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Mechanoregulation of EHEC virulence

Award Number: R01AI132354
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: 05/02/2018
PERIOD OF PERFORMANCE END DATE: 04/30/2029

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Mechanoregulation of EHEC virulence - PROJECT SUMMARY Environmental sensing is at the basis of an organism's ability to adapt its physiology to respond to changes in its niche. Over the past years, it has emerged that bacteria not only perceive and respond to chemical stimuli, but are capable of sensing and processing physical forces as an environmental cue. In the case of bacterial pathogens, we and others have shown that mechanical stimuli can act as a hallmark of host colonization and lead to activation of virulence genes. Despite this realisation, our mechanistic understanding of pathways and systems involved in mechanosensing, transduction and processing of physical forces is currently limited, as is our knowledge regarding the role of mechanoregulation within the host environment. Over the course of this grant, we have made important discoveries regarding the mechanistic basis of mechanoregulation in the human pathogen enterohemorrhagic E. coli (EHEC). In the human host, ingestion of EHEC can lead to enterocolitis and severe complications such as haemolytic uremic syndrome. These hallmarks of infection are caused by the concerted action of virulence factors, including colonization factors and Shiga toxins. We discovered that the transcriptional regulator GrlA regulates the LEE pathogenicity island encoded type 3 secretion system, an important colonization factor, in response to mechanical cues. We showed that GrlA is regulated by subcellular compartmentalisation, and is sequestered on the inner membrane in resting cells. When activated by shear force GrlA dissociates from the membrane and is released into the cytoplasm, where it binds and induces the LEE masterregulator Ler. We also showed the biochemical basis for this mechanism, by identifying both constitutively active GrlA variants, and variants that are `blind' to mechanical cues. Regarding the interplay between intestinal motility and EHEC infection, we have identified Shiga toxin 2 as an effector that leads to enteric nervous system stimulation and increased gut transit. We discovered that the Shiga toxin 2-converting phage, but not Shiga toxin 1 is also subject to mechanical induction via GrlA. In this competing renewal application, we will (1) determine the mechanistic basis for the observed mechanoregulation of Shiga toxin and the toxin encoding phage, (2) characterize Shiga toxin induction in vivo and its impact on gastrointestinal motility, and (3) define the role of Shiga toxin during competition of EHEC with the endogenous microbiota. This work will reveal an alternative regulatory mechanism for a phage-encoded toxin, and define the role of Shiga toxin during bacterial colonization and inter-species competition in the host niche. .


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 = $465,977 )
2025	2025	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Allergy and Infectious Diseases Research	002	7	4/11/2025	NON-COMPETING CONTINUATION	$465,977
2025	2024	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Allergy and Infectious Diseases Research	001	6	2/19/2025	COMPETING CONTINUATION	$2,129
2025	2022	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Allergy and Infectious Diseases Research	000	5	2/19/2025	NON-COMPETING CONTINUATION	-$2,129
														Subtotal = $465,977

Issue Date FY: 2024 ( Subtotal = $465,977 )
2024	2024	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Allergy and Infectious Diseases Research	001	6	9/4/2024	COMPETING CONTINUATION	$46,598
2024	2024	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Allergy and Infectious Diseases Research	000	6	6/21/2024	COMPETING CONTINUATION	$419,379
														Subtotal = $465,977

Issue Date FY: 2022 ( Subtotal = $382,308 )
2022	2022	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Allergy and Infectious Diseases Research	000	5	5/17/2022	NON-COMPETING CONTINUATION	$382,308
														Subtotal = $382,308

Issue Date FY: 2021 ( Subtotal = $382,308 )
2021	2021	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Allergy and Infectious Diseases Research	000	4	4/5/2021	NON-COMPETING CONTINUATION	$382,308
														Subtotal = $382,308

Issue Date FY: 2020 ( Subtotal = $456,039 )
2020	2020	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Allergy and Infectious Diseases Research	000	3	4/9/2020	NON-COMPETING CONTINUATION	$456,039
														Subtotal = $456,039

Issue Date FY: 2019 ( Subtotal = $458,041 )
2019	2019	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Allergy and Infectious Diseases Research	001	2	6/13/2019	SUPPLEMENT FOR EXPANSION	$75,733
2019	2019	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Allergy and Infectious Diseases Research	000	2	4/4/2019	NON-COMPETING CONTINUATION	$382,308
														Subtotal = $458,041

Issue Date FY: 2018 ( Subtotal = $375,280 )
2018	2018	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Allergy and Infectious Diseases Research	000	1	5/1/2018	NEW	$375,280
														Subtotal = $375,280

Grand Total All Awards = $2,985,930

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Mechanoregulation of EHEC virulence

Award Number: R01AI132354

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: 05/02/2018

PERIOD OF PERFORMANCE END DATE: 04/30/2029

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