Novel virulence properties of the Salmonella typhimurium virulence-associated plasmid: Immune suppression and stimulation of splenomegaly

Hoertt, Barbara E.; Ou, Jonathan T.; Kopecko, Dennis J.; Baron, L. S.; Warren, Richard L.

doi:10.1016/0147-619x(89)90086-3

Cited by 29 publications

(17 citation statements)

References 19 publications

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“…Although the Salmonella mechanism(s) of immunosuppression has not been elucidated to date, the lack of abscess formation in plasmid-containing serovar Abortusovis might be due to the presence of a plasmidencoded factor(s) that negatively modulates inflammatory cell recruitment at the site of bacterial injection. In addition, serovar Typhimurium-induced immunosuppression in mice has been reported to require the virulence plasmid (22). Furthermore, the increase of inflammatory cells in the site of inoculation and abscess formation in SU40-immunized ewes may be responsible for slower release of Salmonella antigens and lead to a more effective priming of the sheep lymphoid tissues.…”

Section: Discussionmentioning

confidence: 99%

Virulence Attenuation and Live Vaccine Potential of aroA , crp cdt cya , and Plasmid-Cured Mutants of Salmonella enterica Serovar Abortusovis in Mice and Sheep

et al. 2005

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Three live vaccine candidates of Salmonella enterica subspecies I serotype Abortusovis (aroA, cya crp cdt, and plasmid-cured strains) have been developed, and their efficacies in inducing humoral antibodies and protecting against abortion after challenge with wild-type strain SS44 were evaluated in sheep. Following estrus synchronization, animals were immunized 3 weeks after fertilization and boosted once 3 weeks later. Following challenge with wild-type SS44, pregnancy failure of vaccinated ewes was reduced compared to that of nonimmunized controls. Attenuation of each vaccine was also assessed in challenge experiments with nonimmunized pregnant ewes and in BALB/c mice. All three vaccine candidates appear to be safe for use in sheep and provide a model for the development of live vaccine candidates against naturally occurring ovine salmonellosis.

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Section: Discussionmentioning

confidence: 99%

Virulence Attenuation and Live Vaccine Potential of aroA , crp cdt cya , and Plasmid-Cured Mutants of Salmonella enterica Serovar Abortusovis in Mice and Sheep

et al. 2005

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“…Last, to determine whether the Salmonella virulence plasmid, which has been implicated in causing immunosuppression during Salmonella infection of mice (19), is required for Salmonella to inhibit anti-CD3 -induced T cell proliferation, we tested a virulence plasmid-cured Salmonella strain. As shown in Fig.…”

Section: Spi1 Spi2 Phop Sti and The Virulence Plasmid Are Not Reqmentioning

confidence: 99%

Salmonella inhibit T cell proliferation by a direct, contact-dependent immunosuppressive effect

Velden

Copass

Starnbach

2005

Proc. Natl. Acad. Sci. U.S.A.

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Dendritic cells (DC) are of central importance in the initiation of T cell-mediated adaptive immunity because these professional phagocytes internalize, process, and present microbial antigens to T lymphocytes. T lymphocytes have a pivotal role in controlling and clearing infection with intracellular pathogens through cytokine production. T lymphocytes also can mediate direct lysis of infected cells or activate B and T cells. In this article, we report that DC, when cocultured with Salmonella, fail to efficiently stimulate T cells for proliferation. We show that the failure of T lymphocytes to respond to Salmonella-infected DC is not simply due to Salmonellainduced programmed DC death or interference with up-regulation of costimulatory molecules CD80 and CD86. We cocultured bacteria with purified T lymphocytes, and we demonstrate here that Salmonella have a direct, contact-dependent inhibitory effect on the T cells, even in the absence of DC. This direct, Salmonella-induced inhibitory effect reduces the ability of T cells to proliferate and produce cytokines in response to stimulation and appears to require live bacteria. Cumulatively, these results are evidence that Salmonella may interfere with the development of acquired immunity, providing insights into the complex nature of this hostpathogen interaction.bacterial interference ͉ adaptive immunity P rotection against invading microbes is coordinately regulated by innate and adaptive host defense mechanisms (1, 2). However, many microbial pathogens appear to have evolved successfully to combat, exploit, or evade host immunity (3). For example, naïve mice that are challenged with the enteric bacterium Salmonella enterica serovar Typhimurium fail to control and clear infection and succumb to an acute typhoid-like systemic illness (4). In contrast, mice previously immunized with a live-attenuated Salmonella vaccine strain are protected from lethal challenge (5), demonstrating that acquired resistance against Salmonella can develop in these hosts. It takes up to 6 wk to eradicate the vaccine strain and 60-90 days to acquire immunological memory (5). These observations suggest that adaptive immunity against Salmonella, which critically depends on the successful engagement of T lymphocytes (5), develops rather slowly.A critical step in the development of acquired resistance to intracellular bacterial pathogens is the stimulation of T lymphocytes by infected cells. The following two major subsets of T cells exist among the total population of T lymphocytes: CD4 ϩ T cells, which recognize exogenous antigens and typically are stimulated during infection with vacuolar pathogens, and CD8 ϩ T cells, which recognize cytosolic antigens and are often required to resolve infection with pathogens that escape from the vacuole and enter the host cell cytoplasm. Intriguingly, optimal protection against Salmonella, which reside in a membrane-bound compartment within infected cells, depends on both CD4 ϩ and CD8 ϩ T lymphocytes (5).To monitor the priming of T lymphocytes during Sal...

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“…The 90-kb virulence plasmid of Salmonella typhimurium is responsible for invasion of salmonellae beyond the Peyer's patches of the small intestine to the mesenteric lymph nodes and spleens of mice after oral inoculation (18,40). The specific function(s) that the virulence plasmid confers to S. typhimurium to enable invasive infection has not been determined (15), although it has been suggested that the virulence plasmid may be involved in immunosuppression (23). Several groups have alluded to functions related to intracellular infection or macrophage resistance as being associated with the virulence plasmid; however, no direct proof has been published (15,18).…”

mentioning

confidence: 99%

The Salmonella typhimurium virulence plasmid encodes a positive regulator of a plasmid-encoded virulence gene

Caldwell

Gulig

1991

J Bacteriol

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The 90-kb virulence plasmid of SalmoneUa typhimurium is necessary for invasion beyond the Peyer's patches to the mesenteric lymph nodes and spleens of orally inoculated mice. Two TnS insertions located on the left side of a previously identified 14-kb virulence region (P. A. Gulig and R. Curtiss m, Infect. Immun. 58:3262-3271, 1988) and mapping 272 bp from each other exhibited opposite effects on splenic infection of mice after oral inoculation. spvR23::TnS decreased splenic infection by 1,000-fold, whereas a spv-14::TnS mutant outcompeted wild-type S. typhimurium for splenic infection by 27-fold in mice fed mixtures of mutated and wild-type S. typhimurium. spvR23::Tn5 was complemented by a virulence plasmid subclone with an insert sequence encoding only an 891-bp open reading frame specifying a 33,000-molecular-weight protein. The amino acid sequence of this open reading frame had significant homology to members of the LysR family of positive regulatory proteins; thus, the gene was named spvR (salmonella plasmid virulence). To examine the possible regulatory effects of spvR on other virulence genes, we constructed a lacZ operon fusion in a downstream virulence gene, spvB. When spvR subcloned behind the lac promoter was provided on a separate plasmid in trans to the spvB-lacZ operon fusion, transcription of spvB increased 15-fold. spv-14::TnS, whih conferred a competitive advantage to S. typhimurium, increased the expression of a spvR-lacZ operon fusion in cis. spvR is therefore a positive regulator of spvB and an essential virulence gene of S. typhimurium. As opposed to having spvR subeloned behind the lac promoter, the wild-type spvR gene present on the virulence plasmid did not function to positively regulate spvB-lacZ in trans when salmonellae were grown to the log phase in L broth, suggesting that this regulatory system is activated in vivo during infection.Related high-molecular-weight plasmids of several serotypes and species of invasive salmonellae encode essential virulence functions (reviewed in reference 15). The 90-kb virulence plasmid of Salmonella typhimurium is responsible for invasion of salmonellae beyond the Peyer's patches of the small intestine to the mesenteric lymph nodes and spleens of mice after oral inoculation (18,40). The specific function(s) that the virulence plasmid confers to S. typhimurium to enable invasive infection has not been determined (15), although it has been suggested that the virulence plasmid may be involved in immunosuppression (23). Several groups have alluded to functions related to intracellular infection or macrophage resistance as being associated with the virulence plasmid; however, no direct proof has been published (15,18).The large size of the 90-kb virulence plasmid of S. typhimurium made it desirable to identify smaller specific regions of the plasmid that were involved in conferring virulence. Gulig and Curtiss used in vivo selection of virulence-conferring clones of the virulence plasmid to identify sequences associated with virulence in mice (19). S. t...

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Novel virulence properties of the Salmonella typhimurium virulence-associated plasmid: Immune suppression and stimulation of splenomegaly

Cited by 29 publications

References 19 publications

Virulence Attenuation and Live Vaccine Potential of aroA , crp cdt cya , and Plasmid-Cured Mutants of Salmonella enterica Serovar Abortusovis in Mice and Sheep

Virulence Attenuation and Live Vaccine Potential of aroA , crp cdt cya , and Plasmid-Cured Mutants of Salmonella enterica Serovar Abortusovis in Mice and Sheep

Salmonella inhibit T cell proliferation by a direct, contact-dependent immunosuppressive effect

The Salmonella typhimurium virulence plasmid encodes a positive regulator of a plasmid-encoded virulence gene

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