Adaptation of Arginine Synthesis among Uropathogenic Branches of the <named-content content-type="genus-species">Escherichia coli</named-content> Phylogeny Reveals Adjustment to the Urinary Tract Habitat

ABSTRACT Urinary tract infections (UTIs) are predominantly caused by uropathogenic Escherichia coli (UPEC). UPEC pathogenesis requires passage through a severe population bottleneck involving intracellular bacterial communities (IBCs) that are clonal expansions of a single invading UPEC bacterium in...

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Autores principales:	Michael E. Hibbing, Karen W. Dodson, Vasilios Kalas, Swaine L. Chen, Scott J. Hultgren
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	Escherichia coli arginine metabolism positive selection urinary tract infection Microbiology QR1-502
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spelling	oai:doaj.org-article:23fc2786fb1345899573ba2c852d67742021-11-15T16:19:08ZAdaptation of Arginine Synthesis among Uropathogenic Branches of the <named-content content-type="genus-species">Escherichia coli</named-content> Phylogeny Reveals Adjustment to the Urinary Tract Habitat10.1128/mBio.02318-202150-7511https://doaj.org/article/23fc2786fb1345899573ba2c852d67742020-10-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02318-20https://doaj.org/toc/2150-7511ABSTRACT Urinary tract infections (UTIs) are predominantly caused by uropathogenic Escherichia coli (UPEC). UPEC pathogenesis requires passage through a severe population bottleneck involving intracellular bacterial communities (IBCs) that are clonal expansions of a single invading UPEC bacterium in a urothelial superficial facet cell. IBCs occur only during acute pathogenesis. The bacteria in IBCs form the founder population that develops into persistent extracellular infections. Only a small fraction of UPEC organisms proceed through the IBC cycle, regardless of the inoculum size. This dramatic reduction in population size precludes the utility of genomic mutagenesis technologies for identifying genes important for persistence. To circumvent this bottleneck, we previously identified 29 positively selected genes (PSGs) within UPEC and hypothesized that they contribute to virulence. Here, we show that 8 of these 29 PSGs are required for fitness during persistent bacteriuria. Conversely, 7/8 of these PSG mutants showed essentially no phenotype in acute UTI. Deletion of the PSG argI leads to arginine auxotrophy. Relative to the other arg genes, argI in the B2 clade (which comprises most UPEC strains) of E. coli has diverged from argI in other E. coli clades. Replacement of argI in a UPEC strain with a non-UPEC argI allele complemented the arginine auxotrophy but not the persistent bacteriuria defect, showing that the UPEC argI allele contributes to persistent infection. These results highlight the complex roles of metabolic pathways during infection and demonstrate that evolutionary approaches can identify infection-specific gene functions downstream of population bottlenecks, shedding light on virulence and the genetic evolution of pathogenesis. IMPORTANCE Uropathogenic Escherichia coli (UPEC) is the most common cause of human urinary tract infection (UTI). Population bottlenecks during early stages of UTI make high-throughput screens impractical for understanding clinically important later stages of UTI, such as persistence and recurrence. As UPEC is hypothesized to be adapted to these later pathogenic stages, we previously identified 29 genes evolving under positive selection in UPEC. Here, we found that 8 of these genes, including argI (which is involved in arginine biosynthesis), are important for persistence in a mouse model of UTI. Deletion of argI and other arginine synthesis genes resulted in (i) arginine auxotrophy and (ii) defects in persistent UTI. Replacement of a B2 clade argI with a non-B2 clade argI complemented arginine auxotrophy, but the resulting strain remained attenuated in its ability to cause persistent bacteriuria. Thus, argI may have a second function during UTI that is not related to simple arginine synthesis. This study demonstrates how variation in metabolic genes can impact virulence and provides insight into the mechanisms and evolution of bacterial virulence.Michael E. HibbingKaren W. DodsonVasilios KalasSwaine L. ChenScott J. HultgrenAmerican Society for MicrobiologyarticleEscherichia coliarginine metabolismpositive selectionurinary tract infectionMicrobiologyQR1-502ENmBio, Vol 11, Iss 5 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Escherichia coli arginine metabolism positive selection urinary tract infection Microbiology QR1-502
spellingShingle	Escherichia coli arginine metabolism positive selection urinary tract infection Microbiology QR1-502 Michael E. Hibbing Karen W. Dodson Vasilios Kalas Swaine L. Chen Scott J. Hultgren Adaptation of Arginine Synthesis among Uropathogenic Branches of the <named-content content-type="genus-species">Escherichia coli</named-content> Phylogeny Reveals Adjustment to the Urinary Tract Habitat
description	ABSTRACT Urinary tract infections (UTIs) are predominantly caused by uropathogenic Escherichia coli (UPEC). UPEC pathogenesis requires passage through a severe population bottleneck involving intracellular bacterial communities (IBCs) that are clonal expansions of a single invading UPEC bacterium in a urothelial superficial facet cell. IBCs occur only during acute pathogenesis. The bacteria in IBCs form the founder population that develops into persistent extracellular infections. Only a small fraction of UPEC organisms proceed through the IBC cycle, regardless of the inoculum size. This dramatic reduction in population size precludes the utility of genomic mutagenesis technologies for identifying genes important for persistence. To circumvent this bottleneck, we previously identified 29 positively selected genes (PSGs) within UPEC and hypothesized that they contribute to virulence. Here, we show that 8 of these 29 PSGs are required for fitness during persistent bacteriuria. Conversely, 7/8 of these PSG mutants showed essentially no phenotype in acute UTI. Deletion of the PSG argI leads to arginine auxotrophy. Relative to the other arg genes, argI in the B2 clade (which comprises most UPEC strains) of E. coli has diverged from argI in other E. coli clades. Replacement of argI in a UPEC strain with a non-UPEC argI allele complemented the arginine auxotrophy but not the persistent bacteriuria defect, showing that the UPEC argI allele contributes to persistent infection. These results highlight the complex roles of metabolic pathways during infection and demonstrate that evolutionary approaches can identify infection-specific gene functions downstream of population bottlenecks, shedding light on virulence and the genetic evolution of pathogenesis. IMPORTANCE Uropathogenic Escherichia coli (UPEC) is the most common cause of human urinary tract infection (UTI). Population bottlenecks during early stages of UTI make high-throughput screens impractical for understanding clinically important later stages of UTI, such as persistence and recurrence. As UPEC is hypothesized to be adapted to these later pathogenic stages, we previously identified 29 genes evolving under positive selection in UPEC. Here, we found that 8 of these genes, including argI (which is involved in arginine biosynthesis), are important for persistence in a mouse model of UTI. Deletion of argI and other arginine synthesis genes resulted in (i) arginine auxotrophy and (ii) defects in persistent UTI. Replacement of a B2 clade argI with a non-B2 clade argI complemented arginine auxotrophy, but the resulting strain remained attenuated in its ability to cause persistent bacteriuria. Thus, argI may have a second function during UTI that is not related to simple arginine synthesis. This study demonstrates how variation in metabolic genes can impact virulence and provides insight into the mechanisms and evolution of bacterial virulence.
format	article
author	Michael E. Hibbing Karen W. Dodson Vasilios Kalas Swaine L. Chen Scott J. Hultgren
author_facet	Michael E. Hibbing Karen W. Dodson Vasilios Kalas Swaine L. Chen Scott J. Hultgren
author_sort	Michael E. Hibbing
title	Adaptation of Arginine Synthesis among Uropathogenic Branches of the <named-content content-type="genus-species">Escherichia coli</named-content> Phylogeny Reveals Adjustment to the Urinary Tract Habitat
title_short	Adaptation of Arginine Synthesis among Uropathogenic Branches of the <named-content content-type="genus-species">Escherichia coli</named-content> Phylogeny Reveals Adjustment to the Urinary Tract Habitat
title_full	Adaptation of Arginine Synthesis among Uropathogenic Branches of the <named-content content-type="genus-species">Escherichia coli</named-content> Phylogeny Reveals Adjustment to the Urinary Tract Habitat
title_fullStr	Adaptation of Arginine Synthesis among Uropathogenic Branches of the <named-content content-type="genus-species">Escherichia coli</named-content> Phylogeny Reveals Adjustment to the Urinary Tract Habitat
title_full_unstemmed	Adaptation of Arginine Synthesis among Uropathogenic Branches of the <named-content content-type="genus-species">Escherichia coli</named-content> Phylogeny Reveals Adjustment to the Urinary Tract Habitat
title_sort	adaptation of arginine synthesis among uropathogenic branches of the <named-content content-type="genus-species">escherichia coli</named-content> phylogeny reveals adjustment to the urinary tract habitat
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/23fc2786fb1345899573ba2c852d6774
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Adaptation of Arginine Synthesis among Uropathogenic Branches of the <named-content content-type="genus-species">Escherichia coli</named-content> Phylogeny Reveals Adjustment to the Urinary Tract Habitat

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