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. 2025 Nov 14;232(5):1097-1107.
doi: 10.1093/infdis/jiaf265.

Escherichia coli Type III Secretion System 2 Is Associated With Patient Mortality in Bloodstream Infections

Joshua T Thaden  1 , Phillip Cox  1 , Paa Kwesi Ankrah  1 , Sanjay Khandelwal  2 , Jeffrey S Bourgeois  3 , Orianna Poteete  1 , Felicia Ruffin  1 , Gowthami Arepally  2 , Granger Sutton  4   5 , Lauren Brinkac  4   5 , Thomas H Clarke  4 , Dennis C Ko  3 , Derrick E Fouts  4 , Vance G Fowler  1
Affiliations

Escherichia coli Type III Secretion System 2 Is Associated With Patient Mortality in Bloodstream Infections

Joshua T Thaden et al. J Infect Dis. .

Abstract

Background: Escherichia coli has an extensive accessory genome, though its role in affecting patient mortality is unknown.

Methods: We performed whole genome sequencing with E. coli bacteremia isolates. Pan-genome analysis was used to identify flexible genomic islands associated with in-hospital attributable mortality. Genomic islands of interest were investigated experimentally.

Results: We included 193 E. coli genomes. Two genomic islands were co-present within 41 (21%) genomes and associated with increased attributable mortality in an adjusted analysis (Odds ratio 3.0; 95% confidence interval 1.1-7.9; p=0.03). The two genomic islands together contain genes homologous to a type III secretion system (T3SS): 1) E. coli type III secretion system 2 (ETT2), encoding genes homologous to a T3SS basal body and needle complex, and 2) an ETT2 accessory region (ETT2-AR) encoding genes homologous to a T3SS needle tip, translocases, and adhesin. ETT2/ETT2-AR increased resistance to complement-mediated growth restriction by inhibiting classical complement pathway activation and impacted E. coli-host cell interactions by increasing adhesion to and death of mammalian cells.

Conclusions: Genomic islands ETT2 and ETT2-AR are homologous to a T3SS, co-localize within specific E. coli lineages, associate with increased mortality, and increase bacterial virulence through resistance to complement and enhanced host cell adhesion and death.

Keywords: Escherichia coli; ETT2; bacteremia; bloodstream infection; type III secretion system.

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Conflict of interest statement

Potential conflicts of interest. V. G. F. reports personal fees from Novartis, Debiopharm, Genentech, Achaogen, Affinium, Medicines Co, MedImmune, Bayer, Basilea, Affinergy, Janssen, Contrafect, Regeneron, Destiny, Amphliphi Biosciences, Integrated Biotherapeutics, C3J, Armata, Valanbio, Akagera, Aridis, and Roche; grants from the National Institutes of Health, MedImmune, Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Merck, Medical Biosurfaces, Locus, Affinergy, Contrafect, Karius, Genentech, Regeneron, Deep Blue, Basilea, and Janssen; royalties from UpToDate; stock options from Valanbio and ArcBio; honoraria from the Infectious Diseases Society of America for his service as an associate editor of Clinical Infectious Diseases; and a patent pending for sepsis diagnostics. J. T. T. reports acting as an advisor for Resonantia Diagnostics, Inc and Sanofi. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

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