus. The Cryptococcus MAT locus is a large, complex gene cluster that controls sexual reproduction, infectious spore production, and pathogenicity. We elucidated how these sex- and virulence-determining genes evolved from a nonpathogenic ancestral state. Our studies reveal bipolar/inbreeding mating systems are shared by all of the pathogenic species, and evolved from an ancestral outbreeding/tetrapolar system. Similar transitions occurred in other fungal pathogens of plants and animals, suggesting convergent evolution in concert with host adaptation. In the prior award period, we made major advances characterizing the association of fungal MAT locus evolution with virulence: 1) we sequenced the genomes/MAT loci of 24 species spanning all Cryptococcus pathogens and aligned nonpathogens; 2) we defined Cryptococcus centromeres and implicated inter- centromeric recombination in mating type and genome transitions; 3) we demonstrated the MAT-encoded RPL22 genes have essential, specialized functions. In the current proposal, we hypothesize that mating-type transitions drove pathogen emergence resulting in a gene complex linked to virulence and infectious spore production. Our recent studies reveal unique aspects of MAT biology allowing us to propose new aims to test this hypothesis. Aim 1 focuses on MAT locus structure and evolution, utilizing RNA-Seq and sRNA analysis to define mRNA, asRNA, lncRNA, and siRNA produced by MAT during asexual/sexual reproduction, engineering translocations to model tetrapolar-bipolar transition with CRISPR, and conducting Hi-C analysis to examine nuclear organization of MAT and centromeres. Aim 2 will elucidate MAT functions linked to virulence and development involving 1) MAT-encoded lncRNA ASM1, 2) diverged, specialized, essential ribosomal genes we hypothesize operate as an ancestral imprinting system ensuring sexual reproduction fidelity, and 3) modeling in mice of the role of a newly recognized host factor controlling immune protection against cryptococcal infections: host GM-CSF signaling. Auto-antibodies against the GM-CSF cytokine are a major risk factor for lineage-specific Cryptococcus infections, suggesting unique host features might play a role in evolution of infections due to human pathogenic species. These studies will advance understanding of dynamic microbial genome evolution, associating specific gene clusters to virulence and revealing unique host susceptibility determinants, 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: 2024 ( Subtotal = $479,352 )
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Allergy and Infectious Diseases Research	000	20	6/12/2024	NON-COMPETING CONTINUATION	$479,352
														Subtotal = $479,352

Issue Date FY: 2023 ( Subtotal = $488,951 )
2023	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Allergy and Infectious Diseases Research	000	19	5/4/2023	NON-COMPETING CONTINUATION	$488,951
														Subtotal = $488,951

Issue Date FY: 2022 ( Subtotal = $498,319 )
2022	2022	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	000	18	5/18/2022	NON-COMPETING CONTINUATION	$498,319
														Subtotal = $498,319

Issue Date FY: 2021 ( Subtotal = $507,459 )
2021	2021	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	000	17	6/10/2021	NON-COMPETING CONTINUATION	$507,459
														Subtotal = $507,459

Issue Date FY: 2020 ( Subtotal = $517,431 )
2020	2020	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	001	16	5/26/2020	COMPETING CONTINUATION	$517,436
2020	2019	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	000	15	3/18/2020	NON-COMPETING CONTINUATION	-$5
														Subtotal = $517,431

Issue Date FY: 2019 ( Subtotal = $425,840 )
2019	2019	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	000	15	11/21/2018	NON-COMPETING CONTINUATION	$425,840
														Subtotal = $425,840

Issue Date FY: 2018 ( Subtotal = $425,840 )
2018	2018	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	000	14	11/17/2017	NON-COMPETING CONTINUATION	$425,840
														Subtotal = $425,840

Issue Date FY: 2017 ( Subtotal = $431,040 )
2017	2017	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	000	13	11/15/2016	NON-COMPETING CONTINUATION	$431,040
														Subtotal = $431,040

Issue Date FY: 2016 ( Subtotal = $435,049 )
2016	2016	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	000	12	10/27/2015	NON-COMPETING CONTINUATION	$435,049
														Subtotal = $435,049

Issue Date FY: 2015 ( Subtotal = $431,283 )
2015	2015	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	000	11	11/3/2014	COMPETING CONTINUATION	$431,283
														Subtotal = $431,283

Issue Date FY: 2013 ( Subtotal = $359,305 )
2013	2013	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	000	10	11/15/2012	NON-COMPETING CONTINUATION	$344,016
2013	2013	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	001	10	5/28/2013	NON-COMPETING CONTINUATION	$15,289
														Subtotal = $359,305

Issue Date FY: 2012 ( Subtotal = $382,239 )
2012	2012	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	001	9	5/25/2012	NON-COMPETING CONTINUATION	$38,223
2012	2012	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	000	9	11/15/2011	NON-COMPETING CONTINUATION	$344,016
														Subtotal = $382,239

Issue Date FY: 2011 ( Subtotal = $382,239 )
2011	2011	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	001	8	6/2/2011	NON-COMPETING CONTINUATION	$34,749
2011	2011	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	000	8	11/2/2010	NON-COMPETING CONTINUATION	$347,490
														Subtotal = $382,239

Issue Date FY: 2010 ( Subtotal = $386,100 )
2010	2010	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	000	7	11/18/2009	NON-COMPETING CONTINUATION	$351,000
2010	2010	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	001	7	5/11/2010	NON-COMPETING CONTINUATION	$35,100
														Subtotal = $386,100

Issue Date FY: 2009 ( Subtotal = $390,000 )
2009	2009	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	001	6	11/18/2008	COMPETING CONTINUATION	$390,000
2009	2006	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	000	5	11/18/2008	NON-COMPETING CONTINUATION	$0
														Subtotal = $390,000

Issue Date FY: 2006 ( Subtotal = $375,953 )
2006	2006	DUKE UNIVERSITY	POST OFFICE BOX 40005	DURHAM	NC	27706	DURHAM	USA	Allergy and Infectious Diseases Research	000	5	4/26/2006	NON-COMPETING CONTINUATION	$375,953
														Subtotal = $375,953

Issue Date FY: 2005 ( Subtotal = $385,000 )
2005	2005	DUKE UNIVERSITY	POST OFFICE BOX 40005	DURHAM	NC	27706	DURHAM	USA	Microbiology and Infectious Diseases Research	000	4	4/22/2005	NON-COMPETING CONTINUATION	$385,000
														Subtotal = $385,000

Issue Date FY: 2004 ( Subtotal = $385,000 )
2004	2004	DUKE UNIVERSITY	POST OFFICE BOX 40005	DURHAM	NC	27706	DURHAM	USA	Microbiology and Infectious Diseases Research	000	3	5/17/2004	NON-COMPETING CONTINUATION	$385,000
														Subtotal = $385,000

Issue Date FY: 2003 ( Subtotal = $385,000 )
2003	2003	DUKE UNIVERSITY	POST OFFICE BOX 40005	DURHAM	NC	27706	DURHAM	USA	Microbiology and Infectious Diseases Research	000	2		NON-COMPETING CONTINUATION	$385,000
														Subtotal = $385,000

Issue Date FY: 2002 ( Subtotal = $380,680 )
2002	2002	DUKE UNIVERSITY	POST OFFICE BOX 40005	DURHAM	NC	27706	DURHAM	USA	Microbiology and Infectious Diseases Research	000	1	6/4/2002	NEW	$380,680
														Subtotal = $380,680

Grand Total All Awards = $8,452,080

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Structure, function, and evolution of the Cryptococcus MAT locus

Award Number: R01AI050113

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: 06/15/2002

PERIOD OF PERFORMANCE END DATE: 05/31/2025

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