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Molecular and structural characterization of a novel Escherichia coli interleukin receptor mimic protein

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journal contribution
posted on 2023-02-06, 05:14 authored by DG Moriel, Begona HerasBegona Heras, Jason PaxmanJason Paxman, AW Lo, L Tan, MJ Sullivan, SJ Dando, SA Beatson, GC Ulett, MA Schembri
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.IMPORTANCE 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.

Funding

This work was supported by grants from the Australian National Health and Medical Research Council (NHMRC; APP1042651, APP1084889) and the Australian Research Council (ARC; DP150102287). BH and GCU are supported by ARC Future Fellowships (FT130100580 and FT110101048, respectively). SAB is supported by an NHMRC Career Development Fellowship (APP1090456) and MAS is supported by an NHMRC Senior Research Fellowship (APP1106930).

History

Publication Date

2016-05-01

Journal

mBio

Volume

7

Issue

2

Article Number

e02046-15

Pagination

11p.

Publisher

American Society for Microbiology

ISSN

2161-2129

Rights Statement

© 2016 Moriel et al. This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-ShareAlike 3.0 Unported license, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original author and source are credited.

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