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PRD-containing Virulence Regulators of Pathogenic Streptococci

Award Number: R01AI047928
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: 09/30/2001
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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PRD-containing Virulence Regulators of Pathogenic Streptococci - Bacterial pathogens must rapidly adapt to limiting nutrients during infection. The phosphoenolpyruvate phosphotransferase system (PTS) is a conserved phosphorelay that couples sugar transport with phosphorylation and serves as a monitor of carbohydrate flow in the bacterial cell. The Group A Streptococcus (GAS) is a significant human-restricted pathogen causing a wide array of acute diseases in different host tissues, resulting in over half a million deaths worldwide each year. Relevant to this renewal, GAS and other pathogenic streptococci depend upon carbohydrate uptake systems for their ability to survive in the host. Mga regulates virulence genes encoding immune evasion factors, adhesins, and sugar utilization operons, and we have established over the previous grant period that Mga is directly phosphorylated by the PTS at conserved histidines within PTS regulatory domains (PRD) that alter Mga-regulated gene expression and virulence in GAS. Paralogs exist in GAS (RofA-like proteins, RALPs) as well as orthologs in other G+ pathogens such as S. pneumoniae (MgaSpn) and B. anthracis (AtxA). Mga, with AtxA, form the paradigms for a family of PRD- Containing Virulence Regulators (PCVRs) in G+ pathogens that that allow sugar availability to be sensed by global virulence regulatory pathways and influence the disease process. Based on our substantial published data, we posit that as GAS encounter changing or limiting sugar sources in the host, the PTS phosphorylates Mga in PRD-1 to block dimerization and inhibit its activity, effectively shutting Mga off. Our molecular dissection of the PTS in GAS has shown that glucose levels significantly alter PTS-mediated Mga phosphorylation and the Mga regulon. However, many questions still remain. The goal of this renewal will be to continue our pioneering studies on Mga as an archetype PCVR, while expanding our scope to other putative PCVRs. In Aim 1, we will delineate how glucose uptake in GAS impacts Mga by defining the PTS and non- PTS components for glucose uptake that influence Mga phosphorylation and activity using state-of-the-art LC-MS/MS approaches to monitor phosphohistidines. In Aim 2, we will determine how non-glucose PTS sugars signal through Mga in GAS using growth in PTS sugars with specific PTS EIIC mutants complemented with Tn-seq to map Mga-specific genetic interactions in different PTS sugars. Aim 3 will focus on whether paralogs and homologs of Mga are functional PCVRs by exploring whether the PTS directly phosphorylates and influences the activity of paralogs in GAS (RofA, RivR), homologs in S. dysgalactiae (DmgB) and S. pneumoniae (MgaSpn). Finally, Aim 4 will investigate the role of PTS regulation on Mga and RALP paralogs in two host environments representing glucose levels known to affect Mga; bloodstream infection (high glucose) using ex vivo and in vivo models, and mucosal colonization (low glucose) using a murine IL17-/- NALT model. Advancing our understanding of PCVRs could lead to novel strategies to treat severe infections caused by these important pathogens.


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: 2026 ( Subtotal = $0 )
2026	2023	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BUILDING	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	000	20	12/18/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $383,905 )
2023	2023	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	000	20	6/29/2023	NON-COMPETING CONTINUATION	$383,905
														Subtotal = $383,905

Issue Date FY: 2022 ( Subtotal = $383,905 )
2022	2022	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	000	19	6/23/2022	NON-COMPETING CONTINUATION	$383,905
														Subtotal = $383,905

Issue Date FY: 2021 ( Subtotal = $383,905 )
2021	2021	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	000	18	7/7/2021	NON-COMPETING CONTINUATION	$383,905
														Subtotal = $383,905

Issue Date FY: 2020 ( Subtotal = $383,905 )
2020	2020	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	000	17	5/25/2020	NON-COMPETING CONTINUATION	$383,905
														Subtotal = $383,905

Issue Date FY: 2019 ( Subtotal = $383,905 )
2019	2019	UNIVERSITY OF MARYLAND	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	000	16	6/26/2019	COMPETING CONTINUATION	$383,905
														Subtotal = $383,905

Issue Date FY: 2018 ( Subtotal = -$476 )
2018	2016	UNIVERSITY OF MARYLAND	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	000	15	5/2/2018	SUPPLEMENT FOR EXPANSION	-$476
														Subtotal = -$476

Issue Date FY: 2016 ( Subtotal = $423,360 )
2016	2016	UNIVERSITY OF MARYLAND	4101 CHESAPEAKE BLDG	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	001	15	6/16/2016	SUPPLEMENT FOR EXPANSION	$57,506
2016	2016	UNIVERSITY OF MARYLAND	4101 CHESAPEAKE BLDG	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	000	15	12/11/2015	EXTENSION WITH OR WITHOUT FUNDS	$365,854
														Subtotal = $423,360

Issue Date FY: 2015 ( Subtotal = $453,298 )
2015	2015	UNIVERSITY OF MARYLAND	4101 CHESAPEAKE BLDG	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	000	14	2/4/2015	NON-COMPETING CONTINUATION	$453,298
														Subtotal = $453,298

Issue Date FY: 2014 ( Subtotal = $444,726 )
2014	2014	UNIVERSITY OF MARYLAND	4101 CHESAPEAKE BLDG	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	001	13	3/13/2014	SUPPLEMENT FOR EXPANSION	$78,786
2014	2014	UNIVERSITY OF MARYLAND	4101 CHESAPEAKE BLDG	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	000	13	1/3/2014	NON-COMPETING CONTINUATION	$329,346
2014	2014	UNIVERSITY OF MARYLAND	4101 CHESAPEAKE BLDG	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	002	13	6/4/2014	NON-COMPETING CONTINUATION	$36,594
														Subtotal = $444,726

Issue Date FY: 2013 ( Subtotal = $356,243 )
2013	2013	UNIVERSITY OF MARYLAND	4101 CHESAPEAKE BLDG	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	000	12	1/10/2013	NON-COMPETING CONTINUATION	$341,083
2013	2013	UNIVERSITY OF MARYLAND	4101 CHESAPEAKE BLDG	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	001	12	5/30/2013	NON-COMPETING CONTINUATION	$15,160
														Subtotal = $356,243

Issue Date FY: 2012 ( Subtotal = $379,020 )
2012	2012	UNIVERSITY OF MARYLAND	4101 CHESAPEAKE BLDG	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	000	11	1/27/2012	COMPETING CONTINUATION	$379,020
														Subtotal = $379,020

Issue Date FY: 2011 ( Subtotal = $0 )
2011	2010	UNIVERSITY OF MARYLAND	4101 CHESAPEAKE BLDG	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	000	10	12/8/2010	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2010 ( Subtotal = $280,078 )
2010	2010	UNIVERSITY OF MARYLAND	4101 CHESAPEAKE BLDG	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	001	10	5/26/2010	NON-COMPETING CONTINUATION	$25,461
2010	2010	UNIVERSITY OF MARYLAND	4101 CHESAPEAKE BLDG	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	000	10	11/23/2009	NON-COMPETING CONTINUATION	$254,617
														Subtotal = $280,078

Issue Date FY: 2009 ( Subtotal = $282,907 )
2009	2009	UNIVERSITY OF MARYLAND	4101 CHESAPEAKE BLDG	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	000	9	11/17/2008	NON-COMPETING CONTINUATION	$254,617
2009	2009	UNIVERSITY OF MARYLAND	4101 CHESAPEAKE BLDG	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	001	9	6/5/2009	NON-COMPETING CONTINUATION	$28,290
														Subtotal = $282,907

Issue Date FY: 2008 ( Subtotal = $282,907 )
2008	2008	UNIVERSITY OF MARYLAND	4101 CHESAPEAKE BLDG	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	000	8	11/19/2007	NON-COMPETING CONTINUATION	$282,907
														Subtotal = $282,907

Issue Date FY: 2007 ( Subtotal = $288,387 )
2007	2007	UNIVERSITY OF MARYLAND	4101 CHESAPEAKE BLDG	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	000	7	12/26/2006	NON-COMPETING CONTINUATION	$288,387
														Subtotal = $288,387

Issue Date FY: 2006 ( Subtotal = $314,000 )
2006	2006	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75235	DALLAS	USA	Allergy and Infectious Diseases Research	000	5	12/14/2005	COMPETING CONTINUATION	$314,000
														Subtotal = $314,000

Issue Date FY: 2004 ( Subtotal = $283,320 )
2004	2004	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75235	DALLAS	USA	Microbiology and Infectious Diseases Research	000	4	6/7/2004	NON-COMPETING CONTINUATION	$283,320
														Subtotal = $283,320

Issue Date FY: 2003 ( Subtotal = $314,427 )
2003	2003	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75235	DALLAS	USA	Indicates awards funded from multiple programs	000	3	5/27/2003	NON-COMPETING CONTINUATION	$314,427
														Subtotal = $314,427

Issue Date FY: 2002 ( Subtotal = $248,991 )
2002	2002	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75235	DALLAS	USA	Microbiology and Infectious Diseases Research	000	2	7/19/2002	NON-COMPETING CONTINUATION	$210,600
2002	2002	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75235	DALLAS	USA	Microbiology and Infectious Diseases Research	001	2	8/30/2002	SUPPLEMENT FOR EXPANSION	$38,391
														Subtotal = $248,991

Issue Date FY: 2001 ( Subtotal = $235,600 ) (Continued on the next page)
Grand Total All Awards = $6,506,313

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PRD-containing Virulence Regulators of Pathogenic Streptococci

Award Number: R01AI047928

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: 09/30/2001

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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