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Dissecting the Role of Host-Derived Proteins in Enhancing E. coli Infectivity and Persistence

Award Number: R21AI199107
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: 07/17/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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Dissecting the Role of Host-Derived Proteins in Enhancing E. coli Infectivity and Persistence - PROJECT SUMMARY Fecal-oral transmission is a key route for the spread of enteric pathogens such as enterohemorrhagic Escherichia coli (EHEC), which causes hemorrhagic colitis and life-threatening complications like hemolytic uremic syndrome. EHEC is notable for its extremely low infectious dose—fewer than 100 organisms can initiate disease—yet the mechanisms underlying this high infectivity remain poorly understood. Our preliminary studies in a zebrafish infection model reveal that EHEC harvested from feces is significantly more infectious than the same strain grown in vitro. Mass spectrometry of the bacterial surface proteome identified several host-derived fecal proteins, including serine protease inhibitors (serpins) such as alpha-1 antitrypsin (serpinA1) and serpinE2, that are bound to the bacterial surface after passage through the gut. Removal of these proteins from the bacterial cell envelope abrogates the hyperinfective phenotype, suggesting that specific host fecal proteins may functionally enhance EHEC colonization and transmission. This project aims to define the molecular mechanisms and functional consequences of fecal protein adhesion to the EHEC cell envelope. We hypothesize that host-derived proteins bind to EHEC during passage through the gastrointestinal tract and alter its surface properties to promote survival and/or colonization in the next host. In Aim 1, we will assess how individual and combined fecal proteins affect EHEC infectivity and transmission potential using controlled exposure and challenge experiments in zebrafish larvae. In Aim 2, we will determine the molecular basis of fecal protein binding by EHEC, identify bacterial surface factors that mediate adhesion, and map the protein–protein interaction interfaces. We will also test the hypothesis that host serine protease inhibitors (serpins) bind bacterial serin protease autotransporters (SPATEs) present on the bacterial cell surface, and that these interaction contributes to the enhancement of bacterial infectivity. Together, these studies will reveal a novel mechanism by which fecal passage increases pathogen transmissibility, mediated through specific interactions between host-derived proteins and bacterial surfaces. This work introduces fecal protein adhesion as a new dimension of host-pathogen interaction, with implications for microbial evolution, transmission dynamics, and the development of strategies to interrupt enteric disease spread.


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 = $419,834 )
2026	2026	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Allergy and Infectious Diseases Research	000	1	7/17/2026	NEW	$419,834
														Subtotal = $419,834

Grand Total All Awards = $419,834

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Dissecting the Role of Host-Derived Proteins in Enhancing E. coli Infectivity and Persistence

Award Number: R21AI199107

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: 07/17/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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