Attenuated<i>Salmonella</i>and<i>Shigella</i>as Carriers for DNA Vaccines

Xu, Fengji; Ulmer, Jeffrey B.

doi:10.1080/10611860410001670053

Cited by 21 publications

(13 citation statements)

References 69 publications

(76 reference statements)

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“…Therefore, although the Lys effect may be caused by inhibition of Orn uptake, the DAP effect suggests that a direct influence on the metabolism by Lys is causing the observed effect. It is likely that metabolic pathways leading to and from DAP are inter-regulated in S. flexneri, since this cell wall component plays a critical role during host cell invasion and is later essential for intracellular survival (Xu & Ulmer, 2003). Our discovery of convergent and opposing influences by the Lys and Orn biosynthetic pathways reveals direct control by nutrients in S. flexneri.…”

Section: Discussionmentioning

confidence: 96%

“…Our data show that the invasive system of S. flexneri, in particular, captures and exploits this metabolic information by either delivering or withholding the virulence response, even as other environmental requirements such as temperature, osmolarity and pH, are met. At the least, this may be critical for the expression of the immunogenic components expected from living vaccine strains as well as for the efficiency of Shigella-based DNA vaccines (Xu & Ulmer, 2003). Most importantly, a large part of our knowledge on the physiopathology of S. flexneri and related organisms appears to depend on features conditioned by the quality of the nutritional surroundings.…”

Section: Discussionmentioning

confidence: 99%

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Metabolic control through ornithine and uracil of epithelial cell invasion by Shigella flexneri

Durand

Björk

2009

Microbiology

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This paper shows that compounds in defined growth media strongly influence the expression of the effectors of virulence in the human invasive pathogen Shigella flexneri. Ornithine in conjunction with uracil reduces the haemolytic ability of wild-type cultures more than 20-fold and the expression of the type III secretion system more than 8-fold, as monitored by an mxiC : : lacZ transcriptional reporter. mxiC gene expression is further decreased by the presence of methionine or branched-chain amino acids (15-fold or 25-fold at least, respectively). Lysine and a few other aminated metabolites (cadaverine, homoserine and diaminopimelate) counteract the ornithinemediated inhibition of haemolytic activity and of the expression of a transcriptional activator virF reporter. The complete abolition of invasion of HeLa cells by wild-type bacteria by ornithine, uracil, methionine or branched-chain amino acids establishes that these metabolites are powerful effectors of virulence. These findings provide a direct connection between metabolism and virulence in S. flexneri. The inhibitory potential exhibited by the nutritional environment is stronger than temperature, the classical environmental effector of virulence. The implications and practical application of this finding in prophylaxis and treatment of shigellosis are discussed.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Metabolic control through ornithine and uracil of epithelial cell invasion by Shigella flexneri

Durand

Björk

2009

Microbiology

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“…Nonantibiotic resistance markers have also been developed, including bar, which encodes resistance to the herbicide DL-phosphinothricin (38); merA, which provides resistance to organomercurial compounds (21); and arsAB, which express arsenite resis-tance proteins (9). Plasmid-based expression (PBE) systems can express antigens at high levels; however, high levels of expression of some antigens can have a growth-inhibitory effect (10,51) and thus can reduce the efficacy of the live delivery system.…”

mentioning

confidence: 99%

“…This can generate a range of immune responses, including systemic and mucosal responses at local and distal sites. Other advantages of using attenuated Salmonella include the ease of oral administration, which bypasses the need for needle administration; increased antigen presentation due to the use of a live-vector delivery system, the induction of both Th1 and Th2 immune responses; and the wide range of attenuated Salmonella and recombinant vectors available to researchers (19,20,51).…”

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confidence: 99%

Development of Non-Antibiotic-Resistant, Chromosomally Based, Constitutive and Inducible Expression Systems for aroA -Attenuated Salmonella enterica Serovar Typhimurium

et al. 2009

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Live-vaccine delivery systems expressing two model antigens from Mycoplasma hyopneumoniae, F2 P97 (Adh) and NrdF, were constructed using Salmonella enterica serovar Typhimurium aroA (STM-1), and immunogenicity in mice was evaluated. Recombinant plasmid-based expression (PBE) and chromosomally based expression (CBE) systems were constructed. The PBE system was formed by cloning both antigen genes into pJLA507 to create an operon downstream of temperature-inducible promoters. Constitutive CBE was achieved using a promoter-trapping technique whereby the promoterless operon was stably integrated into the chromosome of STM-1, and the expression of antigens was assessed. The chromosomal position of the operon was mapped in four clones. Inducible CBE was obtained by using the in vivo-induced sspA promoter and recombining the expression construct into aroD. Dual expression of the antigens was detected in all systems, with PBE producing much larger quantities of both antigens. The stability of antigen expression after in vivo passage was 100% for all CBE strains recovered. PBE and CBE strains were selected for comparison in a vaccination trial. The vaccine strains were delivered orally into mice, and significant systemic immunoglobulin M (IgM) and IgG responses against both antigens were detected among all CBE groups. No significant immune response was detected using PBE strains. Expression of recombinant antigens in S. enterica serovar Typhimurium aroA from chromosomally located strong promoters without the use of antibiotic resistance markers is a reliable and effective method of inducing a significant immune response.The use of live, attenuated bacteria as vaccine delivery systems for heterologous antigens has been extensively studied. In particular, attenuated Salmonella strains have been modified to express a wide range of antigens from bacterial, parasitic, and viral sources (reviewed in references 20, 29, and 41). After oral administration, Salmonella can penetrate the Peyer's patches via M cells and colonize the mesenteric lymph nodes, which contain various antigen-presenting cells (reviewed in reference 5). This can generate a range of immune responses, including systemic and mucosal responses at local and distal sites. Other advantages of using attenuated Salmonella include the ease of oral administration, which bypasses the need for needle administration; increased antigen presentation due to the use of a live-vector delivery system, the induction of both Th1 and Th2 immune responses; and the wide range of attenuated Salmonella and recombinant vectors available to researchers (19,20,51).However, there are a number of issues to overcome. Most methods for the expression of heterologous antigens in Salmonella use plasmids to express the antigenic proteins. This can have several drawbacks. The stable maintenance of the expression plasmid in vivo can be difficult to achieve. Tightly regulated promoters are often used to increase plasmid stability, and several in vivo-inducible promoters have delivered promising res...

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“…Attenuated S. typhimurium strains have been successfully used as plasmid DNA vaccine carriers for several pathogens (19,20). In this study, we compared two immunization approaches for the HCV core protein, using an attenuated S. typhimurium as the vector, and found LIAO ET AL.…”

Section: Introductionmentioning

confidence: 97%

Efficient Induction of Mouse Immune Responses to Hepatitis C Virus by Viral Core Protein-Carrying AttenuatedSalmonella typhimurium

et al. 2007

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Hepatitis C virus (HCV) core protein is considered to be an attractive candidate for inclusion in a protective vaccine. However, this protein may attenuate the development of systemic immune responses because of its immunomodulatory properties. In this study, a eukaryotic expression plasmid, pCI-C, and an in vivo-inducible prokaryotic expression plasmid, pZW-C, for HCV core protein were constructed and transformed into attenuated Salmonella typhimurium aroA strain SL7207. The recombinant expression plasmids SL7207/pCI-C and SL7207/pZW-C were used to orally immunize BALB/c mice, and immune responses specific to core protein were assessed. Immunization with bacteria SL7207/pCI-C led to a persistent decrease in the percentage of CD3(+)CD4(+) T cells and triggered weak anti-core IgG production. Splenocytes from SL7207/pCIC-immunized mice developed relatively weak proliferation response, low interferon-gamma secretion, and inferior cytotoxic activity compared with those from mice immunized with SL7207/pZW-C. Boost immunization with SL7207/pCI-C yielded limited improvement in the immune response, whereas boost with bacteria SL7207/pZW-C enhanced immune responses significantly. These results suggest that de novo host synthesis of native HCV core protein may cut down the induction of immune responses. Attenuated S. typhimurium carrying HCV core protein could efficiently activate systemic cellular and humoral responses, and may be a promising strategy for the development of core-based HCV vaccines.

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AttenuatedSalmonellaandShigellaas Carriers for DNA Vaccines

Cited by 21 publications

References 69 publications

Metabolic control through ornithine and uracil of epithelial cell invasion by Shigella flexneri

Metabolic control through ornithine and uracil of epithelial cell invasion by Shigella flexneri

Development of Non-Antibiotic-Resistant, Chromosomally Based, Constitutive and Inducible Expression Systems for aroA -Attenuated Salmonella enterica Serovar Typhimurium

Efficient Induction of Mouse Immune Responses to Hepatitis C Virus by Viral Core Protein-Carrying AttenuatedSalmonella typhimurium

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