scholarly journals Hyperpiliation reduces Pseudomonas aeruginosa pathogenicity by impeding type III secretion

2021 ◽  
Author(s):  
Sara L.N. Kilmury ◽  
Katherine J. Graham ◽  
Ryan P. Lamers ◽  
Lesley T. MacNeil ◽  
Lori L. Burrows
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Cell Surface ◽  
Virulence Factors ◽  
Type Iii Secretion ◽  
Target Cells ◽  
Twitching Motility ◽  
Intrinsic Resistance ◽  
Type Iii ◽  
Pilin Gene ◽  
Dependent Type

ABSTRACTType IVa pili (T4aP) are important virulence factors for many bacterial pathogens. Previous studies suggested that the retraction ATPase, PilT, modulates pathogenicity due to its critical role in pilus dynamics and twitching motility. Here we use a Caenorhabditis elegans slow killing model to show that hyperpiliation, not loss of pilus retraction, reduces virulence of Pseudomonas aeruginosa strains PAK and PA14 by interfering with function of the contact-dependent type III secretion system (T3SS). Hyperactivating point mutations in the P. aeruginosa PilSR two-component system that controls transcription of the major pilin gene, pilA, increased levels of surface pili to the same extent as deleting pilT, without impairing twitching motility. These functionally hyperpiliated PilSR mutants had significant defects in pathogenicity that were rescued by deleting pilA or by increasing the length of T3SS needles via deletion of the needle-length regulator, PscP. Hyperpiliated pilT deletion or pilO point mutants showed similar PilA-dependent impairments in virulence, validating the phenotype. Together, our data support a model where a surfeit of pili prevents effective engagement of contact-dependent virulence factors. These findings suggest that the role of T4aP retraction in virulence should be revised.SIGNIFICANCEPseudomonas aeruginosa is a major contributor to hospital-acquired infections and particularly problematic due to its intrinsic resistance to many front-line antibiotics. Strategies to combat this and other important pathogens include development of anti-virulence therapeutics. We show that the pathogenicity of P. aeruginosa is impaired when the amount of type IVa pili (T4aP) expressed on the cell surface increases, independent of the bacteria’s ability to twitch. We propose that having excess T4aP on the cell surface can physically interfere with productive engagement of the contact-dependent type III secretion toxin delivery system. A better understanding of how T4aP modulate interaction of bacteria with target cells will improve the design of therapeutics targeting components involved in regulation of T4aP expression and function, to reduce the clinical burden of P. aeruginosa and other T4aP-expressing bacteria.

scholarly journals Derivatives of Plant Phenolic Compound Affect the Type III Secretion System of Pseudomonas aeruginosa via a GacS-GacA Two-Component Signal Transduction System

2011 ◽  
Vol 56 (1) ◽  
pp. 36-43 ◽  
Author(s):  
Akihiro Yamazaki ◽  
Jin Li ◽  
Quan Zeng ◽  
Devanshi Khokhani ◽  
William C. Hutchins ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Phenolic Compounds ◽  
Virulence Factors ◽  
Type Iii Secretion ◽  
Small Rnas ◽  
Type Iii Secretion System ◽  
Secretion System ◽  
Human Pathogen ◽  
Content Type ◽  
Type Iii

ABSTRACTAntibiotic therapy is the most commonly used strategy to control pathogenic infections; however, it has contributed to the generation of antibiotic-resistant bacteria. To circumvent this emerging problem, we are searching for compounds that target bacterial virulence factors rather than their viability.Pseudomonas aeruginosa, an opportunistic human pathogen, possesses a type III secretion system (T3SS) as one of the major virulence factors by which it secretes and translocates T3 effector proteins into human host cells. The fact that this human pathogen also is able to infect several plant species led us to screen a library of phenolic compounds involved in plant defense signaling and their derivatives for novel T3 inhibitors. Promoter activity screening ofexoS, which encodes a T3-secreted toxin, identified two T3 inhibitors and two T3 inducers ofP. aeruginosaPAO1. These compounds alterexoStranscription by affecting the expression levels of the regulatory small RNAs RsmY and RsmZ. These two small RNAs are known to control the activity of carbon storage regulator RsmA, which is responsible for the regulation of the key T3SS regulator ExsA. As RsmY and RsmZ are the only targets directly regulated by GacA, our results suggest that these phenolic compounds affect the expression ofexoSthrough the GacSA-RsmYZ-RsmA-ExsA regulatory pathway.

scholarly journals The PscE-PscF-PscG Complex Controls Type III Secretion Needle Biogenesis in Pseudomonas aeruginosa

2005 ◽  
Vol 280 (43) ◽  
pp. 36293-36300 ◽  
Author(s):  
Manuelle Quinaud ◽  
Jacqueline Chabert ◽  
Eric Faudry ◽  
Emmanuelle Neumann ◽  
David Lemaire ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Type Iii Secretion ◽  
Target Cells ◽  
Knock Out ◽  
Bacterial Membranes ◽  
Type Iii ◽  
Temperature Scanning ◽  
Main Component ◽  
First Time ◽  
Hollow Needle

Type III secretion (T3S) systems play key roles in pathogenicity of many Gram-negative bacteria and are employed to inject toxins directly into the cytoplasm of target cells. They are composed of over 20 different proteins that associate into a basal structure that traverses both inner and outer bacterial membranes and a hollow, needle-like structure through which toxins travel. The PscF protein is the main component of the Pseudomonas aeruginosa T3S needle. Here we demonstrate that PscF, when purified on its own, is able to form needle-like fibers of 8 nm in width and >1 μm in length. In addition, we demonstrate for the first time that the T3S needle subunit requires two cytoplasmic partners, PscE and PscG, in P. aeruginosa, which trap PscF in a ternary, 1:1:1 complex, thus blocking it in a monomeric state. Knock-out mutants deficient in PscE and PscG are non-cytotoxic, lack PscF, and are unable to export PscF encoded extrachromosomally. Temperature-scanning circular dichroism measurements show that the PscE-PscF-PscG complex is thermally stable and displays a cooperative unfolding/refolding pattern. Thus, PscE and PscG prevent PscF from polymerizing prematurely in the P. aeruginosa cytoplasm and keep it in a secretion prone conformation, strategies which may be shared by other pathogens that employ the T3S system for infection.

scholarly journals HigB Reciprocally Controls Biofilm Formation and the Expression of Type III Secretion System Genes through Influencing the Intracellular c-di-GMP Level in Pseudomonas aeruginosa

Toxins ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 424 ◽  
Author(s):  
Yueying Zhang ◽  
Bin Xia ◽  
Mei Li ◽  
Jing Shi ◽  
Yuqing Long ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Virulence Factors ◽  
Type Iii Secretion ◽  
Biofilm Formation ◽  
Pathogenic Bacteria ◽  
Regulatory Mechanism ◽  
Type Iii Secretion System ◽  
Secretion System ◽  
Regulatory Pathways ◽  
Type Iii

Toxin-antitoxin (TA) systems play important roles in bacteria persister formation. Increasing evidence demonstrate the roles of TA systems in regulating virulence factors in pathogenic bacteria. The toxin HigB in Pseudomonas aeruginosa contributes to persister formation and regulates the expression of multiple virulence factors and biofilm formation. However, the regulatory mechanism remains elusive. In this study, we explored the HigB mediated regulatory pathways. We demonstrate that HigB decreases the intracellular level of c-di-GMP, which is responsible for the increased expression of the type III secretion system (T3SS) genes and repression of biofilm formation. By analyzing the expression levels of the known c-di-GMP metabolism genes, we find that three c-di-GMP hydrolysis genes are up regulated by HigB, namely PA2133, PA2200 and PA3825. Deletion of the three genes individually or simultaneously diminishes the HigB mediated regulation on the expression of T3SS genes and biofilm formation. Therefore, our results reveal novel functions of HigB in P. aeruginosa.

scholarly journals DsbA of Pseudomonas aeruginosa Is Essential for Multiple Virulence Factors

2003 ◽  
Vol 71 (3) ◽  
pp. 1590-1595 ◽  
Author(s):  
Un-Hwan Ha ◽  
Yanping Wang ◽  
Shouguang Jin
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Virulence Factors ◽  
Protein Secretion ◽  
Hela Cells ◽  
Type Iii Secretion ◽  
Disulfide Bonds ◽  
Secretion System ◽  
Biological Processes ◽  
Twitching Motility ◽  
Important Target

ABSTRACT DsbA is a periplasmic thiol:disulfide oxidoreductase which contributes to the process of protein folding by catalyzing the formation of disulfide bonds. In this study, we demonstrate that the dsbA gene is required for the expression of the type III secretion system under low-calcium inducing conditions, intracellular survival of P. aeruginosa upon infection of HeLa cells, and twitching motility. The diverse phenotypes of the dsbA mutant are likely due to its defect in the folding of proteins that are involved in various biological processes, such as signal sensing, protein secretion, and defense against host clearing. In light of its effect on various virulence factors, DsbA could be an important target for the control of P. aeruginosa infections.

scholarly journals An Adenylate Cyclase-Controlled Signaling Network Regulates Pseudomonas aeruginosa Virulence in a Mouse Model of Acute Pneumonia

2004 ◽  
Vol 72 (3) ◽  
pp. 1677-1684 ◽  
Author(s):  
Roger S. Smith ◽  
Matthew C. Wolfgang ◽  
Stephen Lory
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Adenylate Cyclase ◽  
Virulence Factors ◽  
Type Iii Secretion ◽  
Regulatory Network ◽  
Regulatory Protein ◽  
Type Iii Secretion System ◽  
Secretion System ◽  
Lung Pathology ◽  
Type Iii

ABSTRACT Infections caused by the opportunistic pathogen Pseudomonas aeruginosa involve the interplay of several bacterial virulence factors. It has recently been established that the delivery of toxic effector proteins by the type III secretion system is an important virulence mechanism in several animal models. Furthermore, the expression of the type III secretion system and its effectors has been correlated with a poor clinical outcome during human infections. A novel cyclic AMP (cAMP) regulatory network that controls the expression of virulence factors, including the type III secretion system, was examined to determine its contribution to P. aeruginosa colonization and dissemination in a mouse pneumonia model. Mutants lacking the two genome-encoded adenylate cyclases, CyaA and CyaB, and the cAMP-dependent regulator Vfr were examined. Based on the enumeration of bacteria in lungs, livers, and spleens, as well as the assessment of mouse lung pathology, mutations in the cyaB and vfr genes resulted in a more significantly attenuated phenotype than mutations in cyaA. Moreover, in this model, expression of the type III secretion system was essential for lung colonization and pathology. Strains with mutations in the exsA gene, which encodes a type III regulatory protein, or pscC, which encodes an essential component of the secretion apparatus, were also significantly attenuated. Finally, we demonstrate that virulence can be restored in an adenylate cyclase mutant by the overexpression of exsA, which specifically restores expression of the type III secretion system in the absence of a functional cAMP-dependent regulatory network.

scholarly journals Diminished LcrV Secretion Attenuates Yersinia pseudotuberculosis Virulence

2007 ◽  
Vol 189 (23) ◽  
pp. 8417-8429 ◽  
Author(s):  
Jeanette E. Bröms ◽  
Matthew S. Francis ◽  
Åke Forsberg
Keyword(s):  
Type Iii Secretion ◽  
Yersinia Pseudotuberculosis ◽  
Signal Sequence ◽  
Infection Model ◽  
Target Cells ◽  
Cell Infection ◽  
Host Cell Membrane ◽  
Type Iii ◽  
A Cell

ABSTRACT Many gram-negative bacterial pathogenicity factors that function beyond the outer membrane are secreted via a contact-dependent type III secretion system. Two types of substrates are predestined for this mode of secretion, namely, antihost effectors that are translocated directly into target cells and the translocators required for targeting of the effectors across the host cell membrane. N-terminal secretion signals are important for recognition of the protein cargo by the type III secretion machinery. Even though such signals are known for several effectors, a consensus signal sequence is not obvious. One of the translocators, LcrV, has been attributed other functions in addition to its role in translocation. These functions include regulation, presumably via interaction with LcrG inside bacteria, and immunomodulation via interaction with Toll-like receptor 2. Here we wanted to address the significance of the specific targeting of LcrV to the exterior for its function in regulation, effector targeting, and virulence. The results, highlighting key N-terminal amino acids important for LcrV secretion, allowed us to dissect the role of LcrV in regulation from that in effector targeting/virulence. While only low levels of exported LcrV were required for in vitro effector translocation, as deduced by a cell infection assay, fully functional export of LcrV was found to be a prerequisite for its role in virulence in the systemic murine infection model.

scholarly journals Diversity of Virulence Phenotypes among Type III Secretion Negative Pseudomonas aeruginosa Clinical Isolates

PLoS ONE ◽  
2014 ◽  
Vol 9 (1) ◽  
pp. e86829 ◽  
Author(s):  
Jonida Toska ◽  
Yan Sun ◽  
Dalina Alvarez Carbonell ◽  
Altreisha N. -S. Foster ◽  
Michael R. Jacobs ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Type Iii Secretion ◽  
Clinical Isolates ◽  
Type Iii
Sign in / Sign up

Export Citation Format

Share Document