The molecular mechanism of acute lung injury caused by Pseudomonas aeruginosa: from bacterial pathogenesis to host response
© Sawa; licensee BioMed Central Ltd. 2014
Received: 25 December 2013
Accepted: 28 January 2014
Published: 18 February 2014
Pseudomonas aeruginosa is the most common gram-negative pathogen causing pneumonia in immunocompromised patients. Acute lung injury induced by bacterial exoproducts is associated with a poor outcome in P. aeruginosa pneumonia. The major pathogenic toxins among the exoproducts of P. aeruginosa and the mechanism by which they cause acute lung injury have been investigated: exoenzyme S and co-regulated toxins were found to contribute to acute lung injury. P. aeruginosa secretes these toxins through the recently defined type III secretion system (TTSS), by which gram-negative bacteria directly translocate toxins into the cytosol of target eukaryotic cells. TTSS comprises the secretion apparatus (termed the injectisome), translocators, secreted toxins, and regulatory components. In the P. aeruginosa genome, a pathogenic gene cluster, the exoenzyme S regulon, encodes genes underlying the regulation, secretion, and translocation of TTSS. Four type III secretory toxins, namely ExoS, ExoT, ExoU, and ExoY, have been identified in P. aeruginosa. ExoS is a 49-kDa form of exoenzyme S, a bifunctional toxin that exerts ADP-ribosyltransferase and GTPase-activating protein (GAP) activity to disrupt endocytosis, the actin cytoskeleton, and cell proliferation. ExoT, a 53-kDa form of exoenzyme S with 75% sequence homology to ExoS, also exerts GAP activity to interfere with cell morphology and motility. ExoY is a nucleotidal cyclase that increases the intracellular levels of cyclic adenosine and guanosine monophosphates, resulting in edema formation. ExoU, which exhibits phospholipase A2 activity activated by host cell ubiquitination after translocation, is a major pathogenic cytotoxin that causes alveolar epithelial injury and macrophage necrosis. Approximately 20% of clinical isolates also secrete ExoU, a gene encoded within an insertional pathogenic gene cluster named P. aeruginosa pathogenicity island-2. The ExoU secretory phenotype is associated with a poor clinical outcome in P. aeruginosa pneumonia. Blockade of translocation by TTSS or inhibition of the enzymatic activity of translocated toxins has the potential to decrease acute lung injury and improve clinical outcome.
KeywordsAcute lung injury Pneumonia Pseudomonas aeruginosa Type III secretion system ExoU
Pseudomonas aeruginosa is one of the most common gram-negative pathogens causing pneumonia in immunocompromised patients [1–4]. Ventilated patients are at particularly high risk of developing P. aeruginosa pneumonia [5, 6], and the mortality rate of ventilator-associated pneumonia (VAP) due to P. aeruginosa is significantly higher than that due to other pathogens [7–9]. Some P. aeruginosa strains possess the ability to destroy the integrity of the alveolar epithelial barrier, causing rapid necrosis of the lung epithelium and bacterial dissemination into the circulation [10, 11]. Understanding the mechanism by which virulent strains of P. aeruginosa cause acute lung injury is critical for preventing subsequent sepsis and death. The present review summarizes the progress and explains the mechanisms causing acute lung injury and sepsis, focusing on the type III secretion system (TTSS) of P. aeruginosa.
Acute lung epithelial injury caused by P. aeruginosa
Acute lung injury in animal models
The major toxic exoproducts of Pseudomonas aeruginosa
Locus ID, PA number
Effect on host
(LasR-LasI quorum sensing)
ExsA-activated type III system
Elastase (LasA, LasB)
LasR-LasI quorum sensing
LasR-LasI quorum sensing
Disturbance of membrane lipid metabolism
Discovery of a major cytotoxin: ExoU
The P. aeruginosa toxin exoenzyme S was identified in the late 1970s as an ADP-ribosyltransferase distinct from exotoxin A [17, 18]. Early studies revealed that the exoenzyme S-positive phenotype correlated with increased virulence in lung infections and burn wounds [19–24]. The protein transcriptional regulator ExsA was found to regulate the production of exoenzyme S and co-regulated proteins [25–27]. PAO-S21, an insertional mutant of transposon Tn501 in the exsA gene of P. aeruginosa, is exoenzyme S-deficient [15, 19]. PAO-S21 infection did not result in altered protein flux across the alveolar epithelial barrier . Based on these findings, exoenzyme S, or an unknown exoenzyme S-related toxin regulated by ExsA, was determined to play a major role in acute lung injury. Exoenzyme S activity was later determined to be the result of two highly homologous toxins, ExoS (a 49-kDa form of exoenzyme S) and ExoT (a 53-kDa form of exoenzyme S), encoded by two separate regions of the P. aeruginosa genome [28–31].
The virulent P. aeruginosa strain PA103, lacking the 49-kDa form of the exoenzyme S gene (exoS) but possessing the 53-kDa form (exoT), causes a high degree of acute injury . Because the isogenic mutant lacking the 49-kDa form of exoenzyme S remained capable of causing acute lung injury in a rabbit model, it was initially considered possible that ExoT is the major factor underlying acute lung injury . However, an isogenic mutant lacking ExoT remained capable of causing alveolar epithelial injury in a mouse model . Thus, neither ExoT nor ExoS was the major virulence factor. PA103 was found to secrete a unique unknown 74-kDa protein, the production of which decreased with a transposon mutation in exsA. The gene encoding this 74-kDa protein was cloned, and a mutant missing this protein was created in PA103. PA103 lacking this 74-kDa protein failed to cause acute lung injury in our mouse model [33, 34]. This protein, regulated by ExsA, was named ExoU. Clinical isolates with a cytotoxic phenotype in vitro were found to express ExoU and cause acute epithelial injury in a mouse model . Cytotoxic P. aeruginosa isolates were identified to possess exoU, while noncytotoxic isolates lacked the gene . High cytotoxicity, severity of lung epithelial injury, and bacterial dissemination into the circulation appeared to show a high correlation with the exoU genotype [35, 36]. Therefore, it was concluded that the ability of P. aeruginosa to cause acute lung epithelial injury and sepsis is highly linked to the expression of ExoU, regulated by the transcriptional activator ExsA [33, 34].
Type III secretion system
The secretion systems of gram-negative bacteria
Gram-negative bacteria, which have inner and outer bacterial membranes, use dedicated secretion systems to transport proteins synthesized to the outside environment. The secretion systems of gram-negative bacteria can be classified into six subtypes . The type I secretion system is relatively simple, consisting of only a few proteins. Unlike proteins secreted by the type II secretion system, proteins secreted by the type I secretion system contain no signal sequence at their amino termini; instead, they contain domains at their carboxyl termini necessary for recognition by the type I secretion complex. The type II system conducts so-called sec-dependent secretion . Proteins secreted by the type II system possess amino-terminal signal sequences of 16–26 residues .
Type III secretion systems in animal-associated gram-negative bacteria
Effect on host
Facilitates invasion, etc.
Prevents microtubule assembly, etc.
Pathogenic E. coli
A/E lesion formation
Bacterial entry, apoptosis
Inv, Prg, Spa, Sip
Bacterial entry, apoptosis
Genomic organization of P. aeruginosa TTSS
In the genome of P. aeruginosa PAO1, three type III secretory toxins (excluding ExoU), co-regulated with the exoenzyme S regulon by ExsA, have been identified (Figure 2). These are ExoS (a 49-kDa form of exoenzyme S), ExoT (a 53-kDa form of exoenzyme S, also known as exoenzyme T), and ExoY [31, 49]. The genes encoding these type III secretory toxins (exoS, exoT, and exoY) are distributed in regions of the genome separate from the exoenzyme S regulon [47, 48]. Later, two distinct P. aeruginosa pathogenicity islands, PAPI-1 (108 kb) and PAPI-2 (11 kb), which are absent from the less virulent strain PAO1, were found in the highly virulent clinical strain PA14, and exoU was discovered in the PAPI-2 region of this strain [50, 51]. Approximately 20% of clinical isolates are more virulent; they possess exoU, but not exoS.
The exoenzyme S regulon
Transcriptional activator ExsA
ExsA, encoded by the exsCBA operon (the trans-regulatory locus for exoenzyme S secretion) in the exoenzyme S regulon, is a transcriptional activator of the P. aeruginosa TTSS . In the exoenzyme S regulon, ExsA regulates the transcription of five operons (exsD-pscL, exsCBA, pscG-popD, popN-pcrR, and pscN-pscU) encoding TTSS and the translocation machinery (Figure 2) . Another four or five ExsA-binding sites have been found in the genome for the regulation of effector molecules (type III secretory toxins) and their chaperones .
In Yersinia, ysc genes in the Yop virulon largely encode components of TTSS, and P. aeruginosa possesses homologous psc genes in its exoenzyme regulon [45, 48]. Ysc proteins from Yersinia ysc genes and Psc proteins from P. aeruginosa psc genes are considered as components of their respective needle complexes because of their sequence homology to Salmonella Spa, Prg, and Inv; Shigella Spa and Mxi; and E. coli Esc proteins.
Translocators and V-antigen
Proteins required for the translocation of Pseudomonas aeruginosa Exo effectors
Homolog in Yersinia
Binds to PcrV
Binds to PopB and PopD
Chaperone for PopB and PopD
On eukaryotic cell membrane
On eukaryotic cell membrane
Four type III secretory toxins of P. aeruginosa
Pseudomonas aeruginosa type III effector molecules
Effect on host
49-kDa exoenzyme S
53-kDa exoenzyme S
Inhibition of wound healing
Acute lung injury
B. anthoracis EF
Edema, inhibition of inflammatory cytokine secretion
P. aeruginosa exoenzyme S was originally characterized as a toxin distinct from exotoxin A exhibiting ADP-ribosyltransferase activity . Exoenzyme S ADP-ribosylates vimentins and several Ras-related GTP-binding proteins, including Rab3, Rab4, Ral, Rap1A, and Rap2 [67, 68]. The enzymatic reaction requires a soluble eukaryotic protein, termed factor-activating exoenzyme S (FAS), to ADP-ribosylate all substrates [69, 70]. Analysis of several deletion peptides showed that 222 amino acids at the carboxyl terminal of exoenzyme S possessed FAS-dependent ADP-ribosyltransferase activity [69, 70]. Expression of the ADP-ribosyltransferase domain of exoenzyme S is cytotoxic to eukaryotic cells .
The amino-terminal domain of exoenzyme S has been characterized as a GTPase-activating protein (GAP) for Rho GTPases , suggesting that exoenzyme S is a bifunctional type III secreted cytotoxin . In vivo data indicate that the Rho GAP activity of ExoS stimulates the reorganization of the actin cytoskeleton by inhibiting Rac and Cdc42 and stimulates actin stress fiber formation by inhibiting Rho .
Two immunologically undistinguishable proteins, with apparent molecular sizes of 53- and 49-kDa, co-fractionated with exoenzyme S activity . Later, these two exoenzymes were found to be the products of two different genes . ExoT was found to encode a protein of 457 amino acids, with 75% amino acid homology to ExoS. However, ExoT possessed approximately 0.2% of its ADP-ribosyltransferase activity . ExoT diminishes macrophage motility and phagocytosis, at least in part through disruption of the actin cytoskeleton of eukaryotic cells, and blocks wound healing [75, 76]. Biochemical studies have shown that ExoT is a GAP for RhoA, Rac1, and Cdc42 [77, 78]. These data show that ExoT interferes with the Rho signal transduction pathways, which regulate actin organization, exocytosis, cell cycle progression, and phagocytosis [77, 79].
In 1997, a novel cytotoxin, ExoU (termed PepA by Hauser et al. ), was found to be a major contributory factor to lung injury, and the gene exoU was cloned from the cytotoxic PA103 strain. A region downstream of exoU was found to encode a specific Pseudomonas chaperone for ExoU (SpcU) . In P. aeruginosa, ExoU and SpcU are coordinately expressed as an operon controlled at the transcriptional level by ExsA . Acquisition of the expression of P. aeruginosa ExoU caused increased bacterial virulence and systemic spread in a mouse model of acute pneumonia . Hauser et al. determined the type III secretion genotypes and phenotypes of isolates cultured from patients with VAP: in vitro assays indicated that ExoU most closely linked to mortality in animal models was secreted in detectable amounts in vitro by 10 (29%) of the 35 isolates examined .
ExoY is the fourth type III secretion effector protein controlled by ExoS regulon. ExoY is homologous to the extracellular adenylate cyclases of Bortedella pertussis (CyaA), Bacillus anthracis (EF), and Yersinia pestis (insecticidal toxin) . In assays for adenylate cyclase activity, recombinant ExoY (rExoY) catalyzed the formation of cyclic adenosine monophosphate (cAMP). In contrast to CyaA and EF, rExoY activity was not stimulated or activated by calmodulin. Infection of eukaryotic cells with P. aeruginosa producing catalytically active ExoY resulted in the elevation of intracellular cAMP levels and changes in cell morphology [88, 89]. It is more recently reported that ExoY is likely to be a promiscuous nucleotidal cyclase that increases the intracellular levels of cyclic adenosine and guanosine monophosphates, resulting in edema formation .
Epidemiology of the P. aeruginosa TTSS
Analysis of type III secretory protein phenotypes was performed in 108 isolates derived from patients with P. aeruginosa infections . The mortality rate in patients with P. aeruginosa isolates expressing at least one of the type III secretory proteins was 21% compared with the rate of 3% in patients with isolates expressing no type III secretory protein. In another study, infection with isolates secreting TTSS proteins, particularly isolates with an ExoU-positive phenotype, correlated with severe disease . Recently, additional reports have demonstrated an association between the ExoU genotype or phenotype and a poor clinical outcome of P. aeruginosa pneumonia. exoU-positive isolates were more likely to be fluoroquinolone resistant and exhibit both a gyrA mutation and efflux pump overexpression . Clinical isolates containing the exoU gene were more likely to be resistant to cefepime, ceftazidime, piperacillin tazobactam, carbapenems, and gentamicin . A fluoroquinolone-resistant phenotype in an ExoU-positive strain contributes to the pathogenesis of P. aeruginosa in pneumonia . However, the expression of TTSS exoenzymes in P. aeruginosa isolates from bacteremic patients confers a poor clinical outcome, independent of antibiotic susceptibility . Severity of the illness and expression of type III secretory proteins were the strongest predictors of 30-day mortality from P. aeruginosa bacteremia .
Update the clinical approach against P. aeruginosa pneumonia
P. aeruginosa expresses a variety of factors that confer resistance to a broad array of antibacterial agents. Multidrug-resistant P. aeruginosa (MDRP) is defined as the resistance to carbapenems, aminoglycosides, and fluoroquinolones. The current increase in the incidence of lethal outbreaks of MDRP is especially a serious concern. Multiple genetic rearrangements, such as chromosomal mutations or horizontal gene transfers (plasmids, integrons, phages), are associated with the acquisition of multidrug resistance in these bacteria. The various mechanisms, such as β-lactamases, carbapenemases or aminoglycoside-modifying enzymes, and mutations in antibiotic targets, efflux pumps, impermeability, are associated in these multidrug resistances. In the management of P. aeruginosa pneumonia, the increasing resistance level of these bacteria to most classes of antibacterial agents frequently leads to failure of effective treatment, which is associated with high mortality of the infected patients. Therefore, choosing adequate antibiotics is crucial to increase the survival rate, especially in patients infected with MDRP. Therefore, surveillance in antibiotic resistance must be important to reduce the risk of inadequate antibacterial therapy. In addition, surveillance in TTSSgenotype- and phenotype-associated acute lung injury and sepsis may help to predict the higher risk of lethal outbreaks.
Polymyxin E (colistin) remains the most consistently effective agent against MDPR, while colistin-resistant P. aeruginosa has been already reported as a caution of the emergence of pan-resistant strains in the near future . Different strategies against the different targets must be required before the spread of super-resistant strains. Among various experimental therapeutic approaches, the anti-TTSS therapy is reasonable because acute lung injury due to P. aeruginosa is highly depending on its TTSS-associated virulence as described above. PcrV has a critical role in the TTS-associated virulence of P. aeruginosa as follows . In a series of these studies, active and passive immunization against PcrV in animal models of P. aeruginosa-induced lung injury greatly increased survival . Virulent P. aeruginosa strains expressing PcrV disabled macrophage phagocytosis. However, antibodies against PcrV blocked this critical antiphagocytic effect . Passive protection with anti-PcrV reduced the inflammatory response, minimized bacteremia, and prevented septic shock in mice and rabbits . The protective capacity of the antibody was Fc-independent as F(ab′)2 fragments of polyclonal anti-PcrV were also effective . A murine monoclonal anti-PcrV antibody mAb166 was developed, and its protective effects on acute lung injury were demonstrated when co-instilled with the bacterial challenge or passively transferred to infected animals . The administration of either mAb166 or Fab of mAb166 showed comparable therapeutic effects to rabbit polyclonal anti-PcrV IgG . Based on mAb166, humanized anti-PcrV antibody that was developed by molecular engineering has recently entered phase I/II clinical trials in the USA and Europe for prophylactic and therapeutic uses against P. aeruginosa pneumonia in artificially ventilated patients and cystic fibrosis patients [101–103].
Summary and future implications
P. aeruginosa possesses a sophisticated toxin secretion system to directly inject toxins into the cytosol of target eukaryotic cells. This system, called TTSS, is regulated by the exoenzyme S regulon of P. aeruginosa. Through TTSS, P. aeruginosa translocates the type III secretory toxins ExoS, ExoT, ExoU, and ExoY. By injecting these toxins into the cytosol of eukaryotic cells, P. aeruginosa exploits mammalian enzyme functions to modulate eukaryotic cell signaling.
TS is a professor in Anesthesiology at Kyoto Prefectural University of Medicine, Japan.
Cyclic adenosine monophosphate
Cyclic guanosine monophosphate
Transcriptional regulator ExsA
Factor-activating exoenzyme S
Pseudomonas aeruginosa pathogenicity island
Type III secretion system
The author would like to thank Dr. Jeanine P. Wiener-Kronish, Anesthetist-in-Chief, Henry Isaiah Dorr Professor of Anesthesia, Harvard Medical School for her critical support of his research.
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