Molecular and Structural Characterization of a Novel <named-content content-type="genus-species">Escherichia coli</named-content> 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...

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Autores principales:	Danilo G. Moriel, Begoña Heras, Jason J. Paxman, Alvin W. Lo, Lendl Tan, Matthew J. Sullivan, Samantha J. Dando, Scott A. Beatson, Glen C. Ulett, Mark A. Schembri
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2016
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/fc01d4caa3354732be0b81f157eb1bd7
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spelling	oai:doaj.org-article:fc01d4caa3354732be0b81f157eb1bd72021-11-15T15:41:41ZMolecular and Structural Characterization of a Novel <named-content content-type="genus-species">Escherichia coli</named-content> Interleukin Receptor Mimic Protein10.1128/mBio.02046-152150-7511https://doaj.org/article/fc01d4caa3354732be0b81f157eb1bd72016-05-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02046-15https://doaj.org/toc/2150-7511ABSTRACT 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.Danilo G. MorielBegoña HerasJason J. PaxmanAlvin W. LoLendl TanMatthew J. SullivanSamantha J. DandoScott A. BeatsonGlen C. UlettMark A. SchembriAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 7, Iss 2 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Danilo G. Moriel Begoña Heras Jason J. Paxman Alvin W. Lo Lendl Tan Matthew J. Sullivan Samantha J. Dando Scott A. Beatson Glen C. Ulett Mark A. Schembri Molecular and Structural Characterization of a Novel <named-content content-type="genus-species">Escherichia coli</named-content> Interleukin Receptor Mimic Protein
description	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. 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.
format	article
author	Danilo G. Moriel Begoña Heras Jason J. Paxman Alvin W. Lo Lendl Tan Matthew J. Sullivan Samantha J. Dando Scott A. Beatson Glen C. Ulett Mark A. Schembri
author_facet	Danilo G. Moriel Begoña Heras Jason J. Paxman Alvin W. Lo Lendl Tan Matthew J. Sullivan Samantha J. Dando Scott A. Beatson Glen C. Ulett Mark A. Schembri
author_sort	Danilo G. Moriel
title	Molecular and Structural Characterization of a Novel <named-content content-type="genus-species">Escherichia coli</named-content> Interleukin Receptor Mimic Protein
title_short	Molecular and Structural Characterization of a Novel <named-content content-type="genus-species">Escherichia coli</named-content> Interleukin Receptor Mimic Protein
title_full	Molecular and Structural Characterization of a Novel <named-content content-type="genus-species">Escherichia coli</named-content> Interleukin Receptor Mimic Protein
title_fullStr	Molecular and Structural Characterization of a Novel <named-content content-type="genus-species">Escherichia coli</named-content> Interleukin Receptor Mimic Protein
title_full_unstemmed	Molecular and Structural Characterization of a Novel <named-content content-type="genus-species">Escherichia coli</named-content> Interleukin Receptor Mimic Protein
title_sort	molecular and structural characterization of a novel <named-content content-type="genus-species">escherichia coli</named-content> interleukin receptor mimic protein
publisher	American Society for Microbiology
publishDate	2016
url	https://doaj.org/article/fc01d4caa3354732be0b81f157eb1bd7
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Molecular and Structural Characterization of a Novel <named-content content-type="genus-species">Escherichia coli</named-content> Interleukin Receptor Mimic Protein

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