scholarly journals Shigella flexneri Phagosomal Escape Is Independent of Invasion

2007 ◽  
Vol 75 (10) ◽  
pp. 4826-4830 ◽  
Author(s):  
Susanne Paetzold ◽  
Sebastian Lourido ◽  
Bärbel Raupach ◽  
Arturo Zychlinsky
Keyword(s):  
Cell Invasion ◽  
Type Iii Secretion ◽  
Shigella Flexneri ◽  
Mucosal Inflammation ◽  
Virulence Plasmid ◽  
Secretion Systems ◽  
Type Iii Secretion Systems ◽  
Macrophage Cytotoxicity ◽  
Serovar Typhimurium ◽  
Epithelial Cell Invasion

ABSTRACT Infections with Salmonella enterica serovar Typhimurium and Shigella flexneri result in mucosal inflammation in response to epithelial cell invasion and macrophage cytotoxicity. These processes are mediated by type III secretion systems encoded in homologous virulence loci in the two species, namely, Salmonella pathogenicity island 1 (SPI-1), carried in the genome, and the Shigella entry region (SER), carried in a large virulence plasmid. Here we show that SPI-1 can functionally complement a deletion of SER in S. flexneri, restoring invasion of epithelial cells, macrophage cytotoxicity, and phagosomal escape. Furthermore, S. flexneri phagosomal escape requires the SER and another gene(s) carried on the large virulence plasmid. We demonstrate that the processes of invasion and phagosomal escape can be uncoupled in S. flexneri.

scholarly journals Small-Molecule Type III Secretion System Inhibitors Block Assembly of the Shigella Type III Secreton

2008 ◽  
Vol 191 (2) ◽  
pp. 563-570 ◽  
Author(s):  
Andreas K. J. Veenendaal ◽  
Charlotta Sundin ◽  
Ariel J. Blocker
Keyword(s):  
Type Iii Secretion ◽  
Bacterial Infections ◽  
Shigella Flexneri ◽  
Effector Proteins ◽  
Host Cells ◽  
Incomplete Penetrance ◽  
Secretion Systems ◽  
Bacterial Surface ◽  
Type Iii ◽  
Type Iii Secretion Systems

ABSTRACT Type III secretion systems (T3SSs) are essential virulence devices for many gram-negative bacteria that are pathogenic for plants, animals, and humans. They serve to translocate virulence effector proteins directly into eukaryotic host cells. T3SSs are composed of a large cytoplasmic bulb and a transmembrane region into which a needle is embedded, protruding above the bacterial surface. The emerging antibiotic resistance of bacterial pathogens urges the development of novel strategies to fight bacterial infections. Therapeutics that rather than kill bacteria only attenuate their virulence may reduce the frequency or progress of resistance emergence. Recently, a group of salicylidene acylhydrazides were identified as inhibitors of T3SSs in Yersinia, Chlamydia, and Salmonella species. Here we show that these are also effective on the T3SS of Shigella flexneri, where they block all related forms of protein secretion so far known, as well as the epithelial cell invasion and induction of macrophage apoptosis usually demonstrated by this bacterium. Furthermore, we show the first evidence for the detrimental effect of these compounds on T3SS needle assembly, as demonstrated by increased numbers of T3S apparatuses without needles or with shorter needles. Therefore, the compounds generate a phenocopy of T3SS export apparatus mutants but with incomplete penetrance. We discuss why this would be sufficient to almost completely block the later secretion of effector proteins and how this begins to narrow the search for the molecular target of these compounds.

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 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 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 Discovery of Novel Secreted Virulence Factors fromSalmonella entericaSerovar Typhimurium by Proteomic Analysis of Culture Supernatants

2010 ◽  
Vol 79 (1) ◽  
pp. 33-43 ◽  
Author(s):  
George S. Niemann ◽  
Roslyn N. Brown ◽  
Jean K. Gustin ◽  
Afke Stufkens ◽  
Afshan S. Shaikh-Kidwai ◽  
...  
Keyword(s):  
Virulence Factors ◽  
Type Iii Secretion ◽  
Learning Algorithm ◽  
Effector Proteins ◽  
Secretion Systems ◽  
Type Iii Effectors ◽  
Type Iii ◽  
Type Iii Secretion Systems ◽  
Serovar Typhimurium ◽  
Proteomic Study

ABSTRACTSalmonella entericaserovar Typhimurium is a leading cause of acute gastroenteritis throughout the world. This pathogen has two type III secretion systems (TTSS) encoded inSalmonellapathogenicity islands 1 and 2 (SPI-1 and SPI-2) that deliver virulence factors (effectors) to the host cell cytoplasm and are required for virulence. While many effectors have been identified and at least partially characterized, the full repertoire of effectors has not been catalogued. In this proteomic study, we identified effector proteins secreted into defined minimal medium designed to induce expression of the SPI-2 TTSS and its effectors. We compared the secretomes of the parent strain to those of strains missing essential (ssaK::cat) or regulatory (ΔssaL) components of the SPI-2 TTSS. We identified 20 known SPI-2 effectors. Excluding the translocon components SseBCD, all SPI-2 effectors were biased for identification in the ΔssaLmutant, substantiating the regulatory role of SsaL in TTS. To identify novel effector proteins, we coupled our secretome data with a machine learning algorithm (SIEVE,SVM-basedidentification andevaluation ofvirulenceeffectors) and selected 12 candidate proteins for further characterization. Using CyaA′ reporter fusions, we identified six novel type III effectors and two additional proteins that were secreted into J774 macrophages independently of a TTSS. To assess their roles in virulence, we constructed nonpolar deletions and performed a competitive index analysis from intraperitoneally infected 129/SvJ mice. Six mutants were significantly attenuated for spleen colonization. Our results also suggest that non-type III secretion mechanisms are required for fullSalmonellavirulence.

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 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 Type III secretion systems and the evolution of mutualistic endosymbiosis

2002 ◽  
Vol 99 (19) ◽  
pp. 12397-12402 ◽  
Author(s):  
C. Dale ◽  
G. R. Plague ◽  
B. Wang ◽  
H. Ochman ◽  
N. A. Moran
Keyword(s):  
Type Iii Secretion ◽  
Secretion Systems ◽  
Type Iii ◽  
Type Iii Secretion Systems
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