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Genetically diverse uropathogenic Escherichia coli adopt a common transcriptional program in patients with UTIs.

ABSTRACT: Uropathogenic Escherichia coli (UPEC) is the major causative agent of uncomplicated urinary tract infections (UTIs). A common virulence genotype of UPEC strains responsible for UTIs is yet to be defined, due to the large variation of virulence factors observed in UPEC strains. We hypothesized that studying UPEC functional responses in patients might reveal universal UPEC features that enable pathogenesis. Here we identify a transcriptional program shared by genetically diverse UPEC strains isolated from 14 patients during uncomplicated UTIs. Strikingly, this in vivo gene expression program is marked by upregulation of translational machinery, providing a mechanism for the rapid growth within the host. Our analysis indicates that switching to a more specialized catabolism and scavenging lifestyle in the host allows for the increased translational output. Our study identifies a common transcriptional program underlying UTIs and illuminates the molecular underpinnings that likely facilitate the fast growth rate of UPEC in infected patients.

SUBMITTER: Sintsova A

PROVIDER: S-EPMC6802966 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Genetically diverse uropathogenic <i>Escherichia coli</i> adopt a common transcriptional program in patients with UTIs.

Sintsova Anna A Frick-Cheng Arwen E AE Smith Sara S Pirani Ali A Subashchandrabose Sargurunathan S Snitkin Evan S ES Mobley Harry H

eLife 20191021

Uropathogenic <i>Escherichia coli</i> (UPEC) is the major causative agent of uncomplicated urinary tract infections (UTIs). A common virulence genotype of UPEC strains responsible for UTIs is yet to be defined, due to the large variation of virulence factors observed in UPEC strains. We hypothesized that studying UPEC functional responses in patients might reveal universal UPEC features that enable pathogenesis. Here we identify a transcriptional program shared by genetically diverse UPEC strain ...[more]

PMID: 31633483

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Project description:Uropathogenic Escherichia coli (UPEC) is the primary causative agent of urinary tract infections (UTIs) in humans. Moreover, as one of the most common bacterial pathogens, UPEC imposes a substantial burden on healthcare systems worldwide. Epithelial cells and macrophages are two major components of the innate immune system, which play critical roles in defending the bladder against UPEC invasion. Yet, the routes of communication between these cells during UTI pathogenesis are still not fully understood. In the present study, we investigated the role of membrane-bound nanovesicles (exosomes) in the communication between bladder epithelial cells and macrophages during UPEC infection, using an array of techniques such as flow cytometry, miRNA profiling, RNA sequencing, and western blotting. Moreover, our in vitro findings were validated in a mouse model of UPEC-induced cystitis. We found that UPEC infection induced the bladder epithelial MB49 cell line to secrete large numbers of exosomes (MB49-U-Exo), which were efficiently absorbed by macrophages both in vivo and in vitro. Assimilation of MB49-U-Exo induced macrophages to produce proinflammatory cytokines, including tumor necrosis factor (TNF)α. Exposure of macrophages to MB49-U-Exo reduced their phagocytic activity (by downregulating the expression of phagocytosis-related genes) and increased their rate of apoptosis. Mechanistically, we showed that MB49-U-Exo were enriched in miR-18a-5p, which induced TNFα expression in macrophages by targeting PTEN and activating the MAPK/JNK signaling pathway. Moreover, administration of the exosome secretion inhibitor GW4869 or a TNFα-neutralizing antibody alleviated UPEC-mediated tissue damage in mice with UPEC-induced cystitis by reducing the bacterial burden of the bladder and dampening the associated inflammatory response. Collectively, these findings suggest that MB49-U-Exo regulate macrophage function in a way that exacerbates UPEC-mediated tissue impairment. Thus, targeting exosomal -release or TNFα signaling during UPEC infection may represent promising non-antibiotic strategies for treating UTIs.

Project description:Multidrug-resistant (MDR) Escherichia coli strains are a major global threat to human health, wherein multidrug resistance is primarily spread by MDR plasmid acquisition. MDR plasmids are not widely distributed across the entire E. coli species, but instead are concentrated in a small number of clones. Here, we test if diverse E. coli strains vary in their ability to acquire and maintain MDR plasmids and if this relates to their transcriptional response following plasmid acquisition. We used strains from across the diversity of E. coli strains, including the common MDR lineage sequence type 131 (ST131) and the IncF plasmid pLL35, carrying multiple antibiotic resistance genes. Strains varied in their ability to acquire pLL35 by conjugation, but all were able to stably maintain the plasmid. The effects of pLL35 acquisition on cefotaxime resistance and growth also varied among strains, with growth responses ranging from a small decrease to a small increase in growth of the plasmid carrier relative to the parental strain. Transcriptional responses to pLL35 acquisition were limited in scale and highly strain specific. We observed transcriptional responses at the operon or regulon level-possibly due to stress responses or interactions with resident mobile genetic elements (MGEs). Subtle transcriptional responses consistent across all strains were observed affecting functions, such as anaerobic metabolism, previously shown to be under negative frequency-dependent selection in MDR E. coli Overall, there was no correlation between the magnitudes of the transcriptional and growth responses across strains. Together, these data suggest that fitness costs arising from transcriptional disruption are unlikely to act as a barrier to dissemination of this MDR plasmid in E. coli IMPORTANCE Plasmids play a key role in bacterial evolution by transferring adaptive functions between lineages that often enable invasion of new niches, including driving the spread of antibiotic resistance genes. Fitness costs of plasmid acquisition arising from the disruption of cellular processes could limit the spread of multidrug resistance plasmids. However, the impacts of plasmid acquisition are typically measured in lab-adapted strains rather than natural isolates, which act as reservoirs for the maintenance and transmission of plasmids to clinically relevant strains. Using a clinical multidrug resistance plasmid and a diverse collection of E. coli strains isolated from clinical infections and natural environments, we show that plasmid acquisition had only limited and highly strain-specific effects on bacterial growth and transcription under laboratory conditions. These findings suggest that fitness costs arising from transcriptional disruption are unlikely to act as a barrier to transmission of this plasmid in natural populations of E. coli.

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Genetically diverse uropathogenic Escherichia coli adopt a common transcriptional program in patients with UTIs.

Publications

Genetically diverse uropathogenic <i>Escherichia coli</i> adopt a common transcriptional program in patients with UTIs.

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