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Structure and functions of a bacterial Type IV effector complex

Award Number: R21AI185853
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: 05/22/2024
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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Structure and functions of a bacterial Type IV effector complex - Project Summary Bacterial pathogens use “effector” proteins as part of their virulence strategies to subvert host functions and promote bacterial intracellular survival, proliferation and persistence. These effectors operate individually or collectively to modulate cellular processes, usually in a functionally integrated manner. Bacterial effectors may have antagonistic or convergent activities on cellular pathways or regulate each other’s activities (as “meta-effectors”). How multiple effector activities are coordinated spatially and temporally in host cells remains largely unknown. In our efforts to characterize mechanisms of intracellular proliferation of the intracellular bacterium Brucella abortus, we have uncovered a physical interaction between three Type IV secretion effectors - BspF, BspH and BspI - suggesting that they form a multi- effector complex when delivered into host cells. BspF is a putative acetyltransferase that localizes to the recycling endosome and interacts with the host protein ACAP1, a GTPase activating protein (GAP) of the endocytic GTPase Arf6, thereby inhibiting Arf6 activity and retrograde vesicular transport to promote Brucella intracellular growth. BspH and BspI remain poorly characterized but contain structural Armadillo (ARM) repeats and a GAP domain, respectively, suggesting protein-protein interactions for BspH and host GTPase modulation capabilities for BspI. Consistently, we found that BspI directly interacts with the host GTPases Rac1 and Rab5. Moreover, we found that BspF, BspH and BspI interact in a complex associated with early endosomal structures. We will test the hypothesis that these effector proteins intrinsically form a multi-effector platform that coordinates host GTPase-modulating effector activities on endosomal transport to promote bacterial intracellular growth. Aim 1 will determine key aspects of the structure and assembly of the BspF:H:I complex, using computational, biochemical and structural biology approaches. Aim 2 will i) determine the function of BspI and of the BspF;H:I complex in Brucella’s intracellular cycle and ii) define functional interactions between BspF, BspH and BspI. The proposed research will address seminal questions towards establishing a new paradigm of integration of bacterial effector functions with broad impact to the field of bacterial pathogenesis.


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	2025	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT STREET	BURLINGTON	VT	05405	CHITTENDEN	USA	Allergy and Infectious Diseases Research	000	2	2/26/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $179,155 )
2025	2025	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT STREET	BURLINGTON	VT	05405	CHITTENDEN	USA	Allergy and Infectious Diseases Research	000	2	4/1/2025	NON-COMPETING CONTINUATION	$179,155
														Subtotal = $179,155

Issue Date FY: 2024 ( Subtotal = $210,640 )
2024	2024	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT STREET	BURLINGTON	VT	05405	CHITTENDEN	USA	Allergy and Infectious Diseases Research	001	1	9/12/2024	NEW	$21,063
2024	2024	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT STREET	BURLINGTON	VT	05405	CHITTENDEN	USA	Allergy and Infectious Diseases Research	000	1	5/22/2024	NEW	$189,577
														Subtotal = $210,640

Grand Total All Awards = $389,795

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Structure and functions of a bacterial Type IV effector complex

Award Number: R21AI185853

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: 05/22/2024

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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