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How Listeria senses and responds to different host environments

Award Number: R01AI027655
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: 06/15/1988
PERIOD OF PERFORMANCE END DATE: 04/30/2029

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How Listeria senses and responds to different host environments - Project Summary/Abstract Listeria monocytogenes is facultative intracellular food-borne pathogen that provides an extremely amenable model for basic studies on host-pathogen interactions. During past funding periods, genetic screens led to the discovery that L. monocytogenes upregulates the expression and synthesis of glutathione synthase (GshF) during infection and that glutathione is an allosteric activator of the major virulence transcription factor, PrfA. Mutants lacking GshF fail to fully activate PrfA and consequently form small plaques in tissue culture cells and are approximately 200-fold less virulent in mice. However, virulence of gshF mutants was fully rescued by mutations that locked PrfA in its active configuration, referred to as PrfA* mutants. During the current funding period, we designed a genetic screen with the goal of identifying additional transposon mutants that formed small plaques in tissue culture cells, but were restored to a wild- type phenotype when the mutation was transduced into a PrfA* background. In addition to finding the expected gshF mutants, we found mutants in gloA, which encodes glyoxalase A, the primary component necessary for the glutathione-dependent detoxification of the reactive electrophilic species (RES), methylglyoxal (MGO), which is a toxic side-product of glycolysis in both bacteria and host cells. Mutants lacking gloA were approximately 1000-fold less virulent in mice and like gshF mutants, were restored to full virulence in a PrfA* background, suggesting that MGO is an in vivo cue leading to GshF synthesis and activation of PrfA. MGO reacts with both amino acids and guanine causing DNA damage and mutations. In preliminary data, we confirmed that gloA mutants had a 10-fold increase in their mutation rate when exposed to MGO in vitro, but strikingly, the mutation rate of gloA mutants was approximately 100-1000-fold higher in the spleens and livers of infected mice, suggesting that the in vivo environment encountered by L. monocytogenes is enriched in MGO and consequently highly mutagenic. Double gloA/prfA* mutants were not only fully virulent, they did not suffer increased mutation rates in vivo, suggesting that in the absence of GloA, activated PrfA protects against DNA damage by a yet-to-be discovered mechanism. Based on the literature, we hypothesized that DNA damage caused by MGO was repaired by UvrAB-dependent nucleotide excision repair pathway. Astonishingly, a uvrAB mutation rescued the virulence defect of gloA mutants, but unlike PrfA* mutants, gloA/uvrAB mutants still had an extremely high mutation rate. These data suggest that gloA mutants suffer severe DNA damage in vivo and are killed by the resultant DNA repair process. In this renewal, we propose to characterize the in vivo environment that causes such a high rate of mutations in gloA mutants, determine how PrfA mediates GloA-independent protections from MGO, and lastly explore the hypothesis that gloA mutants are killed by their own DNA repair process.


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 = $481,500 )
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Allergy and Infectious Diseases Research	001	37	5/2/2025	NON-COMPETING CONTINUATION	$481,500
2025	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Allergy and Infectious Diseases Research	000	35	2/11/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $481,500

Issue Date FY: 2024 ( Subtotal = $481,500 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Allergy and Infectious Diseases Research	000	36	4/9/2024	COMPETING CONTINUATION	$433,350
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Allergy and Infectious Diseases Research	001	36	9/4/2024	COMPETING CONTINUATION	$48,150
														Subtotal = $481,500

Issue Date FY: 2023 ( Subtotal = $366,018 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Allergy and Infectious Diseases Research	000	35	4/27/2023	NON-COMPETING CONTINUATION	$366,018
														Subtotal = $366,018

Issue Date FY: 2022 ( Subtotal = $367,279 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Allergy and Infectious Diseases Research	000	34	5/24/2022	NON-COMPETING CONTINUATION	$367,279
														Subtotal = $367,279

Issue Date FY: 2021 ( Subtotal = $368,480 )
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 220	BERKELEY	CA	94710	ALAMEDA	USA	Allergy and Infectious Diseases Research	000	33	4/23/2021	NON-COMPETING CONTINUATION	$368,480
														Subtotal = $368,480

Issue Date FY: 2020 ( Subtotal = $369,624 )
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 220	BERKELEY	CA	94710	ALAMEDA	USA	Allergy and Infectious Diseases Research	001	32	5/15/2020	NON-COMPETING CONTINUATION	$369,624
2020	2018	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 220	BERKELEY	CA	94710	ALAMEDA	USA	Allergy and Infectious Diseases Research	000	30	2/4/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $369,624

Issue Date FY: 2019 ( Subtotal = $370,713 )
2019	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 220	BERKELEY	CA	94710	ALAMEDA	USA	Allergy and Infectious Diseases Research	001	31	5/28/2019	COMPETING CONTINUATION	$370,713
2019	2018	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 220	BERKELEY	CA	94710	ALAMEDA	USA	Allergy and Infectious Diseases Research	000	30	5/22/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $370,713

Issue Date FY: 2018 ( Subtotal = $383,848 )
2018	2018	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	2150 SHATTUCK AVE RM 313	BERKELEY	CA	94704	ALAMEDA	USA	Allergy and Infectious Diseases Research	000	30	2/21/2018	NON-COMPETING CONTINUATION	$383,848
														Subtotal = $383,848

Issue Date FY: 2017 ( Subtotal = $383,848 )
2017	2017	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	2150 SHATTUCK AVE RM 313	BERKELEY	CA	94704	ALAMEDA	USA	Allergy and Infectious Diseases Research	000	29	2/22/2017	NON-COMPETING CONTINUATION	$383,848
														Subtotal = $383,848

Issue Date FY: 2016 ( Subtotal = $383,848 )
2016	2016	UNIVERSITY OF CALIFORNIA, REGENTS	481 UNIVERSITY HALL	BERKELEY	CA	94704	ALAMEDA	USA	Allergy and Infectious Diseases Research	000	28	2/10/2016	NON-COMPETING CONTINUATION	$383,848
														Subtotal = $383,848

Issue Date FY: 2015 ( Subtotal = $383,457 )
2015	2015	UNIVERSITY OF CALIFORNIA, REGENTS	481 UNIVERSITY HALL	BERKELEY	CA	94704	ALAMEDA	USA	Allergy and Infectious Diseases Research	000	27	2/13/2015	NON-COMPETING CONTINUATION	$383,457
														Subtotal = $383,457

Issue Date FY: 2014 ( Subtotal = $382,674 )
2014	2014	UNIVERSITY OF CALIFORNIA, REGENTS	481 UNIVERSITY HALL	BERKELEY	CA	94704	ALAMEDA	USA	Allergy and Infectious Diseases Research	001	26	3/1/2014	COMPETING CONTINUATION	$382,674
2014	2012	UNIVERSITY OF CALIFORNIA, REGENTS	481 UNIVERSITY HALL	BERKELEY	CA	94704	ALAMEDA	USA	Allergy and Infectious Diseases Research	000	25	2/28/2014	NON-COMPETING CONTINUATION	$0
														Subtotal = $382,674

Issue Date FY: 2013 ( Subtotal = $0 )
2013	2012	UNIVERSITY OF CALIFORNIA, REGENTS	481 UNIVERSITY HALL	BERKELEY	CA	94704	ALAMEDA	USA	Allergy and Infectious Diseases Research	000	25	8/27/2013	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2012 ( Subtotal = $436,008 )
2012	2012	UNIVERSITY OF CALIFORNIA, REGENTS	481 UNIVERSITY HALL	BERKELEY	CA	94704	ALAMEDA	USA	Allergy and Infectious Diseases Research	000	25	5/7/2012	NON-COMPETING CONTINUATION	$436,008
														Subtotal = $436,008

Issue Date FY: 2011 ( Subtotal = $427,490 )
2011	2011	UNIVERSITY OF CALIFORNIA, REGENTS	481 UNIVERSITY HALL	BERKELEY	CA	94704	ALAMEDA	USA	Allergy and Infectious Diseases Research	000	24	6/8/2011	NON-COMPETING CONTINUATION	$427,490
														Subtotal = $427,490

Issue Date FY: 2010 ( Subtotal = $431,791 )
2010	2010	UNIVERSITY OF CALIFORNIA, REGENTS	481 UNIVERSITY HALL	BERKELEY	CA	94704	ALAMEDA	USA	Allergy and Infectious Diseases Research	000	23	6/1/2010	NON-COMPETING CONTINUATION	$431,791
														Subtotal = $431,791

Issue Date FY: 2009 ( Subtotal = $423,451 )
2009	2009	UNIVERSITY OF CALIFORNIA, REGENTS	481 UNIVERSITY HALL	BERKELEY	CA	94704	ALAMEDA	USA	Allergy and Infectious Diseases Research	000	22	6/12/2009	NON-COMPETING CONTINUATION	$423,451
														Subtotal = $423,451

Issue Date FY: 2008 ( Subtotal = $411,117 )
2008	2008	UNIVERSITY OF CALIFORNIA, REGENTS	481 UNIVERSITY HALL	BERKELEY	CA	94704	ALAMEDA	USA	Allergy and Infectious Diseases Research	000	21	1/23/2008	COMPETING CONTINUATION	$411,117
														Subtotal = $411,117

Issue Date FY: 2007 ( Subtotal = $353,188 )
2007	2007	UNIVERSITY OF CALIFORNIA, REGENTS	481 UNIVERSITY HALL	BERKELEY	CA	94704	ALAMEDA	USA	Allergy and Infectious Diseases Research	000	20	5/25/2007	NON-COMPETING CONTINUATION	$353,188
														Subtotal = $353,188

Issue Date FY: 2006 ( Subtotal = $364,387 )
2006	2006	UNIVERSITY OF CALIFORNIA, REGENTS	481 UNIVERSITY HALL	BERKELEY	CA	94704	ALAMEDA	USA	Allergy and Infectious Diseases Research	000	19	6/7/2006	NON-COMPETING CONTINUATION	$364,387
														Subtotal = $364,387

Issue Date FY: 2005 ( Subtotal = $373,764 )
2005	2005	UNIVERSITY OF CALIFORNIA, REGENTS	481 UNIVERSITY HALL	BERKELEY	CA	94704	ALAMEDA	USA	Microbiology and Infectious Diseases Research	000	18	5/20/2005	NON-COMPETING CONTINUATION	$373,764
														Subtotal = $373,764

Issue Date FY: 2004 ( Subtotal = $374,317 )
2004	2004	UNIVERSITY OF CALIFORNIA, REGENTS	481 UNIVERSITY HALL	BERKELEY	CA	94704	ALAMEDA	USA	Microbiology and Infectious Diseases Research	000	17	4/26/2004	NON-COMPETING CONTINUATION	$374,317
														Subtotal = $374,317

Issue Date FY: 2003 ( Subtotal = $374,721 ) (Continued on the next page)
Grand Total All Awards = $10,105,455

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How Listeria senses and responds to different host environments

Award Number: R01AI027655

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: 06/15/1988

PERIOD OF PERFORMANCE END DATE: 04/30/2029

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