Escherichia coli Type III Secretion System 2 (ETT2) is Associated with Patient Mortality in Bloodstream Infections.

BACKGROUND: Escherichia coli has an extensive accessory genome, though its role in impacting patient mortality is unknown. METHODS: We performed whole genome sequencing with E. coli bloodstream infection isolates from inpatients at Duke University. Pan-genome analysis was used to identify flexible genomic islands associated with in-hospital attributable mortality (death due to infection). The functions of the flexible genomic islands of interest were investigated with serum growth assays and bacterial-host cell interaction assays. RESULTS: We included 193 E. coli genomes. Two separate genomic islands were co-present within 41 (21%) E. coli isolates and associated with increased attributable mortality (22% [9/41]) vs. 11% [17/152]) in an adjusted analysis (Mortality 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 35 genes homologous to a T3SS basal body and needle complex, and 2) an ETT2 accessory region (ETT2-AR) encoding six genes homologous to a T3SS needle tip, translocases, and adhesin. ETT2/ETT2-AR altered bacterial virulence through two mechanisms. First, ETT2/ETT2-AR increased resistance to complement-mediated growth restriction by inhibiting classical complement pathway activation. Second, ETT2/ETT2-AR influenced 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 in patients with E. coli bloodstream infection, and increase bacterial virulence through resistance to complement and enhanced host cell adhesion and death.

Duke Scholars

Author Vance Garrison Fowler Jr. Medicine, Infectious Diseases

Author Felicia Ruffin  

Author Dennis Ko Molecular Genetics and Microbiology

Author Gowthami Morey Arepally Medicine, Hematology

Author Joshua Thomas Thaden Medicine, Infectious Diseases