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PubMed2000

Complex function for SicA, a Salmonella enterica serovar typhimurium type III secretion-associated chaperone.

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 sicA mutant background rescued sopE expression. These results indicate that the effect of sicA on sopE expression 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.

Antigens, Bacterial↗

PubMed1996

Salmonella spp. are cytotoxic for cultured macrophages.

We have shown by a variety of microscopical and biochemical techniques that Salmonella spp. are cytotoxic for cultured J774A.1 and bone marrow-derived murine macrophages. The cytotoxicity is initially manifested by inhibition of membrane ruffling and macropinocytosis in infected macrophages, and is followed by cell death. Macrophages killed by Salmonella spp. exhibited features of apoptosis such as condensation and fragmentation of chromatin, membrane blebbing, and the presence of cytoplasmic nucleosomes and apoptotic bodies. Cytotoxicity does not require bacterial internalization as cytochalasin D, a drug that prevents bacterial uptake, did not prevent Salmonella-induced macrophage cell death. However, the cytotoxic effects are strictly dependent upon the expression of the invasion-associated Type III protein-secretion system encoded at centisome 63 of the Salmonella chromosome. Wild-type Salmonella typhimurium grown under conditions that do not allow optical expression of this system or strains of Salmonella carrying mutations in genes that encode components of this protein-secretion system were devoid of macrophage cytotoxicity. In addition, mutations in invJ, spaO, sipB, sipC and sipD, which encode proteins that are secreted via this secretion apparatus and are required for bacterial entry into non-phagocytic cells, also abolished the toxicity. In contrast, mutations in sipA and sptP, which encode secreted proteins that are not required for bacterial invasion, had no effect on macrophage cytotoxicity. These results indicate a close correlation between the mechanisms of bacterial internalization into non-phagocytic cells and those that lead to macrophage cytotoxicity. Host-adapted serotypes of Salmonella such as S. typhi, S. gallinarum and S. dublin were also toxic for murine macrophages, indicating that this virulence property is probably present in most Salmonella spp. and is not associated with the mechanisms responsible for host range.

Animals↗

PubMed2004

Type III protein secretion mechanism in mammalian and plant pathogens.

The type III protein secretion system (TTSS) is a complex organelle in the envelope of many Gram-negative bacteria; it delivers potentially hundreds of structurally diverse bacterial virulence proteins into plant and animal cells to modulate host cellular functions. Recent studies have revealed several basic features of this secretion system, including assembly of needle/pilus-like secretion structures, formation of putative translocation pores in the host membrane, recognition of N-terminal/5' mRNA-based secretion signals, and requirement of small chaperone proteins for optimal delivery and/or expression of effector proteins. Although most of our knowledge about the TTSS is derived from studies of mammalian pathogenic bacteria, similar and unique features are learned from studies of plant pathogenic bacteria. Here, we summarize the most salient aspects of the TTSS, with special emphasis on recent findings.

Animals↗

PubMed2002

Type IVB secretion by intracellular pathogens.

A growing number of pathogens are being found to possess specialized secretion systems which they use in various ways to subvert host defenses. One class, called type IV, are defined as having homology to the conjugal transfer systems of naturally occurring plasmids. It has been proposed that pathogens with type IV secretion systems have acquired and adapted the conjugal transfer systems of plasmids and now use them to export toxins. Several well-characterized intracellular pathogens, including Legionella pneumophila, Coxiella burnetii, Brucella abortus, and Rickettsia prowazekii, contain type IV systems which are known or suspected to be of critical importance in their ability to cause disease. Specifically, these systems are believed to be the key factors determining intracellular fate, and thus the ability to replicate and cause disease.

Amino Acid Sequence↗

PubMed2000

The putative invasion protein chaperone SicA acts together with InvF to activate the expression of Salmonella typhimurium virulence genes.

SigD and SigE (Salmonella invasion gene) are proteins needed for optimal invasion of Salmonella typhimurium into eukaryotic cells in vitro. SigD is a secreted protein and SigE is a putative chaperone required for SigD stability and/or secretion. SigD is secreted by a type III secretion apparatus encoded within a pathogenicity island on the Salmonella chromosome known as Salmonella pathogenicity island 1 (SPI1). The expression of sigDE, which is not linked to SPI1, is co-ordinately regulated with the SPI1 genes and is dependent on the transcriptional regulators SirA, HilA and InvF. These three proteins alone are unable to activate transcription from the sigD promoter in Escherichia coli, therefore it is likely that other factors are needed for expression. A screen for genes required for the expression of a sigD-lacZYA reporter fusion found a mutant with a transposon insertion in spaS, an SPI1 gene which encodes a putative inner-membrane component of the type III secretion system. The expression of a SPI1 operon encoding a putative chaperone (SicA) and several secreted proteins (Sips B, C, D and A) was also reduced in this mutant. The regulation defect of the spaS mutant was complemented by sicA and not by spaS. Because sicA is encoded immediately downstream of spaS, the mutation in spaS was likely to be polar on the expression of sicA. In addition, a sicA disruption mutant was as defective as an invF deletion mutant for the expression of sigD, sicA and sipC reporter fusions. The introduction of plasmids encoding invF and sicA into a non-pathogenic E. coli K-12 strain stimulated the transcription of both a sicA- and a sigD-lacZYA promoter fusion. This result suggests that InvF and SicA are sufficient for the expression of these genes. This is the first demonstration of a positive regulatory role for a putative type III secretion system chaperone in the expression of virulence genes.

Bacterial Proteins↗

PubMed2001

Characterization of translocation pores inserted into plasma membranes by type III-secreted Esp proteins of enteropathogenic Escherichia coli.

Many mucosal pathogens use type III secretion systems for the injection of effector proteins into target cells. The type III-secreted proteins EspB and EspD of enteropathogenic Escherichia coli (EPEC) are inserted into the target cell membrane. Together with EspA, these proteins are supposed to constitute a molecular syringe, channelling other effector proteins into the host cell. In this model, EspB and EspD would represent the tip of the needle forming a pore into target cell membranes. Although contact-dependent and Esp-mediated haemolytic activity by EPEC has already been described, the formation of a putative pore resulting in haemolysis has not been demonstrated so far. Here, we show that (i) diffusely adhering (DA)-EPEC strains exhibit a type III-dependent haemolytic activity too; (ii) this activity resides in the secreted proteins and, for DA-EPEC strains, in contrast to EPEC strains, does not require bacterial contact; and (iii) pores are introduced into the target cell membrane. Osmoprotection revealed a minimal pore size of 3-5 nm. The pores induced by type III-secreted proteins of DA-EPEC were characterized by electron microscopy techniques. Analysis by atomic force microscopy demonstrated the pores to be composed of six to eight subunits with a lateral extension of 55-65 nm and to be raised 15-20 nm above the membrane plane. We could also demonstrate an association of EspB and EspD with erythrocyte membranes and an interaction of both proteins with each other in vitro. These results, together with the homologies of EspB and EspD to proposed functional domains of other pore-forming proteins (Yop/Ipa), strongly support the idea that both proteins are directly involved in pore formation, which might represent the type III secretion system translocon.

Animals↗

PubMed1991

[Effect of nifedipine treatment on the renin-aldosterone system and secretion of cortisol and growth hormone in patients with essential hypertension].

The effect of treatment of hypertension with nifedipine on plasma renin activity, blood serum level of aldosterone in the course of renin test, and cortisol and growth hormone concentrations after stimulation with insulin hypoglycemia was followed during two weeks of treatment in 40 patients with essential hypertension. No significant differences in the secretion of the hormones studied, as compared to the patients with the normal arterial blood pressure, were found. After nifedipine treatment no significant changes in the secretion of aldosterone, cortisol and growth hormone were observed despite a significant fall in the arterial blood pressure while there was a moderate stimulatory effect on renin secretion. The results obtained indicate that nifedipine has only small effect on the hormonal system of patients with essential hypertension.

Adult↗

PubMed2000

The type III protein translocation system of enteropathogenic Escherichia coli involves EspA-EspB protein interactions.

Enteropathogenic Escherichia coli (EPEC), like many bacterial pathogens, use a type III secretion system to deliver effector proteins across the bacterial cell wall. In EPEC, four proteins, EspA, EspB, EspD and Tir are known to be exported by a type III secretion system and to be essential for 'attaching and effacing' (A/E) lesion formation, the hallmark of EPEC pathogenicity. EspA was recently shown to be a structural protein and a major component of a large, transiently expressed, filamentous surface organelle which forms a direct link between the bacterium and the host cell. In contrast, EspB is translocated into the host cell where it is localized to both membrane and cytosolic cell fractions. EspA and EspB are required for translocation of Tir to the host cell membrane suggesting that they may both be components of the translocation apparatus. In this study, we show that EspB co-immunoprecipitates with the EspA filaments and that, during EPEC infection of HEp-2 cells, EspB localizes closely with EspA. Using a number of binding assays, we also show that EspB can bind and be copurified with EspA. Nevertheless, binding of EspA filaments to the host cell membranes occurred even in the absence of EspB. These results suggest that following initial attachment of the EspA filaments to the target cells, EspB is delivered into the host cell membrane and that the interaction between EspA and EspB may be important for protein translocation.

Animals↗

PubMed2002

The Salmonella enterica serotype typhimurium effector proteins SipA, SopA, SopB, SopD, and SopE2 act in concert to induce diarrhea in calves.

Salmonella enterica serotype Typhimurium requires a functional type III secretion system encoded by Salmonella pathogenicity island 1 (SPI1) to cause diarrhea. We investigated the role of genes encoding secreted target proteins of the SPI1-associated type III secretion system for enteropathogenicity in calves. Salmonella serotype Typhimurium strains having mutations in sptP, avrA, sspH1, or slrP induced fluid secretion in the bovine ligated ileal loop model at levels similar to that of the wild type. In contrast, mutations in sipA, sopA, sopB, sopD, or sopE2 significantly reduced fluid accumulation in bovine ligated ileal loops at 8 h postinfection. A strain carrying mutations in sipA, sopA, sopB, sopD, and sopE2 (sipA sopABDE2 mutant) caused the same level of fluid accumulation in bovine ligated ileal loops as a strain carrying a mutation in sipB, a SPI1 gene required for the translocation of effector proteins into host cells. A positive correlation was observed between the severity of histopathological lesions detected in the ileal mucosa and the levels of fluid accumulation induced by the different mutants. After oral infection of calves, the Salmonella serotype Typhimurium sipAsopABDE2 mutant caused only mild diarrhea and was more strongly attenuated than strains having only single mutations. These data demonstrate that SipA, SopA, SopB, SopD, and SopE2 are major virulence factors responsible for diarrhea during Salmonella serotype Typhimurium infection of calves.

Administration, Oral↗

PubMed1997

Elevated serum levels of cyclo (His-Pro), an endogenous inhibitor of pituitary prolactin secretion, in systemic lupus erythematosus patients.

Cyclo (His-Pro) or CHP is a cyclic dipeptide that is known to elicit many biologic activities including inhibition of pituitary prolactin (PRL) secretion. PRL stimulates humoral and cell mediated immune responses and hyperprolactinemia has been found in a subset of systemic lupus erythematosus (SLE) patients in association with active disease. To explore whether CHP may play a role in SLE patients, we measured, CHP and PRL levels in sera of 21 SLE patients and 11 normal controls. The results of this study show significantly (P < 0.001) high levels of CHP in SLE compared to controls. However, there was no significant correlation between serum PRL and CHP levels in SLE patients (r = 0.027, P = 0.29). The increase in serum levels of CHP may be in an attempt to increase hypothalamic content of dopamine which in turn would decrease pituitary PRL synthesis in hyperprolactinemic SLE patients.

Adult↗

PubMed2001

Role of sipA in the early stages of Salmonella typhimurium entry into epithelial cells.

Salmonella virulence depends on an ability to invade host cells, which is in turn dependent on a type III protein secretion system encoded in Salmonella pathogenicity island 1 (SPI1). Several protein targets of the SPI1-encoded secretion system are translocated into host cells, where they subvert cellular processes that contribute to bacterial invasion, actin rearrangement, membrane ruffling and other aspects of virulence. We examined the role of sipA (encoding the translocated protein SipA) and found that a sipA mutant was significantly less invasive in Madin-Darby canine kidney (MDCK) cells than in its parental strain at the earliest stages of infection (5 min). The invasion defect associated with sipA was no longer apparent after 15 min of infection. Confocal microscopy of F-actin in tetramethyl rhodamine isothiocyanate (TRITC)-phalloidin-stained MDCK cells revealed no difference in either the frequency or the morphology of membrane ruffles induced by wild-type and sipA mutant strains of S. typhimurium. Time-lapse phase-contrast microscopy of membrane ruffle propagation in live cells confirmed that the sipA mutant induced membrane ruffles as efficiently as the wild-type bacteria. These studies also revealed that, after ruffle propagation, individual sipA mutant S. typhimurium either invaded more slowly than wild-type bacteria or failed to invade at all. Furthermore, although wild-type S. typhimurium typically maintained a position central to the developing membrane ruffle, sipA mutant bacteria frequently moved initially to the periphery of the spreading ruffle and were sometimes observed to detach from it. A wild-type pattern of invasion was restored to the sipA mutant after the introduction of sipA on a plasmid. Together, these data indicate that loss of sipA significantly decreases the efficiency of S. typhimurium invasion at the early stages of infection without affecting its ability to induce membrane ruffles. It thus appears that the secreted effector protein SipA promotes invasion by a previously unrecognized mechanism separate from the induction of membrane ruffling per se.

Actins↗

PubMed2026

Metagenomic polymorphic toxin effector and immunity profiling predicts microbiome development and disease-related dysbiosis.

Bacteria use antagonistic interbacterial weapons, such as polymorphic toxin secretion systems (TSS), to compete for niches in the human gut microbiome. We hypothesized that TSS influence gut microbiome development and disease-related dysbiosis. We developed a bioinformatic marker gene approach (PolyProf) to quantify TSS including ~200 effector and immunity genes and applied it to ~15,000 publicly available human metagenomes. PolyProf alpha and beta diversity readily distinguished 12 different human disease states and enabled the construction of highly accurate linear regression classifier machine learning models. Elastic net machine learning models integrating bacterial taxonomy with PolyProf had strong predictive value for 12 disease states, outperforming models utilizing taxonomy alone. During microbiome development in the first year of life, PolyProf alpha diversity increases, and beta diversity becomes increasingly like the maternal microbiome, influenced by vertical transfer, delivery mode, and breastfeeding. PolyProf is related to strain sharing among adults through social interactions. In summary, TSS genes strongly correlate with microbiome development and interpersonal strain sharing, suggesting roles for interbacterial antagonism. Since PolyProf distinguishes diverse adult disease statuses, these dynamics may contribute to non-genetic inheritance.IMPORTANCEPrevious research has demonstrated that bacteria compete within the gut microbiome using toxin secretion systems (TSS). How TSS contribute to human microbiome development and the microbiome alterations observed in human diseases is not known. This study develops a new bioinformatic tool for profiling TSS-related genes in metagenomic data. Application of this approach to large-scale human fecal metagenomic data demonstrates the dynamic association of TSS during microbiome development, including the exchange of strains among social contacts. TSS gene abundance patterns are highly predictive of 12 disease states. This study advances the field by enabling TSS profiling in metagenomes and by identifying disease and microbiome development biomarkers that provide hypotheses for future mechanistic studies and may be useful for disease diagnosis.

Dysbiosis↗

PubMed2003

Type III protein secretion in Pseudomonas syringae.

The type III secretion system is an essential virulence system used by many Gram-negative bacterial pathogens to deliver effector proteins into host cells. This review summarizes recent advancements in the understanding of the type III secretion system of Pseudomonas syringae, including regulation of the type III secretion genes, assembly of the Hrp pilus, secretion signals, the putative type III effectors identified to date, and their virulence action after translocation into plant cells.

Bacterial Proteins↗

PubMedDate not supplied

Gonadotropins pituitary secretion in systemic lupus erythematosus.

Hormonal abnormalities have been suggested to play a role in the pathogenesis of systemic lupus erythematosus (SLE). In order to define the regulatory mechanism involved, the pituitary reserve for gonadotropins secretion was investigated in eight untreated SLE patients with normal menstrual cycles. Serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were determined on the fifth day of the menstrual cycle before and after intravenous administration of 25 micrograms synthetic luteinizing hormone-releasing hormone (LH-RH). The pulsatile LH and FSH resting values in SLE were not significantly higher than those found in the controls; after LH-RH stimulation no difference was observed between the SLE group and controls. The LH and FSH response to exogenous LH-RH administration in SLE demonstrate the integrity of the hypothalamic-pituitary-ovary axis that explains normal menses and fertility in this disease.

Adolescent↗

PubMed2004

Autotransporter and two-partner secretion: delivery of large-size virulence factors by gram-negative bacterial pathogens.

A number of protein secretion mechanisms have been identified in gram-negative pathogens. Many of these secretion systems are dependent upon the Sec translocase for protein export from the cytoplasm into the periplasm and then utilize other mechanisms for transport from the periplasm through the outer membrane. In this article, we review secretion similarities between autotransporter and two-partner secretion systems, and we report similarities between the autotransporter secretion mechanism with that of intimin/invasins. Considering that many secreted proteins are virulence factors, a better understanding of their secretion mechanisms will aid in the development of disease treatments and new bacterial vaccines.

Bacterial Proteins↗

PubMed2002

Proteomic approaches to Salmonella Pathogenicity Island 2 encoded proteins and the SsrAB regulon.

Type III protein secretion is a common virulence determinant in Gram-negative bacteria and the genetic information is often clustered in pathogenicity islands or on virulence plasmids. We have analyzed the type III secretion system encoded by Salmonella Pathogenicity Island 2 (SPI2) that is indispensable for systemic disease of Salmonella enterica serotype Typhimurium (S. Typhimurium) in mice. Since the low abundance of this secretion system restricted direct analysis by proteomic approaches, several putative proteins were expressed as recombinant products and analyzed by two-dimensional electrophoresis. The map obtained for SPI2 encoded proteins was correlated to the expression pattern of S. Typhimurium. The latter was compared to the proteins induced by SsrAB, the two-component system regulating SPI2 gene expression. Our results exemplify that recombinant expression is a complementary tool for analysis of low abundant proteins or membrane proteins. This approach contributes to the characterization of these proteins by subcellular fractionation. Furthermore, we show that pulse labeling was necessary to analyze growth phase regulated SPI2 proteins that might not be otherwise detectable.

Bacterial Proteins↗

PubMed2004

The HopPtoF locus of Pseudomonas syringae pv. tomato DC3000 encodes a type III chaperone and a cognate effector.

Type III secretion systems are highly conserved among gram-negative plant and animal pathogenic bacteria. Through the type III secretion system, bacteria inject a number of virulence proteins into the host cells. Analysis of the whole genome sequence of Pseudomonas syringae pv. tomato DC3000 strain identified a locus, named HopPtoF, that is homologous to the avirulence gene locus avrPphF in P. syringae pv. phaseolicola. The HopPtoF locus harbors two genes, ShcF(Pto) and HopF(Pto), that are preceded by a single hrp box promoter. We present evidence here to show that ShcF(Pto) and HopF(Pto) encode a type III chaperone and a cognate effector, respectively. ShcF(Pto) interacts with and stabilizes the HopF(Pto) protein in the bacterial cell. Translation of HopF(Pto) starts at a rare initiation codon ATA that limits the synthesis of the HopF(Pto) protein to a low level in bacterial cells.

Amino Acid Sequence↗

PubMed2004

FlaC, a protein of Campylobacter jejuni TGH9011 (ATCC43431) secreted through the flagellar apparatus, binds epithelial cells and influences cell invasion.

Type III secretion systems identified in bacterial pathogens of animals and plants transpose effectors and toxins directly into the cytosol of host cells or into the extracellular milieu. Proteins of the type III secretion apparatus are conserved among diverse and distantly related bacteria. Many type III apparatus proteins have homologues in the flagellar export apparatus, supporting the notion that type III secretion systems evolved from the flagellar export apparatus. No type III secretion apparatus genes have been found in the complete genomic sequence of Campylobacter jejuni NCTC11168. In this study, we report the characterization of a protein designated FlaC of C. jejuni TGH9011. FlaC is homologous to the N- and C-terminus of the C. jejuni flagellin proteins, FlaA and FlaB, but lacks the central portion of these proteins. flaC null mutants form a morphologically normal flagellum and are highly motile. In wild-type C. jejuni cultures, FlaC is found predominantly in the extracellular milieu as a secreted protein. Null mutants of the flagellar basal rod gene (flgF) and hook gene (flgE) do not secrete FlaC, suggesting that a functional flagellar export apparatus is required for FlaC secretion. During C. jejuni infection in vitro, secreted FlaC and purified recombinant FlaC bind to HEp-2 cells. Invasion of HEp-2 cells by flaC null mutants was reduced to a level of 14% compared with wild type, suggesting that FlaC plays an important role in cell invasion.

Bacterial Adhesion↗