Delivery of the Immunosuppressive Antigen Salp15 to Antigen-Presenting Cells by<i>Salmonella enterica</i>Serovar Typhimurium<i>aroA</i>Mutants

Motameni, Amirreza; Juncadella, Ignacio J.; Ananthanarayanan, Shobana K.; Hedrick, Michael N.; Huet-Hudson, Yvette M.; Anguíta, Juan

doi:10.1128/iai.72.6.3638-3642.2004

Cited by 6 publications

(5 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To address the effect of SAM486A on immune cell proliferation in vivo , potential we administered intraperitoneally SAM486A (5 mg/Kg/day, 5-days per week) for 17 days in immunocompetent C57BL/6 mice, and then immunized them subcutaneously 2 weeks later with 50 µg of ovalbumin (OVA) in Complete Freund´s adjuvant and kept on treatment. After 2 weeks, the mice were analysed for ovalbumin-specific serum IgG and IgM levels by ELISA 33 .…”

Section: Methodsmentioning

confidence: 99%

mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer

Zabala-Letona

Arruabarrena-Aristorena

Martín-Martín

et al. 2017

Nature

Self Cite

167

162

View full text Add to dashboard Cite

Activation of the PTEN-PI3K-mTORC1 pathway consolidates metabolic programs that sustain cancer cell growth and proliferation1,2. Here we show that mTORC1 regulates polyamine dynamics, a metabolic route that is essential for oncogenicity. Through the use of integrative metabolomics in a mouse model3 and human biopsies4 of prostate cancer, we identified alterations in tumours impacting on the production of decarboxylated S-adenosylmethionine (dcSAM) and polyamine synthesis. Mechanistically, this metabolic rewiring stems from mTORC1-dependent regulation of S-adenosylmethionine decarboxylase 1 (AMD1) stability. This novel molecular regulation was validated in murine and human cancer specimens. AMD1 was upregulated in prostate cancer specimens with activated mTORC1. Conversely, samples from a clinical trial with the mTORC1 inhibitor everolimus5 exhibited a predominant decrease in AMD1 immunoreactivity that was associated to a decrease in proliferation, in line with the requirement of dcSAM production for oncogenicity. These findings provide fundamental information about the complex regulatory landscape controlled by mTORC1 to integrate and translate growth signals into an oncogenic metabolic program.

show abstract

Section: Methodsmentioning

confidence: 99%

mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer

Zabala-Letona

Arruabarrena-Aristorena

Martín-Martín

et al. 2017

Nature

Self Cite

167

162

View full text Add to dashboard Cite

show abstract

“…In the attempt to construct an efficacious immunogen, we transferred the Cz expression vector into attenuated S. enterica serovar Typhimurium, which has been characterized as a successful delivery system for orally administered vaccines (12,13,14,20,22,36,38,39,54), but it has never been tested as a delivery system for oral DNA vaccines against Chagas' disease. However, T. cruzi invades the host via mucosal surfaces.…”

Section: Discussionmentioning

confidence: 99%

Oral Vaccination withSalmonella entericaas a Cruzipain-DNA Delivery System Confers Protective Immunity againstTrypanosoma cruzi

et al. 2008

View full text Add to dashboard Cite

To stimulate both local and systemic immune responses against Trypanosoma cruzi, Salmonella enterica serovar Typhimurium aroA was exploited as a DNA delivery system for cruzipain (SCz). In a murine model we compared SCz alone (GI) or coadministered with Salmonella carrying a plasmid encoding granulocyte-macrophage colony-stimulating factor (GII), as well as protocols in which SCz priming was followed by boosting with recombinant cruzipain (rCz) admixed with either CpG-ODN (GIII) or MALP-2, a synthetic derivative of a macrophage-activating lipopeptide of 2 kDa from Mycoplasma fermentans (GIV). The results showed that protocols that included four oral doses of SCz (GI) elicited mainly a mucosal response characterized by immunoglobulin A (IgA) secretion and proliferation of gut-associated lymphoid tissue cells, with weak systemic responses. In contrast, the protocol that included a boost with rCz plus CpG (GIII) triggered stronger systemic responses in terms of Cz-specific serum IgG titers, splenocyte proliferation, gamma interferon (IFN-␥) secretion, and delayed-type hypersensitivity response. Trypomastigote challenge of vaccinated mice resulted in significantly lower levels of parasitemia compared to controls. Protection was abolished by depletion of either CD4 ؉ or CD8 ؉ T cells. Parasite control was also evident from the reduction of tissue damage, as revealed by histopathologic studies and serum levels of enzymes that are markers of muscle injury in chronic Chagas' disease (i.e., creatine kinase, aspartate aminotransferase, and lactate dehydrogenase). Enhanced release of IFN-␥ and interleukin-2 was observed in GI and GII upon restimulation of splenocytes in the nonparasitic phase of infection. Our results indicate that Salmonella-mediated delivery of Cz-DNA by itself promotes the elicitation of an immune response that controls T. cruzi infection, thereby reducing parasite loads and subsequent damage to muscle tissues.

show abstract

“…Due to the specificity of Salp15 for CD4 and its capacity to inhibit the activation of CD4 T cells, the use of this tick saliva protein has been suggested for the treatment of immune diseases. In addition, our group has demonstrated the ability of Salp15 to inhibit the development of CD4 T cell-mediated immune responses in vivo upon challenge with different antigens 7 , 10 , 12 . Moreover, Salp15 prevents the development of experimental asthma in a mouse model 7 .…”

Section: Introductionmentioning

confidence: 99%

The immunosuppressive effect of the tick protein, Salp15, is long-lasting and persists in a murine model of hematopoietic transplant

Tomás-Cortázar

Martín-Ruiz

Barriales

et al. 2017

Sci Rep

Self Cite

View full text Add to dashboard Cite

Salp15, a salivary protein of Ixodes ticks, inhibits the activation of naïve CD4 T cells. Treatment with Salp15 results in the inhibition of early signaling events and the production of the autocrine growth factor, interleukin-2. The fate of the CD4 T cells activated in the presence of Salp15 or its long-term effects are, however, unknown. We now show that Salp15 binding to CD4 is persistent and induces a long-lasting immunomodulatory effect. The activity of Salp15 results in sustained diminished cross-antigenic antibody production even after interruption of the treatment with the protein. Transcriptionally, the salivary protein provokes an acute effect that includes known activation markers, such as Il2 or Cd44, and that fades over time. The long-term effects exerted by Salp15 do not involve the induction of either anergy traits nor increased populations of regulatory T cells. Similarly, the treatment with Salp15 does not result in B cell anergy or the generation of myeloid suppressor cells. However, Salp15 induces the increased expression of the ectoenzyme, CD73, in regulatory T cells and increased production of adenosine. Our study provides a profound characterization of the immunomodulatory activity of Salp15 and suggests that its long-term effects are due to the specific regulation of CD73.

show abstract

Delivery of the Immunosuppressive Antigen Salp15 to Antigen-Presenting Cells bySalmonella entericaSerovar TyphimuriumaroAMutants

Cited by 6 publications

References 28 publications

mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer

mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer

Oral Vaccination withSalmonella entericaas a Cruzipain-DNA Delivery System Confers Protective Immunity againstTrypanosoma cruzi

The immunosuppressive effect of the tick protein, Salp15, is long-lasting and persists in a murine model of hematopoietic transplant

Contact Info

Product

Resources

About