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Type VII secretion in Streptococcus gallolyticus pathogenesis

Award Number: R01AI163206
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: 12/01/2023
PERIOD OF PERFORMANCE END DATE: 10/31/2028

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Type VII secretion in Streptococcus gallolyticus pathogenesis - Streptococcus gallolyticus subsp. gallolyticus (Sgg) is implicated in life-threatening bacteremia, infective endocarditis (IE) and colorectal cancer (CRC). Despite its clinical importance, the underlying virulence mechanism of Sgg is poorly understood. A prominent feature of Sgg IE or bacteremia is the well-documented high rate of comorbidity with CRC, averaging around ~60% of cases. This underscores a strong connection between Sgg activities in the intestinal tract and Sgg infection in the circulatory system. Work from our lab and others have sort to understand the detailed interactions between Sgg and the colonic epithelium and how the interactions lead to pathological changes and diseases. Studies have found that Sgg is able to stimulate colon cancer cell proliferation and translocate across an epithelial barrier in a paracellular fashion. In pre-clinical models, Sgg has been shown to “drive” the development of colon tumors. The specific Sgg factors and host pathways underlying these pathogenic activities, however, are largely unknown. Recent findings from our lab demonstrated that a type VII secretion system (T7SS) plays a significant role in Sgg virulence. In preliminary studies to further dissect the activities mediated by the T7SS, a specific T7SS effector, EsxA, was found to be crucial in influencing colonic epithelial homeostasis. Moreover, preliminary data suggests that EsxA functions by acting as a novel ligand for a host cell surface growth factor receptor of critical function and holds great promise as a key virulence factor mediating multiple pathogenic phenotypes of Sgg. To the best of our knowledge, these findings highlight a novel virulence mechanism for Sgg and provide the first experimental evidence for T7SS regulation of a growth factor receptor. The goal of this proposal is to further delineate the importance of EsxA in Sgg virulence and to elucidate the signaling and biological outcomes induced by EsxA, using in vitro cell cultures and animal models well established in our lab. The broad applicability of the proposed virulence mechanism in Sgg strains will also be determined. Successful completion of the proposed studies will fill major knowledge gaps in Sgg virulence and advance a new understanding of T7SS function and microbial regulation of growth factor receptors.


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 = $380,442 )
2026	2026	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Allergy and Infectious Diseases Research	000	3	12/8/2025	NON-COMPETING CONTINUATION	$380,442
														Subtotal = $380,442

Issue Date FY: 2025 ( Subtotal = $444,457 )
2025	2025	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Allergy and Infectious Diseases Research	000	2	11/7/2024	NON-COMPETING CONTINUATION	$366,305
2025	2025	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Allergy and Infectious Diseases Research	001	2	11/29/2024	SUPPLEMENT FOR EXPANSION	$78,152
														Subtotal = $444,457

Issue Date FY: 2024 ( Subtotal = $397,883 )
2024	2024	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Allergy and Infectious Diseases Research	002	1	9/4/2024	NEW	$37,723
2024	2024	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Allergy and Infectious Diseases Research	001	1	7/26/2024	SUPPLEMENT FOR EXPANSION	$20,652
2024	2024	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Allergy and Infectious Diseases Research	000	1	11/22/2023	NEW	$339,508
														Subtotal = $397,883

Grand Total All Awards = $1,222,782

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Type VII secretion in Streptococcus gallolyticus pathogenesis

Award Number: R01AI163206

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: 12/01/2023

PERIOD OF PERFORMANCE END DATE: 10/31/2028

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