scholarly journals Inhibition of Type III Secretion in Salmonella enterica Serovar Typhimurium by Small-Molecule Inhibitors

2007 ◽  
Vol 51 (7) ◽  
pp. 2631-2635 ◽  
Author(s):  
Debra L. Hudson ◽  
Abigail N. Layton ◽  
Terry R. Field ◽  
Alison J. Bowen ◽  
Hans Wolf-Watz ◽  
...  
Keyword(s):  
Small Molecules ◽  
Type Iii Secretion ◽  
Salmonella Enterica Serovar Typhimurium ◽  
Gram Negative Bacteria ◽  
Secretion Systems ◽  
Type Iii ◽  
Type Iii Secretion Systems ◽  
Cultured Epithelial Cells ◽  
Serovar Typhimurium

ABSTRACT Type III secretion systems (T3SS) are conserved in many pathogenic gram-negative bacteria. Small molecules that specifically target T3SS in Yersinia and Chlamydia spp. have recently been identified. Here we show that two such compounds inhibit Salmonella T3SS-1, preventing secretion of T3SS-1 effectors, invasion of cultured epithelial cells, and enteritis in vivo.

scholarly journals Complex Function for SicA, a Salmonella enterica Serovar Typhimurium Type III Secretion-Associated Chaperone

2000 ◽  
Vol 182 (8) ◽  
pp. 2262-2268 ◽  
Author(s):  
Stephanie C. Tucker ◽  
Jorge E. Galán
Keyword(s):  
Type Iii Secretion ◽  
Salmonella Enterica ◽  
Salmonella Enterica Serovar Typhimurium ◽  
Complex Function ◽  
Loss Of Function ◽  
Secretion Systems ◽  
Type Iii ◽  
Type Iii Secretion Systems ◽  
Serovar Typhimurium ◽  
Low Molecular Weight Proteins

ABSTRACT Salmonella enterica encodes a type III secretion system within a pathogenicity island located at centisome 63 that is essential for virulence. All type III secretion systems require the function of a family of low-molecular-weight proteins that aid the secretion process by acting as partitioning factors and/or secretion pilots. One such protein is SicA, which is encoded immediately upstream of the type III secreted proteins SipB and SipC. We found that the absence of SicA results in the degradation of both SipB and SipC. Interestingly, in the absence of SipC, SipB was not only stable but also secreted at wild-type levels in a sicA mutant background, indicating that SicA is not required for SipB secretion. We also found that SicA is capable of binding both SipB and SipC. These results are consistent with a SicA role as a partitioning factor for SipB and SipC, thereby preventing their premature association and degradation. We also found that introduction of a sicA null mutation results in the lack of expression of SopE, another type III-secreted protein. Such an effect was shown to be transcriptional. Introduction of a loss-of-function sipC mutation into the sicAmutant background rescued sopE expression. These results indicate that the effect of sicA on sopEexpression is indirect and most likely exerted through a regulatory factor(s) partitioned by SicA from SipC. These studies therefore describe a surprisingly complex function for the Salmonella enterica type III secretion-associated chaperone SicA.

scholarly journals Tandem Translation Generates a Chaperone for the Salmonella Type III Secretion System Protein SsaQ

2011 ◽  
Vol 286 (41) ◽  
pp. 36098-36107 ◽  
Author(s):  
Xiu-Jun Yu ◽  
Mei Liu ◽  
Steve Matthews ◽  
David W. Holden
Keyword(s):  
Type Iii Secretion ◽  
Ex Vivo ◽  
Eukaryotic Cell ◽  
Effector Proteins ◽  
Secretion Systems ◽  
Type Iii ◽  
Type Iii Secretion Systems ◽  
Function Loss ◽  
Bacterial Cytoplasm

Type III secretion systems (T3SSs) of bacterial pathogens involve the assembly of a surface-localized needle complex, through which translocon proteins are secreted to form a pore in the eukaryotic cell membrane. This enables the transfer of effector proteins from the bacterial cytoplasm to the host cell. A structure known as the C-ring is thought to have a crucial role in secretion by acting as a cytoplasmic sorting platform at the base of the T3SS. Here, we studied SsaQ, an FliN-like putative C-ring protein of the Salmonella pathogenicity island 2 (SPI-2)-encoded T3SS. ssaQ produces two proteins by tandem translation: a long form (SsaQL) composed of 322 amino acids and a shorter protein (SsaQS) comprising the C-terminal 106 residues of SsaQL. SsaQL is essential for SPI-2 T3SS function. Loss of SsaQS impairs the function of the T3SS both ex vivo and in vivo. SsaQS binds to its corresponding region within SsaQL and stabilizes the larger protein. Therefore, SsaQL function is optimized by a novel chaperone-like protein, produced by tandem translation from its own mRNA species.

scholarly journals Characterization of Salmonella enterica Derivatives Harboring Defined aroC and Salmonella Pathogenicity Island 2 Type III Secretion System (ssaV) Mutations by Immunization of Healthy Volunteers

2002 ◽  
Vol 70 (7) ◽  
pp. 3457-3467 ◽  
Author(s):  
Zoë Hindle ◽  
Steven N. Chatfield ◽  
Jo Phillimore ◽  
Matthew Bentley ◽  
Julie Johnson ◽  
...  
Keyword(s):  
Type Iii Secretion ◽  
Salmonella Enterica ◽  
High Titer ◽  
Serum Antibody ◽  
Immunoglobulin A ◽  
Secretion Systems ◽  
Antibody Secreting Cell ◽  
Type Iii ◽  
Type Iii Secretion Systems ◽  
Serovar Typhimurium

ABSTRACT The attenuation and immunogenicity of two novel Salmonella vaccine strains, Salmonella enterica serovar Typhi (Ty2 ΔaroC ΔssaV, designated ZH9) and S. enterica serovar Typhimurium (TML ΔaroC ΔssaV, designated WT05), were evaluated after their oral administration to volunteers as single escalating doses of 107, 108, or 109 CFU. ZH9 was well tolerated, not detected in blood, nor persistently excreted in stool. Six of nine volunteers elicited anti-serovar Typhi lipopolysaccharide (LPS) immunoglobulin A (IgA) antibody-secreting cell (ASC) responses, with three of three vaccinees receiving 108 and two of three receiving 109 CFU which elicited high-titer LPS-specific serum IgG. WT05 was also well tolerated with no diarrhea, although the administration of 108 and 109 CFU resulted in shedding in stools for up to 23 days. Only volunteers immunized with 109 CFU of WT05 mounted detectable serovar Typhimurium LPS-specific ASC responses and serum antibody responses were variable. These data indicate that mutations in type III secretion systems may provide a route to the development of live vaccines in humans and highlight significant differences in the potential use of serovars Typhimurium and Typhi.

scholarly journals Small molecules aimed at type III secretion systems to inhibit bacterial virulence

MedChemComm ◽  
2013 ◽  
Vol 4 (1) ◽  
pp. 68-79 ◽  
Author(s):  
Lun K. Tsou ◽  
Paul D. Dossa ◽  
Howard C. Hang
Keyword(s):  
Small Molecules ◽  
Type Iii Secretion ◽  
Modern Medicine ◽  
Bacterial Virulence ◽  
Bacterial Strains ◽  
Secretion Systems ◽  
Type Iii ◽  
Type Iii Secretion Systems

The development of new anti-bacterial compounds presents a major challenge to modern medicine as bacterial strains resistant to traditional antibiotics are constantly emerging.

scholarly journals Analysis of the Contribution of Salmonella Pathogenicity Islands 1 and 2 to Enteric Disease Progression Using a Novel Bovine Ileal Loop Model and a Murine Model of Infectious Enterocolitis

2005 ◽  
Vol 73 (11) ◽  
pp. 7161-7169 ◽  
Author(s):  
Brian K. Coombes ◽  
Bryan A. Coburn ◽  
Andrew A. Potter ◽  
Susantha Gomis ◽  
Kuldip Mirakhur ◽  
...  
Keyword(s):  
Type Iii Secretion ◽  
Disease Process ◽  
Loop Model ◽  
Enteric Disease ◽  
Wild Type ◽  
Secretion Systems ◽  
Ileal Loop ◽  
Type Iii ◽  
Type Iii Secretion Systems

ABSTRACT We have developed a novel ileal loop model for use in calves to analyze the contribution of Salmonella enterica serovar Typhimurium type III secretion systems to disease processes in vivo. Our model involves constructing ileal loops with end-to-end anastamoses to restore the patency of the small intestine, thereby allowing experimental animals to convalesce following surgery for the desired number of days. This model overcomes the time constraint imposed by ligated ileal loop models that have precluded investigation of Salmonella virulence factors during later stages of the infection process. Here, we have used this model to examine the enteric disease process at 24 h and 5 days following infection with wild-type Salmonella and mutants lacking the virulence-associated Salmonella pathogenicity island 1 (SPI-1) or SPI-2 type III secretion systems. We show that SPI-2 mutants are dramatically attenuated at 5 days following infection and report a new phenotype for SPI-1 mutants, which induce intestinal pathology in calves similar to wild-type Salmonella in the 5-day ileal loop model. Both of these temporal phenotypes for SPI-1 and SPI-2 mutants were corroborated in a second animal model of enteric disease using streptomycin-pretreated mice. These data delineate novel phenotypes for SPI-1 and SPI-2 mutants in the intestinal phase of bovine and murine salmonellosis and provide working models to further investigate the effector contribution to these pathologies.

scholarly journals Salicylidene Acylhydrazides That Affect Type III Protein Secretion in Salmonella enterica Serovar Typhimurium

2007 ◽  
Vol 51 (8) ◽  
pp. 2867-2876 ◽  
Author(s):  
Aurel Negrea ◽  
Eva Bjur ◽  
Sofia Eriksson Ygberg ◽  
Mikael Elofsson ◽  
Hans Wolf-Watz ◽  
...  
Keyword(s):  
Salmonella Enterica ◽  
Salmonella Enterica Serovar Typhimurium ◽  
Effector Proteins ◽  
Secretion Systems ◽  
Type Iii ◽  
Type Iii Secretion Systems ◽  
Serovar Typhimurium ◽  
Type Iii Protein Secretion ◽  
Bacterial Replication

ABSTRACT A collection of nine salicylidene acylhydrazide compounds were tested for their ability to inhibit the activity of virulence-associated type III secretion systems (T3SSs) in Salmonella enterica serovar Typhimurium. The compounds strongly affected Salmonella pathogenicity island 1 (SPI1) T3SS-mediated invasion of epithelial cells and in vitro secretion of SPI1 invasion-associated effector proteins. The use of a SPI1 effector β-lactamase fusion protein implicated intracellular entrapment of the protein construct upon application of a salicylidene acylhydrazide, whereas the use of chromosomal transcriptional gene fusions revealed a compound-mediated transcriptional silencing of SPI1. Salicylidene acylhydrazides also affected intracellular bacterial replication in murine macrophage-like cells and blocked the transport of an epitope-tagged SPI2 effector protein. Two of the compounds significantly inhibited bacterial motility and expression of extracellular flagellin. We conclude that salicylidene acylhydrazides affect bacterial T3SS activity in S. enterica and hence could be used as lead substances when designing specific inhibitors of bacterial T3SSs in order to pharmaceutically intervene with bacterial virulence.

scholarly journals Synthesis and Localization of the Salmonella SPI-1 Type III Secretion Needle Complex Proteins PrgI and PrgJ

2003 ◽  
Vol 185 (11) ◽  
pp. 3480-3483 ◽  
Author(s):  
Anand Sukhan ◽  
Tomoko Kubori ◽  
Jorge E. Galán
Keyword(s):  
Mutant Strain ◽  
Type Iii Secretion ◽  
Wild Type ◽  
Secretion Systems ◽  
Type Iii ◽  
Type Iii Secretion Systems ◽  
Mutant Strains ◽  
Serovar Typhimurium ◽  
Needle Protein ◽  
Protein Instability

ABSTRACT An essential component of type III secretion systems (TTSS) is a supramolecular structure termed the needle complex. In Salmonella enterica, at least four proteins make up this structure: InvG, PrgH, PrgK, and PrgI. Another protein, PrgJ, is thought to play a role in the assembly of this structure, but its function is poorly understood. We have analyzed the expression and localization of PrgJ and the needle protein PrgI in different S. enterica serovar Typhimurium mutant strains. We found that the levels of PrgI and PrgJ were significantly reduced in a TTSS-deficient invA mutant strain and that the decreased levels were due to protein instability. In addition, we found that PrgJ, although associated with the needle complex in wild-type S. enterica serovar Typhimurium, was absent from needle complexes obtained from an invJ mutant strain, which exhibits very long needle substructures. We suggest that PrgJ is involved in capping the needle substructure of the needle complex.

scholarly journals Dual perspective proteomics infectome profiling discovers Salmonella type III secretion system effector functions in macrophages

2021 ◽  
Author(s):  
Jennifer Geddes-McAlister ◽  
A. Sukumaran ◽  
S. L. Vogt ◽  
J. L. Roland ◽  
S. E. Woodward ◽  
...  
Keyword(s):  
Type Iii Secretion ◽  
Bacterial Pathogens ◽  
Host Cells ◽  
Secretion Systems ◽  
Specific Expression ◽  
Type Iii ◽  
Cell Functions ◽  
Serovar Typhimurium ◽  
Dual Perspective

Intracellular bacterial pathogens have evolved sophisticated infection strategies, including the release and secretion of virulence factors to interfere with host cell functions and to perturb immune responses. For Salmonella enterica serovar Typhimurium (S. Typhimurium), the type III secretion systems encoded on Salmonella pathogenicity islands (SPI) 1 and 2 mediates invasion of the bacterium into innate immune cells and regulates bacterial replication and survival within the hostile environment of the host, respectively. Here, we explore the temporal and strain-specific dual perspective response of both the host and pathogen during cellular infection via quantitative proteomics. We report time- and pathogenicity island-specific expression and secretion of infection-associated proteins (i.e., SL1344_1263, SL1344_3112, SL1344_1563, and YnhG) and regulated immune response proteins in macrophage, including Cd86, Cd40, Casp4, C3, IL-1?, and Cd69). Through intracellular macrophage and in vivo murine models of infection, we reveal a role in virulence for three of the bacterial proteins (SL1344_1263, SL1344_1563, and YnhG), defining their importance as novel T3SS effectors. We characterize the temporal intra- and extracellular production of the effectors and identify their interaction networks in host cells, representing inhibitory and stimulatory pathways mounted by invading bacterial pathogens.

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