scholarly journals Spatiotemporal Distribution of Pseudomonas aeruginosa Alkyl Quinolones under Metabolic and Competitive Stress

mSphere ◽  
2020 ◽  
Vol 5 (4) ◽  
Author(s):  
Tianyuan Cao ◽  
Jonathan V. Sweedler ◽  
Paul W. Bohn ◽  
Joshua D. Shrout
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Bacterial Species ◽  
Metabolic Stress ◽  
Opportunistic Pathogen ◽  
Cell Interaction ◽  
Chemical Imaging ◽  
Carbon Limitation ◽  
Bacterial Strains ◽  
Content Type ◽  
High Level

ABSTRACT Pseudomonas aeruginosa is an opportunistic human pathogen important to diseases such as cystic fibrosis. P. aeruginosa has multiple quorum-sensing (QS) systems, one of which utilizes the signaling molecule 2-heptyl-3-hydroxy-4-quinolone (Pseudomonas quinolone signal [PQS]). Here, we use hyperspectral Raman imaging to elucidate the spatiotemporal PQS distributions that determine how P. aeruginosa regulates surface colonization and its response to both metabolic stress and competition from other bacterial strains. These chemical imaging experiments illustrate the strong link between environmental challenges, such as metabolic stress caused by nutritional limitations or the presence of another bacterial species, and PQS signaling. Metabolic stress elicits a complex response in which limited nutrients induce the bacteria to produce PQS earlier, but the bacteria may also pause PQS production entirely if the nutrient concentration is too low. Separately, coculturing P. aeruginosa in the proximity of another bacterial species, or its culture supernatant, results in earlier production of PQS. However, these differences in PQS appearance are not observed for all alkyl quinolones (AQs) measured; the spatiotemporal response of 2-heptyl-4-hydroxyquinoline N-oxide (HQNO) is highly uniform for most conditions. These insights on the spatiotemporal distributions of quinolones provide additional perspective on the behavior of P. aeruginosa in response to different environmental cues. IMPORTANCE Alkyl quinolones (AQs), including Pseudomonas quinolone signal (PQS), made by the opportunistic pathogen Pseudomonas aeruginosa have been associated with both population density and stress. The regulation of AQ production is known to be complex, and the stimuli that modulate AQ responses are not fully clear. Here, we have used hyperspectral Raman chemical imaging to examine the temporal and spatial profiles of AQs exhibited by P. aeruginosa under several potentially stressful conditions. We found that metabolic stress, effected by carbon limitation, or competition stress, effected by proximity to other species, resulted in accelerated PQS production. This competition effect did not require cell-to-cell interaction, as evidenced by the fact that the addition of supernatants from either Escherichia coli or Staphylococcus aureus led to early appearance of PQS. Lastly, the fact that these modulations were observed for PQS but not for all AQs suggests a high level of complexity in AQ regulation that remains to be discerned.

scholarly journals Metapopulation Structure of CRISPR-Cas Immunity inPseudomonas aeruginosaand Its Viruses

mSystems ◽  
2018 ◽  
Vol 3 (5) ◽  
Author(s):  
Whitney E. England ◽  
Ted Kim ◽  
Rachel J. Whitaker
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Critical Role ◽  
Opportunistic Pathogen ◽  
Microbial Populations ◽  
Bacterial Strains ◽  
Viral Control ◽  
Data Set ◽  
Content Type ◽  
Global Population

ABSTRACTViruses that infect the widespread opportunistic pathogenPseudomonas aeruginosahave been shown to influence physiology and critical clinical outcomes in cystic fibrosis (CF) patients. To understand how CRISPR-Cas immune interactions may contribute to the distribution and coevolution ofP. aeruginosaand its viruses, we reconstructed CRISPR arrays from a highly sampled longitudinal data set from CF patients attending the Copenhagen Cystic Fibrosis Clinic in Copenhagen, Denmark (R. L. Marvig, L. M. Sommer, S. Molin, and H. K. Johansen, Nat Genet 47:57–64, 2015,https://doi.org/10.1038/ng.3148). We show that new spacers are not added to or deleted from CRISPR arrays over time within a single patient but do vary among patients in this data set. We compared assembled CRISPR arrays from this data set to CRISPR arrays extracted from 726 additional publicly availableP. aeruginosasequences to show that local diversity in this population encompasses global diversity and that there is no evidence for population structure associated with location or environment sampled. We compare over 3,000 spacers from our global data set to 98 lytic and temperate viruses and proviruses and find a subset of related temperate virus clusters frequently targeted by CRISPR spacers. Highly targeted viruses are matched by different spacers in different arrays, resulting in a pattern of distributed immunity within the global population. Understanding the multiple immune contexts thatP. aeruginosaviruses face can be applied to study ofP. aeruginosagene transfer, the spread of epidemic strains in cystic fibrosis patients, and viral control ofP. aeruginosainfection.IMPORTANCEPseudomonas aeruginosais a widespread opportunistic pathogen and a major cause of morbidity and mortality in cystic fibrosis patients. Microbe-virus interactions play a critical role in shaping microbial populations, as viral infections can kill microbial populations or contribute to gene flow among microbes. Investigating howP. aeruginosauses its CRISPR immune system to evade viral infection aids our understanding of how this organism spreads and evolves alongside its viruses in humans and the environment. Here, we identify patterns of CRISPR targeting and immunity that indicateP. aeruginosaand its viruses evolve in both a broad global population and in isolated human “islands.” These data set the stage for exploring metapopulation dynamics occurring within and between isolated “island” populations associated with CF patients, an essential step to inform future work predicting the specificity and efficacy of virus therapy and the spread of invasive viral elements and pathogenic epidemic bacterial strains.

scholarly journals Secretion of Flagellar Proteins by the Pseudomonas aeruginosa Type III Secretion-Injectisome System

2015 ◽  
Vol 197 (12) ◽  
pp. 2003-2011 ◽  
Author(s):  
Dilek Ince ◽  
Fayyaz S. Sutterwala ◽  
Timothy L. Yahr
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Type Iii Secretion ◽  
Bacterial Species ◽  
Opportunistic Pathogen ◽  
Host Cells ◽  
Inflammasome Activation ◽  
Content Type ◽  
Type Iii ◽  
Amino Terminal ◽  
Flagellar Proteins

ABSTRACTThe opportunistic pathogenPseudomonas aeruginosautilizes an injectisome-type III secretion system (injectisome-T3SS) to elicit cytotoxicity toward epithelial cells and macrophages. Macrophage killing results from the cytotoxic properties of the translocated effector proteins (ExoS, ExoT, ExoU, and ExoY) and inflammasome-mediated induction of pyroptosis. Inflammasome activation can occur following Nlrc4-mediated recognition of cytosolic translocated flagellin (FliC). In the present study, we demonstrate that FliC is a secretion substrate of both the injectisome- and flagellum-associated T3SSs. Molecular analyses indicate that the first 20 amino-terminal residues of FliC are sufficient for secretion by the injectisome-T3SS and that the first 100 residues are sufficient for translocation of FliC into host cells. Although maximal inflammasome activation requires FliC, activation can also occur in the absence of FliC. This prompted us to examine whether other flagellar components might also be translocated into cells to elicit inflammasome activation. Indeed, we find that the flagellar cap (FliD), hook-associated (FlgK and FlgL), hook (FlgE), and rod (FlgE) proteins are secretion substrates of the injectisome-T3SS. None of these proteins, however, result in increased inflammasome activation when they are overexpressed in afliCmutant and appear to be translocated into host cells. While a role in inflammasome activation has been excluded, these data raise the possibility that flagellar components, which are highly conserved between different bacterial species, trigger other specific host responses from the extracellular milieu or contribute to the pathogenesis ofP. aeruginosa.IMPORTANCEThe inflammasome is a host defense mechanism that recognizes invading bacteria and triggers an inflammatory immune response. The opportunistic pathogenP. aeruginosaproduces both inflammasome agonists and antagonists. In this study, we demonstrate that overexpression of an agonist suppresses the activity of an antagonist, thereby resulting in inflammasome activation. Since the relative expression levels of agonists and antagonists likely vary between strains, these differences could be important predictors of whether a particularP. aeruginosastrain elicits inflammasome activation.

scholarly journals Static Growth Promotes PrrF and 2-Alkyl-4(1H)-Quinolone Regulation of Type VI Secretion Protein Expression in Pseudomonas aeruginosa

2020 ◽  
Vol 202 (24) ◽  
Author(s):  
Luke K. Brewer ◽  
Weiliang Huang ◽  
Brandy J. Hackert ◽  
Maureen A. Kane ◽  
Amanda G. Oglesby
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Iron Homeostasis ◽  
Bacterial Species ◽  
Opportunistic Pathogen ◽  
Iron Regulation ◽  
Iron Starvation ◽  
Content Type ◽  
Type Vi Secretion ◽  
Successful Infection ◽  
Static Conditions

ABSTRACT Pseudomonas aeruginosa is an opportunistic pathogen that is frequently associated with both acute and chronic infections. P. aeruginosa possesses a complex regulatory network that modulates nutrient acquisition and virulence, but our knowledge of these networks is largely based on studies with shaking cultures, which are not likely representative of conditions during infection. Here, we provide proteomic, metabolic, and genetic evidence that regulation by iron, a critical metallonutrient, is altered in static P. aeruginosa cultures. Specifically, we observed a loss of iron-induced expression of proteins for oxidative phosphorylation, tricarboxylic acid (TCA) cycle metabolism under static conditions. Moreover, we identified type VI secretion as a target of iron regulation in P. aeruginosa cells under static but not shaking conditions, and we present evidence that this regulation occurs via PrrF small regulatory RNA (sRNA)-dependent production of 2-alkyl-4(1H)-quinolone metabolites. These results yield new iron regulation paradigms in an important opportunistic pathogen and highlight the need to redefine iron homeostasis in static microbial communities. IMPORTANCE Host-mediated iron starvation is a broadly conserved signal for microbial pathogens to upregulate expression of virulence traits required for successful infection. Historically, global iron regulatory studies in microorganisms have been conducted in shaking cultures to ensure culture homogeneity, yet these conditions are likely not reflective of growth during infection. Pseudomonas aeruginosa is a well-studied opportunistic pathogen and model organism for iron regulatory studies. Iron homeostasis is maintained through the Fur protein and PrrF small regulatory sRNAs, the functions of which are highly conserved in many other bacterial species. In the current study, we examined how static growth affects the known iron and PrrF regulons of P. aeruginosa, leading to the discovery of novel PrrF-regulated virulence processes. This study demonstrates how the utilization of distinct growth models can enhance our understanding of basic physiological processes that may also affect pathogenesis.

scholarly journals Complete Genome Sequence of Pseudomonas aeruginosa Strain AA2 (LMG 27630), an Early Isolate Recovered from the Airway of a German Cystic Fibrosis Patient

2020 ◽  
Vol 9 (26) ◽  
Author(s):  
Andrea Sass ◽  
Tom Coenye
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Respiratory Tract ◽  
Cystic Fibrosis Patient ◽  
Genome Sequence ◽  
Complete Genome Sequence ◽  
Opportunistic Pathogen ◽  
Content Type ◽  
Airway Infections ◽  
Early Isolate

ABSTRACT Pseudomonas aeruginosa is an opportunistic pathogen that is able to cause various infections, including airway infections in cystic fibrosis patients. Here, we present the complete closed and annotated genome sequence of P. aeruginosa AA2, an isolate obtained early during infection of the respiratory tract of a German cystic fibrosis patient.

scholarly journals PA0335, a Gene Encoding Histidinol Phosphate Phosphatase, Mediates Histidine Auxotrophy in Pseudomonas aeruginosa

2019 ◽  
Vol 86 (5) ◽  
Author(s):  
Yulu Wang ◽  
Liyue Wang ◽  
Jian Zhang ◽  
Xintong Duan ◽  
Yuqi Feng ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Amino Acid ◽  
Opportunistic Pathogen ◽  
Growth Defect ◽  
Histidine Biosynthesis ◽  
Common Amino Acid ◽  
Content Type ◽  
Growth And Survival ◽  
Origin And Evolution ◽  
Histidinol Phosphate Phosphatase

ABSTRACT The biosynthesis of histidine, a proteinogenic amino acid, has been extensively studied due to its importance in bacterial growth and survival. Histidinol-phosphate phosphatase (Hol-Pase), which is responsible for the penultimate step of histidine biosynthesis, is generally the last enzyme to be characterized in many bacteria because its origin and evolution are more complex compared to other enzymes in histidine biosynthesis. However, none of the enzymes in histidine biosynthesis, including Hol-Pase, have been characterized in Pseudomonas aeruginosa, which is an important opportunistic Gram-negative pathogen that can cause serious human infections. In our previous work, a transposon mutant of P. aeruginosa was found to display a growth defect on glucose-containing minimal solid medium. In this study, we found that the growth defect was due to incomplete histidine auxotrophy caused by PA0335 inactivation. Subsequently, PA0335 was shown to encode Hol-Pase, and its function and enzymatic activity were investigated using genetic and biochemical methods. In addition to PA0335, the roles of 12 other predicted genes involved in histidine biosynthesis in P. aeruginosa were examined. Among them, hisC2 (PA3165), hisH2 (PA3152), and hisF2 (PA3151) were found to be dispensable for histidine synthesis, whereas hisG (PA4449), hisE (PA5067), hisF1 (PA5140), hisB (PA5143), hisI (PA5066), hisC1 (PA4447), and hisA (PA5141) were essential because deletion of each resulted in complete histidine auxotrophy; similar to the case for PA0335, hisH1 (PA5142) or hisD (PA4448) deletion caused incomplete histidine auxotrophy. Taken together, our results outline the histidine synthesis pathway of P. aeruginosa. IMPORTANCE Histidine is a common amino acid in proteins. Because it plays critical roles in bacterial metabolism, its biosynthetic pathway in many bacteria has been elucidated. However, the pathway remains unclear in Pseudomonas aeruginosa, an important opportunistic pathogen in clinical settings; in particular, there is scant knowledge about histidinol-phosphate phosphatase (Hol-Pase), which has a complex origin and evolution. In this study, P. aeruginosa Hol-Pase was identified and characterized. Furthermore, the roles of all other predicted genes involved in histidine biosynthesis were examined. Our results illustrate the histidine synthesis pathway of P. aeruginosa. The knowledge obtained from this study may help in developing strategies to control P. aeruginosa-related infections. In addition, some enzymes of the histidine synthesis pathway from P. aeruginosa might be used as elements of histidine synthetic biology in other industrial microorganisms.

scholarly journals Evolutionary Analysis Points to Divergent Physiological Roles of Type 1 Fimbriae in Salmonella and Escherichia coli

mBio ◽  
2013 ◽  
Vol 4 (2) ◽  
Author(s):  
Dagmara I. Kisiela ◽  
Sujay Chattopadhyay ◽  
Veronika Tchesnokova ◽  
Sandip Paul ◽  
Scott J. Weissman ◽  
...  
Keyword(s):  
Bacterial Species ◽  
Structural Diversity ◽  
Evolutionary Analysis ◽  
Content Type ◽  
E Coli ◽  
Type 1 Fimbriae ◽  
Gene Shuffling ◽  
Immune Pressure ◽  
High Level

ABSTRACTSalmonellaandEscherichia colimannose-binding type 1 fimbriae exhibit highly similar receptor specificities, morphologies, and mechanisms of assembly but are nonorthologous in nature, i.e., not closely related evolutionarily. Their operons differ in chromosomal location, gene arrangement, and regulatory components. In the current study, we performed a comparative genetic and structural analysis of the major structural subunit, FimA, fromSalmonellaandE. coliand found that FimA pilins undergo diverse evolutionary adaptation in the different species. Whereas theE. coli fimAlocus is characterized by high allelic diversity, frequent intragenic recombination, and horizontal movement,Salmonella fimAshows structural diversity that is more than 5-fold lower without strong evidence of gene shuffling or homologous recombination. In contrast toSalmonellaFimA, the amino acid substitutions in theE. colipilin heavily target the protein regions that are predicted to be exposed on the external surface of fimbriae. Altogether, our results suggest thatE. coli, but notSalmonella, type 1 fimbriae display a high level of structural diversity consistent with a strong selection for antigenic variation under immune pressure. Thus, type 1 fimbriae in these closely related bacterial species appear to function in distinctly different physiological environments.IMPORTANCEE. coliandSalmonellaare enteric bacteria that are closely related from an evolutionary perspective. They are both notorious human pathogens, though with somewhat distinct ecologies and virulence mechanisms. Type 1 fimbriae are rod-shaped surface appendages found in mostE. coliandSalmonellaisolates. In both species, they mediate bacterial adhesion to mannose receptors on host cells and share essentially the same morphology and assembly mechanisms. Here we show that despite the strong resemblances in function and structure, they are exposed to very different natural selection environments. Sequence analysis indicates thatE. coli, but notSalmonella, fimbriae are subjected to strong immune pressure, resulting in a high level of major fimbrial protein gene shuffling and interbacterial transfer. Thus, evolutionary analysis tools can provide evidence of divergent physiological roles of functionally similar traits in different bacterial species.

scholarly journals Complete and Draft Genome Sequences of Eight Oceanic Pseudomonas aeruginosa Strains

2017 ◽  
Vol 5 (44) ◽  
Author(s):  
Yohei Kumagai ◽  
Susumu Yoshizawa ◽  
Keiji Nakamura ◽  
Yoshitoshi Ogura ◽  
Tetsuya Hayashi ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Bacterial Species ◽  
Draft Genome ◽  
Open Ocean ◽  
Genome Sequences ◽  
Content Type

ABSTRACT Pseudomonas aeruginosa is one of the most common model bacterial species, and genomes of hundreds of strains of this species have been sequenced to date. However, currently there is only one available genome of an oceanic isolate. Here, we report two complete and six draft genome sequences of P. aeruginosa isolates from the open ocean.

scholarly journals N-Acetylcysteine Selectively Antagonizes the Activity of Imipenem in Pseudomonas aeruginosa by an OprD-Mediated Mechanism

2015 ◽  
Vol 59 (6) ◽  
pp. 3246-3251 ◽  
Author(s):  
Jerónimo Rodríguez-Beltrán ◽  
Gabriel Cabot ◽  
Estela Ynés Valencia ◽  
Coloma Costas ◽  
German Bou ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Pseudomonas Aeruginosa ◽  
Acinetobacter Baumannii ◽  
Outer Membrane ◽  
Bacterial Species ◽  
Outer Membrane Proteins ◽  
Antibiotic Activity ◽  
Simultaneous Treatment ◽  
Content Type ◽  
Sds Page

ABSTRACTThe modulating effect ofN-acetylcysteine (NAC) on the activity of different antibiotics has been studied inPseudomonas aeruginosa. Our results demonstrate that, in contrast to previous reports, only the activity of imipenem is clearly affected by NAC. MIC and checkerboard determinations indicate that the NAC-based modulation of imipenem activity is dependent mainly on OprD. SDS-PAGE of outer membrane proteins (OMPs) after NAC treatments demonstrates that NAC does not modify the expression of OprD, suggesting that NAC competitively inhibits the uptake of imipenem through OprD. Similar effects on imipenem activity were obtained withP. aeruginosaclinical isolates. Our results indicate that imipenem-susceptibleP. aeruginosastrains become resistant upon simultaneous treatment with NAC and imipenem. Moreover, the generality of the observed effects of NAC on antibiotic activity was assessed with two additional bacterial species,Escherichia coliandAcinetobacter baumannii. Caution should be taken during treatments, as the activity of imipenem may be modified by physiologically attainable concentrations of NAC, particularly during intravenous and nebulized regimes.

scholarly journals Genomic and Transcriptional Mapping of PaMx41, Archetype of a New Lineage of Bacteriophages Infecting Pseudomonas aeruginosa

2016 ◽  
Vol 82 (22) ◽  
pp. 6541-6547 ◽  
Author(s):  
Indira Cruz-Plancarte ◽  
Adrián Cazares ◽  
Gabriel Guarneros
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Gc Content ◽  
Open Water ◽  
Opportunistic Pathogen ◽  
Structural Proteomics ◽  
Nucleic Acid Metabolism ◽  
Broad Host Range ◽  
Phage Group ◽  
Coding Sequences ◽  
Content Type

ABSTRACTPreviously, a collection of virulent phages infectingPseudomonas aeruginosawas isolated from open water reservoirs and residual waters. Here, we described the comparative genomics of a set of five related phages from the collection, the physical structure of the genome, the structural proteomics of the virion, and the transcriptional program of archetypal phage PaMx41. The phage genomes were closely associated with each other and with those of two otherP. aeruginosaphages, 119X and PaP2, which were previously filed in the databases. Overall, the genomes were approximately 43 kb, harboring 53 conserved open reading frames (ORFs) and three short ORFs in indel regions and containing 45% GC content. The genome of PaMx41 was further characterized as a linear, terminally redundant DNA molecule. A total of 16 ORFs were associated with putative functions, including nucleic acid metabolism, morphogenesis, and lysis, and eight virion proteins were identified through mass spectrometry. However, the coding sequences without assigned functions represent 70% of the ORFs. The PaMx41 transcription program was organized in early, middle, and late expressed genomic modules, which correlated with regions containing functionally related genes. The high genomic conservation among these distantly isolated phages suggests that these viruses undergo selective pressure to remain unchanged. The 119X lineage represents a unique set of phages that corresponds to a novel phage group. The features recognized in the genomes and the broad host range of clinical strains suggest that these phages are candidates for therapy applications.IMPORTANCEPseudomonas aeruginosais an opportunistic pathogen that causes stubborn nosocomial infections that are frequently resistant to multiple antibiotics. Bacterial viruses (bacteriophages or phages) represent a natural mechanism for pathogenic bacterial control. Here, a group of virulent phages, previously shown to infect a broad range of clinicalP. aeruginosastrains, was characterized at the genomic and molecular levels. These phages belong to a unique and tightly related group. In addition, we conducted a transcriptional study of an archetypal phage of this group to characterize the role of many unknown coding sequences based on expression temporalities. These results contribute to our knowledge of 119X-like phages and, in general, provide information concerningP. aeruginosapodophage diversity and lytic cycles.

scholarly journals cAMP and Vfr Control Exolysin Expression and Cytotoxicity of Pseudomonas aeruginosa Taxonomic Outliers

2018 ◽  
Vol 200 (12) ◽  
Author(s):  
Alice Berry ◽  
Kook Han ◽  
Julian Trouillon ◽  
Mylène Robert-Genthon ◽  
Michel Ragno ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Epithelial Cells ◽  
Transcriptional Activation ◽  
Opportunistic Pathogen ◽  
Secretion System ◽  
Intracellular Camp ◽  
Virulence Determinants ◽  
Cell Infection ◽  
Content Type

ABSTRACT The two-partner secretion system ExlBA, expressed by strains of Pseudomonas aeruginosa belonging to the PA7 group, induces hemorrhage in lungs due to disruption of host cellular membranes. Here we demonstrate that the exlBA genes are controlled by a pathway consisting of cAMP and the virulence factor regulator (Vfr). Upon interaction with cAMP, Vfr binds directly to the exlBA promoter with high affinity (equilibrium binding constant [ K eq ] of ≈2.5 nM). The exlB and exlA expression was diminished in the Vfr-negative mutant and upregulated with increased intracellular cAMP levels. The Vfr binding sequence in the exlBA promoter was mutated in situ , resulting in reduced cytotoxicity of the mutant, showing that Vfr is required for the exlBA expression during intoxication of epithelial cells. Vfr also regulates function of type 4 pili previously shown to facilitate ExlA activity on epithelial cells, which indicates that the cAMP/Vfr pathway coordinates these two factors needed for full cytotoxicity. As in most P. aeruginosa strains, the adenylate cyclase CyaB is the main provider of cAMP for Vfr regulation during both in vitro growth and eukaryotic cell infection. We discovered that the absence of functional Vfr in the reference strain PA7 is caused by a frameshift in the gene and accounts for its reduced cytotoxicity, revealing the conservation of ExlBA control by the CyaB-cAMP/Vfr pathway in P. aeruginosa taxonomic outliers. IMPORTANCE The human opportunistic pathogen Pseudomonas aeruginosa provokes severe acute and chronic human infections associated with defined sets of virulence factors. The main virulence determinant of P. aeruginosa taxonomic outliers is exolysin, a membrane-disrupting pore-forming toxin belonging to the two-partner secretion system ExlBA. In this work, we demonstrate that the conserved CyaB-cAMP/Vfr pathway controls cytotoxicity of outlier clinical strains through direct transcriptional activation of the exlBA operon. Therefore, despite the fact that the type III secretion system and exolysin are mutually exclusive in classical and outlier strains, respectively, these two major virulence determinants share similarities in their mechanisms of regulation.

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