title: Molecular and Structural Characterization of a Novel Escherichia coli Interleukin Receptor Mimic Protein.
abstract: Urinary tract infection (UTI) is a disease of extremely high incidence in both community and nosocomial settings. UTIs cause significant morbidity and mortality, with approximately 150 million cases globally per year. Uropathogenic Escherichia coli (UPEC) is the primary cause of UTI and is generally treated empirically. However, the rapidly increasing incidence of UTIs caused by multidrug-resistant UPEC strains has led to limited available treatment options and highlights the urgent need to develop alternative treatment and prevention strategies. In this study, we performed a comprehensive analysis to define the regulation, structure, function, and immunogenicity of recently identified UPEC vaccine candidate C1275 (here referred to as IrmA). We showed that the irmA gene is highly prevalent in UPEC, is cotranscribed with the biofilm-associated antigen 43 gene, and is regulated by the global oxidative stress response OxyR protein. Localization studies identified IrmA in the UPEC culture supernatant. We determined the structure of IrmA and showed that it adopts a unique domain-swapped dimer architecture. The dimeric structure of IrmA displays similarity to those of human cytokine receptors, including the interleukin-2 receptor (IL-2R), interleukin-4 receptor (IL-4R), and interleukin-10 receptor (IL-10R) binding domains, and we showed that purified IrmA can bind to their cognate cytokines. Finally, we showed that plasma from convalescent urosepsis patients contains high IrmA antibody titers, demonstrating the strong immunogenicity of IrmA. Taken together, our results indicate that IrmA may play an important role during UPEC infection.
  
  
  OBJECTIVE
  Uropathogenic E. coli (UPEC) is the primary cause of urinary tract infection (UTI), a disease of major significance to human health. Globally, the incidence of UPEC-mediated UTI is strongly associated with increasing antibiotic resistance, making this extremely common infection a major public health concern. In this report, we describe the regulatory, structural, functional, and immunogenic properties of a candidate UPEC vaccine antigen, IrmA. We demonstrate that IrmA is a small UPEC protein that forms a unique domain-swapped dimer with structural mimicry to several human cytokine receptors. We also show that IrmA binds to IL-2, IL-4, and IL-10, is strongly immunogenic in urosepsis patients, and is coexpressed with factors associated with biofilm formation. Overall, this work suggests a potential novel contribution for IrmA in UPEC infection.
authors.affiliation: Australian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia.
authors.forename: Danilo G
authors.initials: DG
authors.lastname: Moriel
authors.affiliation: La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Australia m.schembri@uq.edu.au b.heras@latrobe.edu.au.
authors.forename: Begoña
authors.initials: B
authors.lastname: Heras
authors.affiliation: La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Australia.
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Paxman
authors.affiliation: Australian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia.
authors.forename: Alvin W
authors.initials: AW
authors.lastname: Lo
authors.affiliation: Australian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia.
authors.forename: Lendl
authors.initials: L
authors.lastname: Tan
authors.affiliation: Menzies Health Institute Queensland and School of Medical Sciences, Griffith University, Gold Coast, QLD, Australia.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Sullivan
authors.affiliation: Institute for Glycomics, Griffith University, Gold Coast, QLD, Australia.
authors.forename: Samantha J
authors.initials: SJ
authors.lastname: Dando
authors.affiliation: Australian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Beatson
authors.affiliation: Menzies Health Institute Queensland and School of Medical Sciences, Griffith University, Gold Coast, QLD, Australia.
authors.forename: Glen C
authors.identifier: http://orcid.org/0000-0002-9638-8091
authors.initials: GC
authors.lastname: Ulett
authors.affiliation: Australian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia m.schembri@uq.edu.au b.heras@latrobe.edu.au.
authors.forename: Mark A
authors.identifier: http://orcid.org/0000-0003-4863-9260
authors.initials: MA
authors.lastname: Schembri
mesh_terms: D000907:Antibodies, Bacterial / Q000097:blood; D016207:Cytokines / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D018716:Molecular Mimicry / Q000235:genetics*; D018123:Receptors, Interleukin / Q000737:chemistry* / Q000235:genetics*; D056689:Uropathogenic Escherichia coli / Q000737:chemistry* / Q000235:genetics* / Q000276:immunology
chemical_list: D000907:Antibodies, Bacterial; D016207:Cytokines; D029968:Escherichia coli Proteins; D018123:Receptors, Interleukin