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Effector-mediated ubiquitin manipulation in Legionella pneumophila pathogenesis

Award Number: R01AI127465
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: 08/01/2017
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Effector-mediated ubiquitin manipulation in Legionella pneumophila pathogenesis - The ubiquitin network regulates virtually every host processes, particularly membrane trafficking and immunity. The bacterial pathogen Legionella pneumophila extensively modulates host processes using hundreds of effectors translocated into the host cytosol by its Dot/Icm transporter. The use of activity-based probes, bioinformatics analysis coupled with careful biochemical and structural analyses has identified at 28 Legionella effectors involved in co-opting ubiquitin signaling. These proteins function either as canonical E3 ubiquitin ligases, deubiquitinases or as ubiquitin ligases that defy the catalytic mechanism of canonical ubiquitination. To explore additional effectors involved in co-opting the host ubiquitin network, we have created mutants that lack a specific set or each of the known effectors involved in ubiquitin signaling. Using biotin ligase-mediated proximity labeling, we have identified additional Dot/Icm substrates capable of catalyzing ubiquitination. We have also obtained evidence for the existence of Legionella proteins that directly modify ubiquitin. The goal of this project is to determine the function of these proteins, their catalytic mechanism and their cooperation with host ubiquitination components by biochemical and structural analyses. We will also study the regulation of their activity by factors from the bacterium and determine how such activity contributes to the biogenesis of the phagosome supportive of intracellular bacterial replication. Finally, we will design experiments to address the issue of the potential functional redundancy among Dot/Icm effectors (with or without E3 ubiquitin ligase activity) in the recruitment of Sec22b to the bacterial phagosome. Results from these experiments will reveal not only novel mechanisms of host function exploitation by intracellular pathogens, but also insights into the regulation of host ubiquitination pathways, both of which have the potential to be capitalized to develop novel methods for diagnosis and treatment of diseases.


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 = $461,309 )
2025	2025	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Allergy and Infectious Diseases Research	000	7	3/25/2025	NON-COMPETING CONTINUATION	$461,309
														Subtotal = $461,309

Issue Date FY: 2024 ( Subtotal = $462,086 )
2024	2024	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Allergy and Infectious Diseases Research	002	6	4/2/2024	NON-COMPETING CONTINUATION	$462,086
2024	2023	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Allergy and Infectious Diseases Research	001	5	12/7/2023	COMPETING CONTINUATION	$102
2024	2020	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Allergy and Infectious Diseases Research	000	4	12/7/2023	NON-COMPETING CONTINUATION	-$102
														Subtotal = $462,086

Issue Date FY: 2023 ( Subtotal = $476,574 )
2023	2023	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE STE 1900	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Allergy and Infectious Diseases Research	000	5	4/7/2023	COMPETING CONTINUATION	$476,574
														Subtotal = $476,574

Issue Date FY: 2020 ( Subtotal = $392,377 )
2020	2020	PURDUE UNIVERSITY	155 S GRANT ST	WEST LAFAYETTE	IN	47907	TIPPECANOE	USA	Allergy and Infectious Diseases Research	000	4	7/10/2020	NON-COMPETING CONTINUATION	$392,377
														Subtotal = $392,377

Issue Date FY: 2019 ( Subtotal = $392,206 )
2019	2019	PURDUE UNIVERSITY	401 SOUTH GRANT ST	WEST LAFAYETTE	IN	47907	TIPPECANOE	USA	Allergy and Infectious Diseases Research	000	3	7/5/2019	NON-COMPETING CONTINUATION	$392,206
														Subtotal = $392,206

Issue Date FY: 2018 ( Subtotal = $392,120 )
2018	2018	PURDUE UNIVERSITY	401 SOUTH GRANT ST	WEST LAFAYETTE	IN	47907	TIPPECANOE	USA	Allergy and Infectious Diseases Research	000	2	7/9/2018	NON-COMPETING CONTINUATION	$392,120
														Subtotal = $392,120

Issue Date FY: 2017 ( Subtotal = $405,709 )
2017	2017	PURDUE UNIVERSITY	401 SOUTH GRANT ST	WEST LAFAYETTE	IN	47907	TIPPECANOE	USA	Allergy and Infectious Diseases Research	000	1	7/14/2017	NEW	$405,709
2017	2017	PURDUE UNIVERSITY	401 SOUTH GRANT ST	WEST LAFAYETTE	IN	47907	TIPPECANOE	USA	Allergy and Infectious Diseases Research	001	1	7/21/2017	NEW	$0
														Subtotal = $405,709

Grand Total All Awards = $2,982,381

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Effector-mediated ubiquitin manipulation in Legionella pneumophila pathogenesis

Award Number: R01AI127465

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: 08/01/2017

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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