NIH grant: Dissecting the Role of Host-Derived Proteins in Enhancing E. coli Infectivity and Persistence (1R21AI199107-01)

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NIH grant 1R21AI199107-01: Dissecting the Role of Host-Derived Proteins in Enhancing E. coli Infectivity and Persistence
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: Anne-Marie  Krachler. Award: $419834.
Start: 2026-07-17T00:00:00.
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.

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