Genome analysis of Salmonella enterica serovar enteritis strains isolated from poultry and humans in Burkina Faso.

Whole-genome sequencing (WGS) was used to characterize four Salmonella enterica Enteritidis isolates from poultry (n=2) and human (n=2) from Ouagadougou, Burkina Faso. Antimicrobial resistance genes, chromosomal mutations, and mobile genetic elements were identified by analysis of WGS data using sequence homology.

Prevalence and Subtype Characterization of Campylobacter in Ceca of Commercial Broiler Chickens at Processing - A 452 Flock, Seven-year Survey.

Human Campylobacter infections have been associated with chicken and other poultry meat products. Environmental conditions such as temperature and season can affect Campylobacter recoverability from chicken meat products. In the presented study, we sought to investigate the relationship between ambient weather conditions and the isolation of Campylobacter from chicken flocks, as well as the subtype of these isolates. Campylobacter was isolated from the ceca of broilers collected in a commercial processing facility over 7 years, representing 452 flocks. Isolates were subjected to whole-genome sequencing and subtyping by multilocus sequence typing (MLST). Approximately 60% (269/452) of flocks sampled were positive for Campylobacter. There was no significant effect on the presence of detectable Campylobacter by month, season, temperature, or rainfall during grow-out or transportation. Sixty-eight different STs were detected; 45 C. jejuni and 23 C. coli. Diversity as measured by Shannon's diversity index was higher in the spring and fall than in mid-winter and summer. We concluded that in the warm temperate climate of the Southeastern U.S., seasonality does not affect the rate of Campylobacter isolation from broilers, but the diversity of isolates was higher in the milder spring and fall seasons.

Exudate From Retail Chicken Liver Packaging Allows for Survival of Naturally Occurring Campylobacter, Coliforms, and Aerobic Microorganisms Under Drying Conditions.

Campylobacter spp. are a leading cause of human foodborne illness associated with chicken meat products in the United States. Chicken livers, including exudate from packaging, commonly carry Campylobacter and could be a source of illness if mishandled. Survivability of naturally occurring Campylobacter, total aerobic bacteria, and coliforms was determined under drying conditions in two consumer simulated environments: moist sponge and solid surface. Fresh chicken liver exudate was dispensed onto sponges and glass slides and allowed to dry under ambient conditions for 7 days. Bacterial concentration was measured at 0, 6, 24, 48, 72, and 168 h. Total aerobic population did not decrease by more than one log over 7 days and did not correlate to water activity or time in either simulation. Coliform concentrations increased in sponge simulations but decreased in solid surface simulations. Further, coliform concentrations were significantly higher in sponge simulations than in solid surface. Campylobacter was naturally present in exudate and survived at least to 6 h in every trial. Campylobacter was recoverable at 24 h in some sponge trials. However, Campylobacter concentration was strongly correlated to water activity. Fresh chicken liver exudate could present a risk of campylobacteriosis to consumers if mishandled even after drying.

Polymerase chain reaction for the in vitro detection of the pESI plasmid associated with the globally circulating Salmonella Infantis outbreak strain.

A globally circulating strain of Salmonella enterica serotype Infantis containing the pESI plasmid has increased in prevalence in poultry meat samples and cases of human infections. In this study, a polymerase chain reaction (PCR) protocol was designed to detect the pESI plasmid and confirm the Infantis serotype of Salmonella isolates. Primers were tested bioinformatically to predict specificity, sensitivity, and precision. A total of 54 isolates of Salmonella serotypes Infantis, Senftenberg, and Alachua were tested, with and without the pESI plasmid carriage. Isolates of 31 additional serotypes were also screened to confirm specificity to Infantis. Specificity, sensitivity, and precision of each primer were >0.95. All isolates tested produced the expected band sizes. This PCR protocol provides a rapid and clear result for the detection of the pESI plasmid and serotype Infantis and will allow for the in vitro detection for epidemiological studies where whole-genome sequencing is not available.

Buffered Peptone Water Formulation Does Not Influence Growth of pESI-positive Salmonella enterica Serovar Infantis.

Salmonella enterica is a major cause of human foodborne illness and is often attributed to poultry food sources. S. enterica serovar Infantis, specifically those carrying the pESI plasmid, has become a frequently isolated serotype from poultry meat samples at processing and has caused numerous recent human infections. In 2016, the USDA-Food Safety and Inspection Service changed the official sampling method for raw poultry products from BPW to using neutralizing BPW (nBPW) as the rinsing agent in order to prevent residual antimicrobial effects from acidifying and oxidizing processing aids. This change was contemporaneous to the emergence of pESI-positive ser. Infantis as a prevalent serovar in poultry, prompting some to question if nBPW could be selecting for this prevalent serovar. We performed two experiments: a comparison of ser. Infantis growth in BPW versus nBPW, and a simulation of regulatory sampling methods. We found that when inoculated into both broths, ser. Infantis initially grows slightly slower in nBPW than in BPW but little difference was seen in abundance after 6 h of growth. Additionally, the use of nBPW to simulate poultry rinse sample and overnight cold shipping to a regulatory lab did not affect the survival or subsequent growth of ser. Infantis in BPW. We concluded that the change in USDA-FSIS methodology to include nBPW in sampling procedures has likely not affected the emergence of S. ser. Infantis as a prevalent serovar in chicken and turkey meat product samples.

High-throughput functional annotation of natural products by integrated activity profiling.

Determining mechanism of action (MOA) is one of the biggest challenges in natural products discovery. Here, we report a comprehensive platform that uses Similarity Network Fusion (SNF) to improve MOA predictions by integrating data from the cytological profiling high-content imaging platform and the gene expression platform Functional Signature Ontology, and pairs these data with untargeted metabolomics analysis for de novo bioactive compound discovery. The predictive value of the integrative approach was assessed using a library of target-annotated small molecules as benchmarks. Using Kolmogorov-Smirnov (KS) tests to compare in-class to out-of-class similarity, we found that SNF retains the ability to identify significant in-class similarity across a diverse set of target classes, and could find target classes not detectable in either platform alone. This confirmed that integration of expression-based and image-based phenotypes can accurately report on MOA. Furthermore, we integrated untargeted metabolomics of complex natural product fractions with the SNF network to map biological signatures to specific metabolites. Three examples are presented where SNF coupled with metabolomics was used to directly functionally characterize natural products and accelerate identification of bioactive metabolites, including the discovery of the azoxy-containing biaryl compounds parkamycins A and B. Our results support SNF integration of multiple phenotypic screening approaches along with untargeted metabolomics as a powerful approach for advancing natural products drug discovery.

Increased Prevalence of Salmonella Infantis Isolated from Raw Chicken and Turkey Products in the United States Is Due to a Single Clonal Lineage Carrying the pESI Plasmid.

Infantis has recently become one of the most common serotypes of Salmonella isolated in the U.S. from raw meat samples collected in processing facilities and in retail stores. Investigations have determined that the majority of these isolates contain the pESI plasmid, but there has not been a large-scale investigation of the chromosome of these isolates. Here, we investigated 3276 whole-genome sequences of Salmonella Infantis with and without the pESI plasmid to understand chromosomal differences between plasmid carriage groups. S. Infantis genomes arranged into multiple clades with a single clade containing the isolates carrying the plasmid. Fifty-eight SNPs were identified in complete linkage disequilibrium between isolates that did and did not carry the plasmid. However, there were no unique genes present only in the genomes of isolates containing the plasmid. On average, isolates with the plasmid did contain more insertion sequences than those without (p < 0.05). Given that S. Infantis isolates carrying pESI form a single clade, it can be inferred that the increase in carriage of this plasmid in the U.S. is due to rapid clonal expansion of a single strain rather than as a result of multiple transfer events. As this S. Infantis clone does not contain any unique chromosomal genes, its proliferation appears to be due to pESI plasmid-encoded genes that may be advantageous in the chickens and turkeys or in their environment.

PARP1-SNAI2 transcription axis drives resistance to PARP inhibitor, Talazoparib.

The synthetic lethal association between BRCA deficiency and poly (ADP-ribose) polymerase (PARP) inhibition supports PARP inhibitor (PARPi) clinical efficacy in BRCA-mutated tumors. PARPis also demonstrate activity in non-BRCA mutated tumors presumably through induction of PARP1-DNA trapping. Despite pronounced clinical response, therapeutic resistance to PARPis inevitably develops. An abundance of knowledge has been built around resistance mechanisms in BRCA-mutated tumors, however, parallel understanding in non-BRCA mutated settings remains insufficient. In this study, we find a strong correlation between the epithelial-mesenchymal transition (EMT) signature and resistance to a clinical PARPi, Talazoparib, in non-BRCA mutated tumor cells. Genetic profiling demonstrates that SNAI2, a master EMT transcription factor, is transcriptionally induced by Talazoparib treatment or PARP1 depletion and this induction is partially responsible for the emerging resistance. Mechanistically, we find that the PARP1 protein directly binds to SNAI2 gene promoter and suppresses its transcription. Talazoparib treatment or PARP1 depletion lifts PARP1-mediated suppression and increases chromatin accessibility around SNAI2 promoters, thus driving SNAI2 transcription and drug resistance. We also find that depletion of the chromatin remodeler CHD1L suppresses SNAI2 expression and reverts acquired resistance to Talazoparib. The PARP1/CHD1L/SNAI2 transcription axis might be therapeutically targeted to re-sensitize Talazoparib in non-BRCA mutated tumors.

Distribution and Transfer of Plasmid Replicon Families among Multidrug-Resistant Enterococcus faecalis and Enterococcus faecium from Poultry.

The presence and transfer of plasmids from commensal bacteria to more pathogenic bacteria may contribute to the dissemination of antimicrobial resistance. However, the prevalence of plasmids from commensal bacteria, such as the enterococci, in food animals remains largely unknown. In this study, the diversity and prevalence of plasmid families from multidrug-resistant (MDR; resistance to three or more antimicrobials) enterococci from poultry carcasses were determined. Plasmid-positive MDR enterococci were also tested for the ability to transfer plasmids to other enterococci using conjugation. MDR Enterococcus faecalis (n = 98) and Enterococcus faecium (n = 696) that were isolated from poultry carcass rinsates between 2004 and 2011 were tested for the presence of 21 plasmid replicon (rep) families using multiplex PCR. Approximately 48% of E. faecalis (47/98) and 16% of E. faecium (110/696) were positive for at least one rep-family. Fourteen rep-families were detected overall, and ten rep-families were shared between E. faecalis and E. faecium. The rep7 and rep17 families were unique to E. faecalis, while the rep5 and rep8 families were unique to E. faecium. The rep9 family was predominant in both E. faecalis and E. faecium for all the years tested. The greatest number of rep-families detected was in 2005 (n = 10), and the least was in 2009 (n = 1). Eight rep-families were transferred from E. faecalis donors to the E. faecalis JH2-2 recipient using conjugation. Results from this study showed that E. faecalis and E. faecium from poultry carcasses contain numerous and diverse rep-families that are capable of conjugal transfer.

Resistance Genes, Plasmids, Multilocus Sequence Typing (MLST), and Phenotypic Resistance of Non-Typhoidal Salmonella (NTS) Isolated from Slaughtered Chickens in Burkina Faso.

The emergence of antimicrobial-resistant bacteria in developing countries increases risks to the health of both such countries' residents and the global community due to international travel. It is consequently necessary to investigate antimicrobial-resistant pathogens in countries such as Burkina Faso, where surveillance data are not available. To study the epidemiology of antibiotic resistance in Salmonella, 102 Salmonella strains isolated from slaughtered chickens were subjected to whole-genome sequencing (WGS) to obtain information on antimicrobial resistance (AMR) genes and other genetic factors. Twenty-two different serotypes were identified using WGS, the most prevalent of which were Hato (28/102, 27.5%) and Derby (23/102, 22.5%). All strains analyzed possessed at least one and up to nine AMR genes, with the most prevalent being the non-functional aac(6')-Iaa gene, followed by aph(6)-Id. Multi-drug resistance was found genotypically in 36.2% of the isolates for different classes of antibiotics, such as fosfomycin and ß-lactams, among others. Plasmids were identified in 43.1% of isolates (44/102), and 25 plasmids were confirmed to carry AMR genes. The results show that chicken can be considered as a reservoir of antibiotic-resistant Salmonella strains. Due to the prevalence of these drug-resistant pathogens and the potential for foodborne illnesses, poultry processing and cooking should be performed with attention to prescribed safe handling methods to avoid cross-contamination with chicken products.

Analysis of Salmonella enterica Isolated from a Mixed-Use Watershed in Georgia, USA: Antimicrobial Resistance, Serotype Diversity, and Genetic Relatedness to Human Isolates.

As the cases of Salmonella enterica infections associated with contaminated water are increasing, this study was conducted to address the role of surface water as a reservoir of S. enterica serotypes. We sampled rivers and streams (n = 688) over a 3-year period (2015 to 2017) in a mixed-use watershed in Georgia, USA, and 70.2% of the total stream samples tested positive for Salmonella. A total of 1,190 isolates were recovered and characterized by serotyping, antimicrobial susceptibility testing, and pulsed-field gel electrophoresis (PFGE). A wide range of serotypes was identified, including those commonly associated with humans and animals, with S. enterica serotype Muenchen being predominant (22.7%) and each serotype exhibiting a high degree of strain diversity by PFGE. About half (46.1%) of the isolates had PFGE patterns indistinguishable from those of human clinical isolates in the CDC PulseNet database. A total of 52 isolates (4.4%) were resistant to antimicrobials, out of which 43 isolates were multidrug resistant (MDR; resistance to two or more classes of antimicrobials). These 52 resistant Salmonella isolates were screened for the presence of antimicrobial resistance genes, plasmid replicons, and class 1 integrons, out of which four representative MDR isolates were selected for whole-genome sequencing analysis. The results showed that 28 MDR isolates resistant to 10 antimicrobials had blacmy-2 on an A/C plasmid. Persistent contamination of surface water with a high diversity of Salmonella strains, some of which are drug resistant and genetically indistinguishable from human isolates, supports a role of environmental surface water as a reservoir for and transmission route of this pathogen. IMPORTANCE Salmonella has been traditionally considered a foodborne pathogen, as it is one of the most common etiologies of foodborne illnesses worldwide; however, recent Salmonella outbreaks attributed to fresh produce and water suggest a potential environmental source of Salmonella that causes some human illnesses. Here, we investigated the prevalence, diversity, and antimicrobial resistance of Salmonella isolated from a mixed-use watershed in Georgia, USA, in order to enhance the overall understanding of waterborne Salmonella. The persistence and widespread distribution of Salmonella in surface water confirm environmental sources of the pathogen. A high proportion of waterborne Salmonella with clinically significant serotypes and genetic similarity to strains of human origin supports the role of environmental water as a significant reservoir of Salmonella and indicates a potential waterborne transmission of Salmonella to humans. The presence of antimicrobial-resistant and MDR Salmonella demonstrates additional risks associated with exposure to contaminated environmental water.

SAM-Competitive PRMT5 Inhibitor PF-06939999 Demonstrates Antitumor Activity in Splicing Dysregulated NSCLC with Decreased Liability of Drug Resistance.

Protein arginine methyltransferase 5 (PRMT5) overexpression in hematologic and solid tumors methylates arginine residues on cellular proteins involved in important cancer functions including cell-cycle regulation, mRNA splicing, cell differentiation, cell signaling, and apoptosis. PRMT5 methyltransferase function has been linked with high rates of tumor cell proliferation and decreased overall survival, and PRMT5 inhibitors are currently being explored as an approach for targeting cancer-specific dependencies due to PRMT5 catalytic function. Here, we describe the discovery of potent and selective S-adenosylmethionine (SAM) competitive PRMT5 inhibitors, with in vitro and in vivo characterization of clinical candidate PF-06939999. Acquired resistance mechanisms were explored through the development of drug resistant cell lines. Our data highlight compound-specific resistance mutations in the PRMT5 enzyme that demonstrate structural constraints in the cofactor binding site that prevent emergence of complete resistance to SAM site inhibitors. PRMT5 inhibition by PF-06939999 treatment reduced proliferation of non-small cell lung cancer (NSCLC) cells, with dose-dependent decreases in symmetric dimethyl arginine (SDMA) levels and changes in alternative splicing of numerous pre-mRNAs. Drug sensitivity to PF-06939999 in NSCLC cells associates with cancer pathways including MYC, cell cycle and spliceosome, and with mutations in splicing factors such as RBM10. Translation of efficacy in mouse tumor xenograft models with splicing mutations provides rationale for therapeutic use of PF-06939999 in the treatment of splicing dysregulated NSCLC.

Genomic Comparison of Conjugative Plasmids from Salmonella enterica and Escherichia coli Encoding Beta-Lactamases and Capable of Mobilizing Kanamycin Resistance Col-like Plasmids.

Salmonella enterica and Escherichia coli are important human pathogens that frequently contain plasmids, both large and small, carrying antibiotic resistance genes. Large conjugative plasmids are known to mobilize small Col plasmids, but less is known about the specificity of mobilization. In the current study, six S. enterica and four E. coli strains containing large plasmids were tested for their ability to mobilize three different kanamycin resistance Col plasmids (KanR plasmids). Large conjugative plasmids from five isolates, four S. enterica and one E. coli, were able to mobilize KanR plasmids of various types. Plasmids capable of mobilizing the KanR plasmids were either IncI1 or IncX, while IncI1 and IncX plasmids with no evidence of conjugation had disrupted transfer regions. Conjugative plasmids of similar types mobilized similar KanR plasmids, but not all conjugative plasmid types were capable of mobilizing all of the KanR plasmids. These data describe some of the complexities and specificities of individual small plasmid mobilization.

Exocyst protein subnetworks integrate Hippo and mTOR signaling to promote virus detection and cancer.

The exocyst is an evolutionarily conserved protein complex that regulates vesicular trafficking and scaffolds signal transduction. Key upstream components of the exocyst include monomeric RAL GTPases, which help mount cell-autonomous responses to trophic and immunogenic signals. Here, we present a quantitative proteomics-based characterization of dynamic and signal-dependent exocyst protein interactomes. Under viral infection, an Exo84 exocyst subcomplex assembles the immune kinase Protein Kinase R (PKR) together with the Hippo kinase Macrophage Stimulating 1 (MST1). PKR phosphorylates MST1 to activate Hippo signaling and inactivate Yes Associated Protein 1 (YAP1). By contrast, a Sec5 exocyst subcomplex recruits another immune kinase, TANK binding kinase 1 (TBK1), which interacted with and activated mammalian target of rapamycin (mTOR). RALB was necessary and sufficient for induction of Hippo and mTOR signaling through parallel exocyst subcomplex engagement, supporting the cellular response to virus infection and oncogenic signaling. This study highlights RALB-exocyst signaling subcomplexes as mechanisms for the integrated engagement of Hippo and mTOR signaling in cells challenged by viral pathogens or oncogenic signaling.

Serotyping of sub-Saharan Africa Salmonella strains isolated from poultry feces using multiplex PCR and whole genome sequencing.

BACKGROUND: Salmonella enterica remains a leading cause of food-borne diseases worldwide. Serotype information is important in food safety and public health activities to reduce the burden of salmonellosis. In the current study, two methods were used to determine serotypes of 111 strains of Salmonella isolated from poultry feces in Burkina Faso. First, Salmonella Multiplex Assay for Rapid Typing (SMART) Polymerase Chain Reaction (PCR) was used to determine the serovars of the S. enterica isolates. Second, serovar prediction based on whole genome sequencing (WGS) data was performed using SeqSero 2.0. RESULTS: Among the 111 Salmonella isolates, serotypes for 17 (15.31%) isolates were identified based on comparison to a panel of representative SMART codes previously determined for the 50 most common serovars in the United States. Forty-four (44) new SMART codes were developed for common and uncommon serotypes. A total of 105 (94.59%) isolates were serotyped using SeqSero 2.0 for serovar prediction based on WGS data. CONCLUSION: We determined that SeqSero 2.0 was more comprehensive for identifying Salmonella serotypes from Burkina Faso than SMART PCR.

A stress-induced tyrosine-tRNA depletion response mediates codon-based translational repression and growth suppression.

Eukaryotic transfer RNAs can become selectively fragmented upon various stresses, generating tRNA-derived small RNA fragments. Such fragmentation has been reported to impact a small fraction of the tRNA pool and thus presumed to not directly impact translation. We report that oxidative stress can rapidly generate tyrosine-tRNAGUA fragments in human cells-causing significant depletion of the precursor tRNA. Tyrosine-tRNAGUA depletion impaired translation of growth and metabolic genes enriched in cognate tyrosine codons. Depletion of tyrosine tRNAGUA or its translationally regulated targets USP3 and SCD repressed proliferation-revealing a dedicated tRNA-regulated growth-suppressive pathway for oxidative stress response. Tyrosine fragments are generated in a DIS3L2 exoribonuclease-dependent manner and inhibit hnRNPA1-mediated transcript destabilization. Moreover, tyrosine fragmentation is conserved in C. elegans. Thus, tRNA fragmentation can coordinately generate trans-acting small RNAs and functionally deplete a tRNA. Our findings reveal the existence of an underlying adaptive codon-based regulatory response inherent to the genetic code.

Carriage and Gene Content Variability of the pESI-Like Plasmid Associated with Salmonella Infantis Recently Established in United States Poultry Production.

Salmonella Infantis carrying extended spectrum ß-lactamase blaCTX-M-65 on a pESI-like megaplasmid has recently emerged in United States poultry. In order to determine the carriage rate and gene content variability of this plasmid in U.S. Salmonella Infantis, whole genome sequences of Salmonella isolates from humans and animals in the U.S. and internationally containing the pESI-like plasmid were analyzed. The U.S. Department of Agriculture Food Safety and Inspection Service (FSIS) identified 654 product sampling isolates containing pESI-like plasmids through hazard analysis and critical control point (HACCP) verification testing in 2017 and 2018. The Centers for Disease Control and Prevention identified 55 isolates with pESI-like plasmids in 2016-2018 through the National Antimicrobial Resistance Monitoring System. Approximately 49% of pESI-like plasmids from FSIS verification isolates and 71% from CDC NARMS contained blaCTX-M-65. Pan-plasmid genome analysis was also performed. All plasmids contained traN and more than 95% contained 172 other conserved genes; 61% contained blaCTX-M-65. In a hierarchical clustering analysis, some plasmids from U.S. animal sources clustered together and some plasmids from South America clustered together, possibly indicating multiple plasmid lineages. However, most plasmids contained similar genes regardless of origin. Carriage of the pESI-like plasmid in U.S. appears to be limited to Salmonella Infantis and carriage rates increased from 2017 to 2018.

Transferable Plasmids of Salmonella enterica Associated With Antibiotic Resistance Genes.

Salmonella enterica is a common foodborne illness in the United States and globally. An increasing number of Salmonella infections are resistant to antibiotics, and many of the genes responsible for those resistances are carried by plasmids. Plasmids are important mediators of horizontal gene exchange, which could potentially increase the spread of antibiotic resistance (AR) genes. Twenty-eight different incompatibility groups of plasmids have been described in Enterobacteriaceae. Incompatibility groups differ in their accessory gene content, replication mechanisms, and their associations with Salmonella serotypes and animal sources. Plasmids also differ in their ability to conjugate or be mobilized, essential genes, and conditions required for transfer. It is important to understand the differences in gene content and transfer mechanisms to accurately determine the impact of plasmids on the dissemination and persistence of antibiotic resistance genes. This review will cover the most common plasmid incompatibility groups present in S. enterica with a focus on the transfer mechanisms and associated antibiotic resistance genes.

Genomic Analysis of Multidrug-Resistant Escherichia coli from Surface Water in Northeast Georgia, United States: Presence of an ST131 Epidemic Strain Containing blaCTX-M-15 on a Phage-Like Plasmid.

Surface water is suspected of playing a role in the development and spread of antimicrobial-resistant (AR) bacteria, including human pathogens. In our previous study, 496 Escherichia coli isolates were recovered from water samples collected over a 2-year period from the Upper Oconee watershed, Athens, GA, United States, of which 34 (6.9%) were AR isolates. Of these, six isolates were selected based on their multidrug resistance (MDR) phenotypes, the presence of mobile genetic elements, and their pathogenic potential and were subjected to whole-genome sequence (WGS) analysis to enhance our understanding of environmental MDR E. coli isolates. This study is the first report on genomic characterization of MDR E. coli from environmental water in the United States through a WGS approach. The sequences of the six MDR E. coli isolates were analyzed and the locations of their AR genes were identified. One of the E. coli isolates was an ST131 epidemic strain, which also produced an extended-spectrum ß-lactamase encoded by the blaCTX-M-15 gene, carried on a plasmid that is a member of a very rarely reported family of phage-like plasmids. This is the first time an in-depth sequence analysis has been done on a blaCTX-M-15- containing phage-like plasmid, the presence of which suggests a new emerging mechanism of AR gene transmission.

Molecular determinants of nephron vascular specialization in the kidney.

Although kidney parenchymal tissue can be generated in vitro, reconstructing the complex vasculature of the kidney remains a daunting task. The molecular pathways that specify and sustain functional, phenotypic and structural heterogeneity of the kidney vasculature are unknown. Here, we employ high-throughput bulk and single-cell RNA sequencing of the non-lymphatic endothelial cells (ECs) of the kidney to identify the molecular pathways that dictate vascular zonation from embryos to adulthood. We show that the kidney manifests vascular-specific signatures expressing defined transcription factors, ion channels, solute transporters, and angiocrine factors choreographing kidney functions. Notably, the ontology of the glomerulus coincides with induction of unique transcription factors, including Tbx3, Gata5, Prdm1, and Pbx1. Deletion of Tbx3 in ECs results in glomerular hypoplasia, microaneurysms and regressed fenestrations leading to fibrosis in subsets of glomeruli. Deciphering the molecular determinants of kidney vascular signatures lays the foundation for rebuilding nephrons and uncovering the pathogenesis of kidney disorders.