Evolution of Pseudomonas aeruginosa type III secretion in cystic fibrosis: a paradigm of chronic infection

Jain, Manu; Bar-Meir, Maskit; McColley, Susanna A.; Cullina, Joanne; Potter, Eileen; Powers, Catherine A.; Prickett, Michelle; Seshadri, Roopa; Jovanovic, Borko; Petrocheilou, Argyri; King, John D.; Hauser, Alan R.

doi:10.1016/j.trsl.2008.10.003

Cited by 45 publications

(48 citation statements)

References 30 publications

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“…Patients with chronic P. aeruginosa infections preferentially express virulence factors that increase persistence and immune system evasion (138)(139)(140)(141)(142). Examples of RsmA-regulated virulence factors associated with chronic disease include the ability to form biofilm and the type VI secretion system (T6SS), described below (80,143,144).…”

Section: P Aeruginosamentioning

confidence: 99%

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Regulation of Bacterial Virulence by Csr (Rsm) Systems

Vakulskas

Potts

Babitzke

et al. 2015

Microbiol Mol Biol Rev

302

400

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SUMMARY Most bacterial pathogens have the remarkable ability to flourish in the external environment and in specialized host niches. This ability requires their metabolism, physiology, and virulence factors to be responsive to changes in their surroundings. It is no surprise that the underlying genetic circuitry that supports this adaptability is multilayered and exceedingly complex. Studies over the past 2 decades have established that the CsrA/RsmA proteins, global regulators of posttranscriptional gene expression, play important roles in the expression of virulence factors of numerous proteobacterial pathogens. To accomplish these tasks, CsrA binds to the 5′ untranslated and/or early coding regions of mRNAs and alters translation, mRNA turnover, and/or transcript elongation. CsrA activity is regulated by noncoding small RNAs (sRNAs) that contain multiple CsrA binding sites, which permit them to sequester multiple CsrA homodimers away from mRNA targets. Environmental cues sensed by two-component signal transduction systems and other regulatory factors govern the expression of the CsrA-binding sRNAs and, ultimately, the effects of CsrA on secretion systems, surface molecules and biofilm formation, quorum sensing, motility, pigmentation, siderophore production, and phagocytic avoidance. This review presents the workings of the Csr system, the paradigm shift that it generated for understanding posttranscriptional regulation, and its roles in virulence networks of animal and plant pathogens.

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Section: P Aeruginosamentioning

confidence: 99%

“…One reason for this is the frequent occurrence of mutations affecting the MucA/AlgU and AlgZ/AlgR signal transduction systems (141,142). MucA is a membranebound anti-sigma factor that sequesters AlgU (sigma 22), preventing it from activating the expression of ϳ300 genes, including genes for the T3SS (184)(185)(186)(187).…”

Section: P Aeruginosamentioning

confidence: 99%

Regulation of Bacterial Virulence by Csr (Rsm) Systems

Vakulskas

Potts

Babitzke

et al. 2015

Microbiol Mol Biol Rev

302

400

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“…A common phenotype observed in CF isolates is the loss of T3SS gene expression (12,13). One mechanism that accounts for reduced T3SS expression involves the MucA/AlgU signal transduction system (see Fig.…”

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confidence: 99%

The AlgZR Two-Component System Recalibrates the RsmAYZ Posttranscriptional Regulatory System To Inhibit Expression of the Pseudomonas aeruginosa Type III Secretion System

Intile

Diaz

Urbanowski

et al. 2013

Journal of Bacteriology

124

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bPseudomonas aeruginosa causes chronic airway infections in cystic fibrosis (CF) patients. A classic feature of CF airway isolates is the mucoid phenotype. Mucoidy arises through mutation of the mucA anti-sigma factor and subsequent activation of the AlgU regulon. Inactivation of mucA also results in reduced expression of the Vfr transcription factor. Vfr regulates several important virulence factors, including a type III secretion system (T3SS). In the present study, we report that ExsA expression, the master regulator of T3SS gene expression, is further reduced in mucA mutants through a Vfr-independent mechanism involving the RsmAYZ regulatory system. RsmA is an RNA binding protein required for T3SS gene expression. Genetic experiments suggest that the AlgZR two-component system, part of the AlgU regulon, inhibits ExsA expression by increasing the expression of RsmY and RsmZ, two small noncoding RNAs that sequester RsmA from target mRNAs. Epistasis analyses revealed that increasing the concentration of free RsmA, through either rsmYZ deletion or increased RsmA expression, partially restored T3SS gene expression in the mucA mutant. Furthermore, increasing RsmA availability in combination with Vfr complementation fully restored T3SS expression. Recalibration of the RsmAYZ system by AlgZR, however, did not alter the expression of other selected RsmAdependent targets. We account for this observation by showing that ExsA expression is more sensitive to changes in free RsmA than other members of the RsmA regulon. Together, these data indicate that recalibration of the RsmAYZ system partially accounts for reduced T3SS gene expression in mucA mutants. Pseudomonas aeruginosa is a Gram-negative bacterium with the ability to cause both acute and chronic infections (1, 2). Immunocompromised individuals often develop acute P. aeruginosa infections that can become systemic, with lethal sepsis as a common outcome (3). Isolates from acute P. aeruginosa infections are generally characterized by the presence of a functional type III secretion system (T3SS) (4, 5). The T3SS injects multiple effectors directly into the host cell cytoplasm, where they function to deregulate signal transduction mechanisms and promote phagocytic avoidance and host cell killing (6-8). In contrast to acute infections, the airways of most adults with the genetic disorder cystic fibrosis (CF) are chronically colonized with P. aeruginosa. CF patients are initially colonized with environmental strains of P. aeruginosa that subsequently undergo diversification via mutation and selection by the CF airway environment to generate a population of cells adapted for persistence, host immune defense, antibiotic resistance, and biofilm formation (9-11).A common phenotype observed in CF isolates is the loss of T3SS gene expression (12, 13). One mechanism that accounts for reduced T3SS expression involves the MucA/AlgU signal transduction system (see Fig. 8 for a model). MucA is a membranebound anti-sigma factor that sequesters the alternative sigma factor AlgU to c...

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“…Type 3 secretion system (T3SS) expression has been linked to increased risk of P. aeruginosa infection in hospitalized patients (1) and to increased morbidity and mortality in VAP caused by this organism (2). Initial infections in patients with CF also are associated with T3SS-positive strains (3). In contrast, T3SS-negative strains are isolated with increasing frequency from chronically infected CF patients over time, and animal models of chronic infection indicate important roles in other virulence traits, such as biofilm formation and quorum-sensing systems (4).…”

mentioning

confidence: 99%

Cheating by type 3 secretion system-negative Pseudomonas aeruginosa during pulmonary infection

Czechowska¹,

McKeithen-Mead

Moussawi³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance Bacterial pathogens frequently use type 3 secretion systems (T3SS) to counteract host immune responses to infection. T3SS expression is associated with increased virulence of Pseudomonas aeruginosa in humans and in animal models, but T3SS-negative bacteria often are isolated from acutely and chronically infected patients. We tested whether T3SS-negative bacteria could “cheat” during mixed infections with T3SS-positive bacteria in a murine model of acute pneumonia. Bacterial cheating occurred in the inflamed lung but only when T3SS-positive bacteria secreted the phospholipase A 2 effector, Exotoxin U. Phenotypically T3SS-expressing and –non-expressing bacteria co-exist within P. aeruginosa populations, suggesting that bacterial cheating might allow T3SS-negative organisms to establish themselves within a host.

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Evolution of Pseudomonas aeruginosa type III secretion in cystic fibrosis: a paradigm of chronic infection

Cited by 45 publications

References 30 publications

Regulation of Bacterial Virulence by Csr (Rsm) Systems

Regulation of Bacterial Virulence by Csr (Rsm) Systems

The AlgZR Two-Component System Recalibrates the RsmAYZ Posttranscriptional Regulatory System To Inhibit Expression of the Pseudomonas aeruginosa Type III Secretion System

Cheating by type 3 secretion system-negative Pseudomonas aeruginosa during pulmonary infection

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