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Flagellar Motor Biogenesis in Polarly-Flagellated Bacterial Pathogens

Award Number: R01AI065539
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: 02/15/2006
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Flagellar Motor Biogenesis in Polarly-Flagellated Bacterial Pathogens - Project Summary Bacterial flagella function as two machines: a type III secretion system (T3SS) that secretes most of the extracytoplasmic components of the flagellum and a reversible rotary motor that promotes swimming motility required for many bacteria pathogens to infect hosts to promote disease. Peritrichous flagellates such as E. coli and Salmonella species have served as models to understand various processes for flagellar biogenesis and function. However, many significant bacterial pathogens, including Campylobacter jejuni, Vibrio cholerae, Helicobacter pylori, and Pseudomonas aeruginosa are polar flagellates that produce flagellar motors in limited numbers only at polar regions. These polar flagellar motors are characteristically more structurally complex than their peritrichous counterparts. By using C. jejuni as a model system to understand polar flagellar motor biogenesis and function in bacterial pathogens, we found that the increased structural complexity in polar flagellar motors is due to both unique structures and conserved substructures formed by a different collection of proteins. Importantly, these structural alterations enhance mechanical functions of both the C. jejuni flagellar T3SS and the rotary motor. We discovered that the C. jejuni flagellar T3SS has an enhanced ability to secrete flagellar proteins and assemble flagella even when lacking components usually essential for other T3SSs to function. Furthermore, we discovered the structural alterations in the C. jejuni flagellum contribute to a common feature of polar flagellar motors of many pathogens – the generation of higher torque for high motility velocities in a range of physiological viscosities. We also identified C. jejuni flagellar T3SS and motor components that promote its ability to multitask in cellular activities beyond motility. The major goal of this proposal is to analyze how these specific structures and substructures form and adapt the C. jejuni flagellum with enhanced mechanics to augment its function as a secretory machine and rotary motor. In Aim 1, we will analyze the composition and arrangement of proteins forming the C. jejuni flagellar T3SS and determine how fueling mechanics are altered relative to other T3SSs to allow it to secrete proteins and assemble flagella even without usually essential parts. In Aim 2, we will analyze how novel disk structures form and how the rotor component of the motor has expanded to affect the number and placement of stator units required to generate high torque for flagellar rotation and a high velocity of motility. In Aim 3, we will explore two C. jejuni proteins that we hypothesize function as a unique molecular brake or clutch to control output of a high-torque polar flagellar motor and regulate optimal motility velocities in different viscosities. Completion of these aims will provide new insights into many bacterial pathogens for: 1) how T3SSs can alter and ensure fueling to enhance secretory activity and organelle assembly; 2) how polar flagellar motors are naturally endowed to generate high torque for propulsion; 3) how novel substructures of polar flagellar motors form; and 4) how motility velocities facilitated by high-torque polar flagellar motors can be modulated in environments with different viscosities.


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 = $0 )
2024	2023	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Allergy and Infectious Diseases Research	001	18	7/23/2024	SUPPLEMENT FOR EXPANSION	$0
2024	2023	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Allergy and Infectious Diseases Research	000	18	7/23/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $657,398 )
2023	2023	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Allergy and Infectious Diseases Research	002	18	6/23/2023	SUPPLEMENT FOR EXPANSION	$75,263
2023	2023	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Allergy and Infectious Diseases Research	000	17	12/14/2022	SUPPLEMENT FOR EXPANSION	$45,271
2023	2023	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Allergy and Infectious Diseases Research	001	18	6/22/2023	NON-COMPETING CONTINUATION	$536,864
														Subtotal = $657,398

Issue Date FY: 2022 ( Subtotal = $536,864 )
2022	2022	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Allergy and Infectious Diseases Research	004	17	6/23/2022	NON-COMPETING CONTINUATION	$536,864
2022	2021	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Allergy and Infectious Diseases Research	003	16	1/10/2022	COMPETING CONTINUATION	$345,943
2022	2020	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Allergy and Infectious Diseases Research	001	15	12/7/2021	NON-COMPETING CONTINUATION	-$345,943
2022	2010	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Trans-NIH Recovery Act Research Support	002	5	1/10/2022	SUPPLEMENT FOR EXPANSION	-$345,943
2022	2010	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Trans-NIH Recovery Act Research Support	000	5	12/7/2021	SUPPLEMENT FOR EXPANSION	$345,943
														Subtotal = $536,864

Issue Date FY: 2021 ( Subtotal = $552,587 )
2021	2021	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Allergy and Infectious Diseases Research	000	16	4/21/2021	COMPETING CONTINUATION	$552,587
														Subtotal = $552,587

Issue Date FY: 2020 ( Subtotal = $473,580 )
2020	2020	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Allergy and Infectious Diseases Research	000	15	6/9/2020	NON-COMPETING CONTINUATION	$473,580
														Subtotal = $473,580

Issue Date FY: 2019 ( Subtotal = $473,580 )
2019	2019	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Allergy and Infectious Diseases Research	000	14	6/14/2019	NON-COMPETING CONTINUATION	$473,580
														Subtotal = $473,580

Issue Date FY: 2018 ( Subtotal = $739,568 )
2018	2018	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Allergy and Infectious Diseases Research	001	13	6/22/2018	NON-COMPETING CONTINUATION	$473,580
2018	2016	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Allergy and Infectious Diseases Research	000	11	11/20/2017	COMPETING CONTINUATION	$265,988
														Subtotal = $739,568

Issue Date FY: 2017 ( Subtotal = $207,691 )
2017	2017	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Allergy and Infectious Diseases Research	002	12	7/1/2017	NON-COMPETING CONTINUATION	$473,679
2017	2016	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Allergy and Infectious Diseases Research	001	11	12/27/2016	COMPETING CONTINUATION	$0
2017	2015	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Allergy and Infectious Diseases Research	000	10	12/27/2016	NON-COMPETING CONTINUATION	-$265,988
														Subtotal = $207,691

Issue Date FY: 2016 ( Subtotal = $488,729 )
2016	2016	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75390	DALLAS	USA	Allergy and Infectious Diseases Research	000	11	4/30/2016	COMPETING CONTINUATION	$488,729
														Subtotal = $488,729

Issue Date FY: 2015 ( Subtotal = $397,500 )
2015	2015	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75390	DALLAS	USA	Allergy and Infectious Diseases Research	000	10	6/26/2015	NON-COMPETING CONTINUATION	$397,500
														Subtotal = $397,500

Issue Date FY: 2014 ( Subtotal = $397,500 )
2014	2014	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75390	DALLAS	USA	Allergy and Infectious Diseases Research	000	9	6/18/2014	NON-COMPETING CONTINUATION	$397,500
														Subtotal = $397,500

Issue Date FY: 2013 ( Subtotal = $373,650 )
2013	2013	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75390	DALLAS	USA	Allergy and Infectious Diseases Research	000	8	7/1/2013	NON-COMPETING CONTINUATION	$373,650
														Subtotal = $373,650

Issue Date FY: 2012 ( Subtotal = $456,629 )
2012	2012	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75390	DALLAS	USA	Allergy and Infectious Diseases Research	001	7	6/28/2012	NON-COMPETING CONTINUATION	$430,548
2012	2012	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75390	DALLAS	USA	Allergy and Infectious Diseases Research	000	6	2/3/2012	SUPPLEMENT FOR EXPANSION	$26,081
														Subtotal = $456,629

Issue Date FY: 2011 ( Subtotal = $396,250 )
2011	2011	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75390	DALLAS	USA	Allergy and Infectious Diseases Research	001	6	6/28/2011	COMPETING CONTINUATION	$396,250
2011	2010	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75235	DALLAS	USA	Allergy and Infectious Diseases Research	000	5	6/28/2011	NON-COMPETING CONTINUATION	$0
														Subtotal = $396,250

Issue Date FY: 2010 ( Subtotal = $388,412 )
2010	2010	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75390	DALLAS	USA	Allergy and Infectious Diseases Research	001	5	1/14/2010	NON-COMPETING CONTINUATION	$333,124
2010	2010	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75390	DALLAS	USA	Trans-NIH Recovery Act Research Support	002	5	9/20/2010	SUPPLEMENT FOR EXPANSION	$55,288
2010	2009	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75235	DALLAS	USA	Allergy and Infectious Diseases Research	000	4	12/17/2009	NON-COMPETING CONTINUATION	$0
														Subtotal = $388,412

Issue Date FY: 2009 ( Subtotal = $490,203 )
2009	2009	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75390	DALLAS	USA	Allergy and Infectious Diseases Research	002	4	9/28/2009	NON-COMPETING CONTINUATION	$153,714
2009	2009	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75390	DALLAS	USA	Allergy and Infectious Diseases Research	001	4	6/23/2009	NON-COMPETING CONTINUATION	$33,649
2009	2009	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75390	DALLAS	USA	Allergy and Infectious Diseases Research	000	4	2/2/2009	NON-COMPETING CONTINUATION	$302,840
														Subtotal = $490,203

Issue Date FY: 2008 ( Subtotal = $336,489 )
2008	2008	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75235	DALLAS	USA	Allergy and Infectious Diseases Research	000	3	1/24/2008	NON-COMPETING CONTINUATION	$336,489
														Subtotal = $336,489

Grand Total All Awards = $8,087,886

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Flagellar Motor Biogenesis in Polarly-Flagellated Bacterial Pathogens

Award Number: R01AI065539

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: 02/15/2006

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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