Glutathione Activates Type III Secretion System Through Vfr in Pseudomonas aeruginosa

Zhang, Yani; Zhang, Chao; Du, Xiaomin; Zhou, Yun; Kong, Weina; Lau, Gee W.; Chen, Gukui; Kohli, Gurjeet S.; Yang, Liang; Wang, Tietao; Liang, Haihua

doi:10.3389/fcimb.2019.00164

Cited by 25 publications

(37 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The presence of P. aeruginosa in these infections is also associated with increased infection severity and mortality (43,(47)(48)(49)(50). Previous studies (15)(16)(17)(18)21), as well as our in vitro experiments, suggest an important role for GSH biosynthesis for P. aeruginosa during infection. Here, we comprehensively assessed the fitness of P. aeruginosa WT and ΔgshA in four mouse models of infection: the surgical wound, abscess, acute burn wound, and acute pneumonia models.…”

Section: Resultssupporting

confidence: 67%

“…GSH biosynthesis has been shown to affect quorum sensing (15), type III and VI secretion systems (T3SS and T6SS) (16), production of the secondary metabolites pyocyanin and pyoverdine (17,18), motility (16)(17)(18), biofilm formation (16)(17)(18), sensitivity to oxidative and nitrosative stress (16)(17)(18), and sensitivity to antibiotics (19,20). GSH-deficient P. aeruginosa mutants have attenuated virulence in Drosophila (17) and Caenorhabditis elegans (21) infection models, as well as a mouse model of acute pneumonia (16). Glutathione-deficient mutants in other bacterial species are also attenuated for virulence in mouse models of infection, including Salmonella enterica in an intraperitoneal model (22), Listeria monocytogenes in an intravenous model (9), and Burkholderia pseudomallei in an acute pneumonia model (23).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Role of Pseudomonas aeruginosa Glutathione Biosynthesis in Lung and Soft Tissue Infection

et al. 2020

View full text Add to dashboard Cite

The opportunistic pathogen Pseudomonas aeruginosa is a leading cause of morbidity and mortality worldwide. To survive in both the environment and the host, P. aeruginosa must cope with redox stress. In P. aeruginosa, a primary mechanism for protection from redox stress is the antioxidant glutathione (GSH). GSH is a low-molecular-weight thiol-containing tripeptide (l-γ-glutamyl-l-cysteinyl-glycine) that can function as a reversible reducing agent. GSH plays an important role in P. aeruginosa physiology and is known to modulate several cellular and social processes that are likely important during infection. However, the role of GSH biosynthesis during mammalian infection is not well understood. In this study, we created a P. aeruginosa mutant defective in GSH biosynthesis to examine how loss of GSH biosynthesis affects P. aeruginosa virulence. We found that GSH is critical for normal growth in vitro and provides protection against hydrogen peroxide, bleach, and ciprofloxacin. We also studied the role of P. aeruginosa GSH biosynthesis in four mouse infection models, including the surgical wound, abscess, burn wound, and acute pneumonia models. We discovered that the GSH biosynthesis mutant was slightly less virulent in the acute pneumonia infection model but was equally virulent in the three other models. This work provides new and complementary data regarding the role of GSH in P. aeruginosa during mammalian infection.

show abstract

Section: Resultssupporting

confidence: 67%

mentioning

confidence: 99%

Role of Pseudomonas aeruginosa Glutathione Biosynthesis in Lung and Soft Tissue Infection

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Deleting gshA and gshB from P. aeruginosa attenuates several virulence-associated phenotypes including motility and biofilm formation. GSH was also shown to activate both the P. aeruginosa T3SS and a subset of T6SS genes 22 . Glutathione binding to the Listeria monocytogenes master regulator PrfA is also critical to the virulence of this intracellular pathogen 23 .…”

Section: Resultsmentioning

confidence: 97%

An intra-bacterial activity for a T3SS effector

Qaidi

Scott

Hays

et al. 2020

Sci Rep

View full text Add to dashboard Cite

Many Gram-negative bacterial pathogens interact with mammalian cells by using type iii secretion systems (T3SS) to inject virulence proteins into host cells. A subset of these injected protein 'effectors' are enzymes that inhibit the function of host proteins by catalyzing the addition of unusual posttranslational modifications. The E. coli and Citrobacter rodentium NleB effectors, as well as the Salmonella enterica SseK effectors are glycosyltransferases that modify host protein substrates with N-acetyl glucosamine (GlcNAc) on arginine residues. This post-translational modification disrupts the normal functioning of host immune response proteins. T3SS effectors are thought to be inactive within the bacterium and fold into their active conformations after they are injected, due to the activity of chaperones that keep the effectors in a structural state permissive for secretion. While performing mass spectrometry experiments to identify glycosylation substrates of nleB orthologs, we unexpectedly observed that the bacterial glutathione synthetase (GshB) is glycosylated by NleB on arginine residue R256. NleB-mediated glycosylation of GshB resulted in enhanced GshB activity, leading to an increase in glutathione production, and promoted C. rodentium survival in oxidative stress conditions. these data represent, to our knowledge, the first intra-bacterial activity for a T3SS effector and show that arginine-GlcnAcylation, once thought to be restricted to host cell compartments, also plays an important role in regulating bacterial physiology.

show abstract

“…However, A. baumannii Crp is quite closely related to global regulators Crp from E. coli (50% identical) and Vfr from P. aeruginosa (54% identical), with the conserved Cys opposite the ligand binding pocket, which for E. coli Crp is cyclic AMP (cAMP) (60). Glutathione is an allosteric activator of Vfr transcriptional upregulation of the type III secretion system in P. aeruginosa (61); the same is true of the global regulator PrfA in Listeria monocytogenes (62,63). The small molecule activator of A. baumannii Crp-like protein is unknown.…”

Section: Resultsmentioning

confidence: 99%

The Response of Acinetobacter baumannii to Hydrogen Sulfide Reveals Two Independent Persulfide-Sensing Systems and a Connection to Biofilm Regulation

Walsh

Wang

Edmonds

et al. 2020

mBio

View full text Add to dashboard Cite

Acinetobacter baumannii is an opportunistic nosocomial pathogen that is the causative agent of several serious infections in humans, including pneumonia, sepsis, and wound and burn infections. A. baumannii is also capable of forming proteinaceous biofilms on both abiotic and epithelial cell surfaces. Here, we investigate the response of A. baumannii toward sodium sulfide (Na2S), known to be associated with some biofilms at oxic/anoxic interfaces. The addition of exogenous inorganic sulfide reveals that A. baumannii encodes two persulfide-sensing transcriptional regulators, a primary σ54-dependent transcriptional activator (FisR), and a secondary system controlled by the persulfide-sensing biofilm growth-associated repressor (BigR), which is only induced by sulfide in a fisR deletion strain. FisR activates an operon encoding a sulfide oxidation/detoxification system similar to that characterized previously in Staphylococcus aureus, while BigR regulates a secondary persulfide dioxygenase (PDO2) as part of yeeE-yedE-pdo2 sulfur detoxification operon, found previously in Serratia spp. Global S-sulfuration (persulfidation) mapping of the soluble proteome reveals 513 persulfidation targets well beyond FisR-regulated genes and includes five transcriptional regulators, most notably the master biofilm regulator BfmR and a poorly characterized catabolite regulatory protein (Crp). Both BfmR and Crp are well known to impact biofilm formation in A. baumannii and other organisms, respectively, suggesting that persulfidation of these regulators may control their activities. The implications of these findings on bacterial sulfide homeostasis, persulfide signaling, and biofilm formation are discussed. IMPORTANCE Although hydrogen sulfide (H2S) has long been known as a respiratory poison, recent reports in numerous bacterial pathogens reveal that H2S and more downstream oxidized forms of sulfur collectedly termed reactive sulfur species (RSS) function as antioxidants to combat host efforts to clear the infection. Here, we present a comprehensive analysis of the transcriptional and proteomic response of A. baumannii to exogenous sulfide as a model for how this important human pathogen manages sulfide/RSS homeostasis. We show that A. baumannii is unique in that it encodes two independent persulfide sensing and detoxification pathways that govern the speciation of bioactive sulfur in cells. The secondary persulfide sensor, BigR, impacts the expression of biofilm-associated genes; in addition, we identify two other transcriptional regulators known or projected to regulate biofilm formation, BfmR and Crp, as highly persulfidated in sulfide-exposed cells. These findings significantly strengthen the connection between sulfide homeostasis and biofilm formation in an important human pathogen.

show abstract

Glutathione Activates Type III Secretion System Through Vfr in Pseudomonas aeruginosa

Cited by 25 publications

References 48 publications

Role of Pseudomonas aeruginosa Glutathione Biosynthesis in Lung and Soft Tissue Infection

Role of Pseudomonas aeruginosa Glutathione Biosynthesis in Lung and Soft Tissue Infection

An intra-bacterial activity for a T3SS effector

The Response of Acinetobacter baumannii to Hydrogen Sulfide Reveals Two Independent Persulfide-Sensing Systems and a Connection to Biofilm Regulation

Contact Info

Product

Resources

About