Tuesday, November 4, 2025 11/4/2025

Molecular Mechanisms of Bacterial Toxins Targeting the Actin Cytoskeleton

Award Number: R01GM114666
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2015
PERIOD OF PERFORMANCE END DATE: 07/31/2026

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Molecular Mechanisms of Bacterial Toxins Targeting the Actin Cytoskeleton - With the climate change-related emergence of new pathogens and the reemergence of old, once-controlled pathogens, as well as in light of rapidly developing antibiotic resistance, society is in urgent need of a more thorough understanding of the bacterial pathogenicity and its major mediators – toxins and toxic effector proteins (effectors). The actin cytoskeleton is a common target for numerous bacterial effectors. However, the mechanisms by which many actin-targeting bacterial toxins exhibit their pathogenicity remain poorly understood. The long-term goal of the proposal is to decipher the in-depth molecular and cellular mechanisms of bacterial effectors targeting the actin cytoskeleton to i) enable alternative ways of targeting pathogens and ii) get a deeper understanding of the actin cytoskeleton per se. The current proposal is directly relevant to the NIH mission as it focuses on three families of bacterial effectors, all produced by human pathogens. Furthermore, the proposal is of interest for a general understanding of human physiology as each of the above toxins reveals novel properties of the actin cytoskeleton. Thus, Aim 1 focuses on deciphering the novel hitherto unprecedented ability of VopF and VopL effectors produced by Vibrio cholerae and Vibrio parahaemolyticus to potentiate actin processive polymerization at the pointed ends. Aim 2 addresses the properties of SipA, an effector from Salmonella enterica that exerts a novel mode of binding to actin, bestowing the pathogen an ability to adhere to and invade the polarized host cell. In Aim 3, the proposal will decipher the mechanisms of actin-dependent membrane remodeling by Legionella pneumophila effectors. Understanding these and related processes is particularly important given that all intracellular pathogens depend heavily on hijacking host membrane organization to survive and thrive inside the affected cell. The research strategy for the toxin characterization will be based on using several highly complementary experimental approaches. The effects of the toxins on actin dynamics in bulk and at the single-filament level will be combined with cell biology and structural biology approaches. Specifically, bulk actin dynamics will be monitored via modifications of the pyrene-actin polymerization approach. The effects of the toxins on the actin dynamics at the single-filament level will be characterized by total internal reflection fluorescence microscopy, which will be enforced by microfluidics (in collaboration with Dr. Shekhar) for deciphering the mechanisms employed by VopF/VopL toxins (Aim 1). A modification of this technique will be used to decipher the mechanisms of a membrane-reorganizing protein MavH (Aim 3). The structures of VopF with the actin pointed end (Aim1), and SipA bound along the filament side (Aim 2) will be characterized by the cryoEM reconstruction in collaboration with Dr. Egelman’s group. Fluorescence anisotropy will be used to describe the strengths of the interactions between actin and the effectors. The proposed study is significant and innovative as it fills major gaps in our understanding of the toxicity of several life-threatening pathogens and reveals novel ways of operation of the actin cytoskeleton.


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 = $656,852 )
2025	2025	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Biomedical Research and Research Training	001	9	2/28/2025	SUPPLEMENT FOR EXPANSION	$328,426
2025	2025	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Biomedical Research and Research Training	003	11	7/22/2025	NON-COMPETING CONTINUATION	$328,426
2025	2024	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Biomedical Research and Research Training	002	10	2/28/2025	COMPETING CONTINUATION	$24,161
2025	2023	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Biomedical Research and Research Training	001	9	2/28/2025	SUPPLEMENT FOR EXPANSION	-$4,371
2025	2023	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Biomedical Research and Research Training	000	9	2/28/2025	NON-COMPETING CONTINUATION	-$19,791
														Subtotal = $656,852

Issue Date FY: 2024 ( Subtotal = $348,826 )
2024	2024	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Biomedical Research and Research Training	002	10	7/10/2024	COMPETING CONTINUATION	$348,826
2024	2023	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Biomedical Research and Research Training	001	9	7/5/2024	SUPPLEMENT FOR EXPANSION	$0
2024	2023	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Biomedical Research and Research Training	000	9	7/5/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $348,826

Issue Date FY: 2023 ( Subtotal = $389,444 )
2023	2023	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Biomedical Research and Research Training	000	9	5/12/2023	NON-COMPETING CONTINUATION	$318,997
2023	2023	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Biomedical Research and Research Training	001	9	5/15/2023	SUPPLEMENT FOR EXPANSION	$70,447
														Subtotal = $389,444

Issue Date FY: 2022 ( Subtotal = $374,780 )
2022	2022	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Biomedical Research and Research Training	001	8	9/6/2022	SUPPLEMENT FOR EXPANSION	$55,783
2022	2022	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Biomedical Research and Research Training	000	8	8/12/2022	NON-COMPETING CONTINUATION	$318,997
														Subtotal = $374,780

Issue Date FY: 2021 ( Subtotal = $318,997 )
2021	2021	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Biomedical Research and Research Training	002	7	6/3/2021	NON-COMPETING CONTINUATION	$318,997
2021	2020	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Biomedical Research and Research Training	001	6	5/17/2021	COMPETING CONTINUATION	$27,189
2021	2019	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Biomedical Research and Research Training	000	5	5/17/2021	NON-COMPETING CONTINUATION	-$27,189
														Subtotal = $318,997

Issue Date FY: 2020 ( Subtotal = $533,609 )
2020	2020	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Biomedical Research and Research Training	002	6	8/6/2020	SUPPLEMENT FOR EXPANSION	$197,500
2020	2020	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Biomedical Research and Research Training	001	6	7/28/2020	COMPETING CONTINUATION	$336,109
2020	2019	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Biomedical Research and Research Training	000	5	7/20/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $533,609

Issue Date FY: 2019 ( Subtotal = $304,150 )
2019	2019	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Biomedical Research and Research Training	000	5	5/21/2019	NON-COMPETING CONTINUATION	$304,150
														Subtotal = $304,150

Issue Date FY: 2018 ( Subtotal = $304,150 )
2018	2018	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Biomedical Research and Research Training	000	4	5/11/2018	NON-COMPETING CONTINUATION	$304,150
														Subtotal = $304,150

Issue Date FY: 2017 ( Subtotal = $304,150 )
2017	2017	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Biomedical Research and Research Training	000	3	6/7/2017	NON-COMPETING CONTINUATION	$304,150
														Subtotal = $304,150

Issue Date FY: 2016 ( Subtotal = $304,150 )
2016	2016	OHIO STATE UNIVERSITY	1800 CANNON DR/700 LINCOLN TOW	COLUMBUS	OH	43210	FRANKLIN	USA	Biomedical Research and Research Training	000	2	5/18/2016	NON-COMPETING CONTINUATION	$304,150
														Subtotal = $304,150

Issue Date FY: 2015 ( Subtotal = $304,150 )
2015	2015	OHIO STATE UNIVERSITY	1800 CANNON DR/700 LINCOLN TOW	COLUMBUS	OH	43210	FRANKLIN	USA	Biomedical Research and Research Training	000	1	8/28/2015	NEW	$304,150
														Subtotal = $304,150

Grand Total All Awards = $4,143,258

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Molecular Mechanisms of Bacterial Toxins Targeting the Actin Cytoskeleton

Award Number: R01GM114666

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/01/2015

PERIOD OF PERFORMANCE END DATE: 07/31/2026

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