Thursday, July 3, 2025 7/3/2025

Role of Carbon Metabolism and Virulence of Shigella flexneri

Award Number: R37AI016935
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: 07/01/2025
PERIOD OF PERFORMANCE END DATE: 06/30/2030

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Role of Carbon Metabolism and Virulence of Shigella flexneri - PROJECT SUMMARY (See instructions): The long-term goal of the proposed research is to understand the adaptation of the invasive pathogen Shigella to the human gut environment. Shigella species are associated with bacillary dysentery, a potentially fatal diarrheal disease. With the rise in drug resistance and no effective vaccine available, the global health burden of shigellosis, already significant, is increasing. During the course of an infection, Shigella must transit the gastrointestinal tract, penetrate the mucous layer, and invade and replicate within intestinal epithelial cells. To adapt these diverse environments, Shigella senses the availability of carbon sources or products of carbon metabolism. Our hypothesis is that Shigella uses these signals to regulate the expression of genes, including virulence genes, to maximize survival and growth in a particular niche. A mechanistic understanding of these regulatory pathways is needed to design effective methods for treatment and prevention of Shigella infection. We have the tools and expertise to carry out these studies. Our work has demonstrated the importance of the alarmone (p)ppGpp, a signaling molecule produced in response to carbon starvation, for Shigella invasion and spread in cultured epithelial cells. We will move these studies into a model that more closely resembles the gut epithelium during natural infection. Human intestinal organoids, or mini-intestines , which contain multiple differentiated cell types and display an innate immune response, will be used to study the effects of ppGpp on Shigella pathways leading to adaptation to the host environment and virulence gene expression. Using Dual RNA-Seq, we will determine both the Shigella and the host genes that are regulated in response to ppGpp during organoid infection, and this will give insights into the host-pathogen interplay and guide the construction of mutants to ascertain the relevance of both host and pathogen regulatory networks for the disease outcome. We recently discovered that the Type I interferon beta (IFN-Beta) innate immune signaling pathway plays a role in Shigella infection. While IFN-Beta is somewhat effective in preventing Shigella from entering host cells, the bacteria that do get in spread more rapidly and cause larger lesions. This indicates that Shigella has a mechanism(s) for not only overcoming IFN-Beta-induced protective responses but also hijacking the host innate immune response to increase its virulence. We propose to use dual RNA-Seq and genetic analysis of Shigella-infected intestinal cells to investigate how this pathogen subverts the host interferon response.


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 = $391,709 )
2025	2025	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Allergy and Infectious Diseases Research	000	39	7/1/2025	EXTENSION WITH OR WITHOUT FUNDS	$391,709
														Subtotal = $391,709

Issue Date FY: 2024 ( Subtotal = $396,250 )
2024	2024	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Allergy and Infectious Diseases Research	000	38	4/16/2024	NON-COMPETING CONTINUATION	$396,250
														Subtotal = $396,250

Issue Date FY: 2023 ( Subtotal = $396,250 )
2023	2023	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Allergy and Infectious Diseases Research	000	37	4/17/2023	NON-COMPETING CONTINUATION	$396,250
														Subtotal = $396,250

Issue Date FY: 2022 ( Subtotal = $396,250 )
2022	2022	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Allergy and Infectious Diseases Research	000	36	4/26/2022	NON-COMPETING CONTINUATION	$396,250
														Subtotal = $396,250

Issue Date FY: 2021 ( Subtotal = $396,250 )
2021	2021	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR MN 13	AUSTIN	TX	78712	TRAVIS	USA	Allergy and Infectious Diseases Research	000	35	4/13/2021	NON-COMPETING CONTINUATION	$396,250
														Subtotal = $396,250

Issue Date FY: 2020 ( Subtotal = $394,583 )
2020	2020	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR MN 13	AUSTIN	TX	78712	TRAVIS	USA	Allergy and Infectious Diseases Research	002	34	9/16/2020	COMPETING CONTINUATION	$0
2020	2020	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR MN 13	AUSTIN	TX	78712	TRAVIS	USA	Allergy and Infectious Diseases Research	001	34	7/1/2020	COMPETING CONTINUATION	$0
2020	2020	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR MN 13	AUSTIN	TX	78712	TRAVIS	USA	Allergy and Infectious Diseases Research	000	34	5/11/2020	COMPETING CONTINUATION	$394,583
														Subtotal = $394,583

Issue Date FY: 2013 ( Subtotal = $0 )
2013	2012	UNIVERSITY OF TEXAS AT AUSTIN	COLLEGE OF PHARMACY	AUSTIN	TX	78712	TRAVIS	USA	Allergy and Infectious Diseases Research	000	28	9/6/2013	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2012 ( Subtotal = $364,107 )
2012	2012	UNIVERSITY OF TEXAS AT AUSTIN	P.O. BOX 7159	AUSTIN	TX	78713	TRAVIS	USA	Allergy and Infectious Diseases Research	000	28	11/30/2011	NON-COMPETING CONTINUATION	$327,696
2012	2012	UNIVERSITY OF TEXAS AT AUSTIN	P.O. BOX 7159	AUSTIN	TX	78713	TRAVIS	USA	Allergy and Infectious Diseases Research	001	28	5/30/2012	NON-COMPETING CONTINUATION	$36,411
														Subtotal = $364,107

Issue Date FY: 2011 ( Subtotal = $364,107 )
2011	2011	UNIVERSITY OF TEXAS AT AUSTIN	P.O. BOX 7159	AUSTIN	TX	78713	TRAVIS	USA	Allergy and Infectious Diseases Research	001	27	6/6/2011	NON-COMPETING CONTINUATION	$33,100
2011	2011	UNIVERSITY OF TEXAS AT AUSTIN	P.O. BOX 7159	AUSTIN	TX	78713	TRAVIS	USA	Allergy and Infectious Diseases Research	000	27	11/19/2010	NON-COMPETING CONTINUATION	$331,007
														Subtotal = $364,107

Issue Date FY: 2010 ( Subtotal = $367,785 )
2010	2010	UNIVERSITY OF TEXAS AT AUSTIN	P.O. BOX 7159	AUSTIN	TX	78713	TRAVIS	USA	Allergy and Infectious Diseases Research	000	26	11/20/2009	NON-COMPETING CONTINUATION	$334,350
2010	2010	UNIVERSITY OF TEXAS AT AUSTIN	P.O. BOX 7159	AUSTIN	TX	78713	TRAVIS	USA	Allergy and Infectious Diseases Research	001	26	5/28/2010	NON-COMPETING CONTINUATION	$33,435
														Subtotal = $367,785

Issue Date FY: 2009 ( Subtotal = $483,964 )
2009	2009	UNIVERSITY OF TEXAS AT AUSTIN	P.O. BOX 7159	AUSTIN	TX	78713	TRAVIS	USA	Allergy and Infectious Diseases Research	000	25	10/29/2008	NON-COMPETING CONTINUATION	$334,350
2009	2009	UNIVERSITY OF TEXAS AT AUSTIN	P.O. BOX 7159	AUSTIN	TX	78713	TRAVIS	USA	Allergy and Infectious Diseases Research	001	25	5/20/2009	NON-COMPETING CONTINUATION	$37,150
2009	2009	UNIVERSITY OF TEXAS AT AUSTIN	P.O. BOX 7159	AUSTIN	TX	78713	TRAVIS	USA	Allergy and Infectious Diseases Research	002	25	9/21/2009	NON-COMPETING CONTINUATION	$112,464
														Subtotal = $483,964

Issue Date FY: 2008 ( Subtotal = $371,500 )
2008	2008	UNIVERSITY OF TEXAS AT AUSTIN	PO BOX 7159	AUSTIN	TX	78712	TRAVIS	USA	Allergy and Infectious Diseases Research	000	24	12/7/2007	EXTENSION WITH OR WITHOUT FUNDS	$371,500
														Subtotal = $371,500

Issue Date FY: 2007 ( Subtotal = $279,713 )
2007	2007	UNIVERSITY OF TEXAS AT AUSTIN	PO BOX 7159	AUSTIN	TX	78712	TRAVIS	USA	Allergy and Infectious Diseases Research	000	23	11/10/2006	NON-COMPETING CONTINUATION	$279,713
														Subtotal = $279,713

Issue Date FY: 2006 ( Subtotal = $288,068 )
2006	2006	UNIVERSITY OF TEXAS AT AUSTIN	PO BOX 7159	AUSTIN	TX	78712	TRAVIS	USA	Allergy and Infectious Diseases Research	000	22	11/9/2005	NON-COMPETING CONTINUATION	$288,068
														Subtotal = $288,068

Issue Date FY: 2005 ( Subtotal = $295,000 )
2005	2005	UNIVERSITY OF TEXAS AT AUSTIN	PO BOX 7159	AUSTIN	TX	78712	TRAVIS	USA	Microbiology and Infectious Diseases Research	000	21	11/26/2004	NON-COMPETING CONTINUATION	$295,000
														Subtotal = $295,000

Issue Date FY: 2004 ( Subtotal = $295,000 )
2004	2004	UNIVERSITY OF TEXAS AT AUSTIN	PO BOX 7159	AUSTIN	TX	78712	TRAVIS	USA	Microbiology and Infectious Diseases Research	000	20	12/8/2003	NON-COMPETING CONTINUATION	$295,000
														Subtotal = $295,000

Issue Date FY: 2003 ( Subtotal = $147,500 )
2003	2003	UNIVERSITY OF TEXAS AT AUSTIN	PO BOX 7159	AUSTIN	TX	78712	TRAVIS	USA	Microbiology and Infectious Diseases Research	000	19	6/5/2003	COMPETING CONTINUATION	$147,500
														Subtotal = $147,500

Grand Total All Awards = $5,628,036

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Role of Carbon Metabolism and Virulence of Shigella flexneri

Award Number: R37AI016935

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: 07/01/2025

PERIOD OF PERFORMANCE END DATE: 06/30/2030

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