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Biological and structural diversity of bacterial type IV secretion systems

Award Number: R35GM131892
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: 06/07/2019
PERIOD OF PERFORMANCE END DATE: 02/28/2029

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Biological and structural diversity of bacterial type IV secretion systems - The transmission of macromolecules across biological membranes is a fundamental process in all cells. In the earliest studies of genetic exchange in bacteria dating back to the 1940’s, the F plasmid (then termed ‘sex factor’) was shown to self-transfer and, through recombination, mediate transfer of the entire E. coli chromosome to recipient bacteria. In the ensuing ~80 years, studies have established the broad medical importance of F and other mobile genetic elements (MGEs) in shaping of bacterial genomes and as vectors for dissemination of antibiotic resistance and other fitness traits among bacterial populations. MGEs also encode conjugative pili or other cell surface adhesins, which promote intercellular contacts necessary for DNA transfer and establishment of robust, antibiotic-resistant biofilm communities. MGEs are transmitted intercellularly through nanomachines termed type IV secretion systems (T4SSs). The T4SSs are present in most bacterial species, where they have functionally diversified into two large subfamilies, the DNA transfer or conjugation systems and the ‘effector translocators’ that deliver effector proteins into eukaryotic host cells during infection. In our 33 years of investigations, my group has identified many mechanistic and architectural features of these nanomachines, including the first view of the translocation route for a DNA substrate through a T4SS. We have consistently implemented emerging technologies, and in this last MIRA cycle we solved structures of 4 model T4SSs in their native contexts of the bacterial cell envelope by in situ cryoelectron tomography (CryoET). We also solved a structure of a large subassembly of the F-encoded T4SS at near-atomic resolution by single-particle cryoelectron microscopy (spCryoEM). We pioneered studies of F pilus dynamics by labeling Cys-derivatized pilins with fluorescent maleimide conjugates, systematically deciphered contributions of F-encoded machine subunits to assembly of the translocation channel and F pilus, and probed functions of substrate processing factors and surface adhesins in early and late stages of substrate transfer. Moving forward, we will address three major gaps in our knowledge of these dynamic nanomachines: 1) How are substrates recruited to and delivered into and through the T4SS channel? 2) How do T4SSs elaborate conjugative pili and for what biological ends? 3) How do T4SSs promote formation and disassembly of ‘mating junctions’ and how are these junctions architecturally configured? We will continue to use powerful in vivo biochemical approaches, such as site-directed photocrosslinking, in combination with state-of-the-art super-resolution fluorescence microscopy, in situ CryoET, and spCryoEM approaches to further probe T4SS structure-function relationships. This project entails no engineering efforts that might generate strains with unforeseen biological consequences regarding human health, and all work will be compliant with relevant NIH and institutional biosafety measures. We anticipate our multidisciplinary initiatives will continue to generate important new information about the architecture, biogenesis, and mechanism of action of T4SSs.


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 = $482,040 )
2026	2026	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Biomedical Research and Research Training	000	8	2/5/2026	NON-COMPETING CONTINUATION	$433,836
2026	2026	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Biomedical Research and Research Training	001	8	3/17/2026	NON-COMPETING CONTINUATION	$48,204
														Subtotal = $482,040

Issue Date FY: 2025 ( Subtotal = $482,040 )
2025	2025	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Biomedical Research and Research Training	002	7	2/21/2025	NON-COMPETING CONTINUATION	$433,836
2025	2025	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Biomedical Research and Research Training	003	7	8/8/2025	NON-COMPETING CONTINUATION	$48,204
2025	2024	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Biomedical Research and Research Training	000	6	11/25/2024	COMPETING CONTINUATION	$0
2025	2023	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Biomedical Research and Research Training	001	5	2/18/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $482,040

Issue Date FY: 2024 ( Subtotal = $482,040 )
2024	2024	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Biomedical Research and Research Training	000	6	4/2/2024	COMPETING CONTINUATION	$482,040
														Subtotal = $482,040

Issue Date FY: 2023 ( Subtotal = $466,953 )
2023	2023	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Biomedical Research and Research Training	000	5	4/25/2023	NON-COMPETING CONTINUATION	$466,953
														Subtotal = $466,953

Issue Date FY: 2022 ( Subtotal = $466,953 )
2022	2022	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Biomedical Research and Research Training	000	4	4/26/2022	NON-COMPETING CONTINUATION	$466,953
														Subtotal = $466,953

Issue Date FY: 2021 ( Subtotal = $474,753 )
2021	2021	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Biomedical Research and Research Training	000	3	4/19/2021	NON-COMPETING CONTINUATION	$466,953
2021	2021	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Biomedical Research and Research Training	001	3	6/3/2021	SUPPLEMENT FOR EXPANSION	$7,800
														Subtotal = $474,753

Issue Date FY: 2020 ( Subtotal = $464,958 )
2020	2020	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Biomedical Research and Research Training	000	2	4/29/2020	NON-COMPETING CONTINUATION	$464,958
														Subtotal = $464,958

Issue Date FY: 2019 ( Subtotal = $460,967 )
2019	2019	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Biomedical Research and Research Training	000	1	6/5/2019	NEW	$460,967
														Subtotal = $460,967

Grand Total All Awards = $3,780,704

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Biological and structural diversity of bacterial type IV secretion systems

Award Number: R35GM131892

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: 06/07/2019

PERIOD OF PERFORMANCE END DATE: 02/28/2029

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