A <i>Brucella</i> spp. Protease Inhibitor Limits Antigen Lysosomal Proteolysis, Increases Cross-Presentation, and Enhances CD8+ T Cell Responses

Coria, Lorena M.; Ibáñez, Andrés; Tkach, Mercedes; Sabbione, Florencia; Bruno, Luciana; Carabajal, Marianela V.; Berguer, Paula M.; Barrionuevo, Paula; Schillaci, Roxana; Trevani, Analía Silvina; Giambartolomei, Guillermo H.; Pasquevich, Karina A.; Cassataro, Juliana

doi:10.4049/jimmunol.1501188

Cited by 28 publications

(28 citation statements)

References 49 publications

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“…This may also be the case in the HKS model contributing to the induction of a stronger immune response against this antigen. Of note, study of other protease inhibitors has shown that the protease inhibitory activity by itself does not induce immune response against the coadministered antigen; it is the combination of U-Omp19’s immunostimulatory properties together with a delay in antigen degradation that explain the adjuvant properties of U-Omp19 ( 21 , 23 ).…”

Section: Discussionmentioning

confidence: 99%

“…We have demonstrated that it has self-adjuvanting properties ( 20 ) and can also enhance immune responses against the model antigen chicken ovalbumin (OVA) ( 21 , 22 ). The mechanisms responsible for the adjuvant activity of U-Omp19 rely in the inhibition of stomach and gut proteases and recruitment of immune cells to the gastrointestinal mucosa ( 21 ) as well as increased maturation of DCs and enhanced presentation of the antigen by means of delaying antigen digestion at the lysosomes ( 23 ). Thus, mucosal as well as systemic OVA-specific immune responses, Th1, and CD8 + are enhanced if U-Omp19 is codelivered orally.…”

Section: Introductionmentioning

confidence: 99%

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U-Omp19 from Brucella abortus Is a Useful Adjuvant for Vaccine Formulations against Salmonella Infection in Mice

et al. 2017

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Most pathogens infect through mucosal surfaces, and parenteral immunization typically fails to induce effective immune responses at these sites. Development of oral-administered vaccines capable of inducing mucosal as well as systemic immunity while bypassing the issues of antigen degradation and immune tolerance could be crucial for the control of enteropathogens. This study demonstrates that U-Omp19, a bacterial protease inhibitor with immunostimulatory features, coadministered with Salmonella antigens by the oral route, enhances mucosal and systemic immune responses in mice. U-Omp19 was able to increase antigen-specific production of IFN-γ and IL-17 and mucosal (IgA) antibody response. Finally, oral vaccination with U-Omp19 plus Salmonella antigens conferred protection against virulent challenge with Salmonella Typhimurium, with a significant reduction in bacterial loads. These findings prove the efficacy of this novel adjuvant in the Salmonella infection model and support the potential of U-Omp19 as a suitable adjuvant in oral vaccine formulations against mucosal pathogens requiring T helper (Th)1–Th17 protective immune responses.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

U-Omp19 from Brucella abortus Is a Useful Adjuvant for Vaccine Formulations against Salmonella Infection in Mice

et al. 2017

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“…Viability of cells was more than 95% in all the experiments as measured by trypan blue exclusion test. Mouse bone marrow-derived macrophages (BMM) were generated by differentiation of bone marrow progenitors from C57BL/6 wild type mice, TRIF KO or TLR7 KO mice (provided by Federal University of Minas Gerais, Belo Horizonte, Brazil) with rM-CSF (PeproTech), as previously described [ 22 ].…”

Section: Methodsmentioning

confidence: 99%

B. abortus RNA is the component involved in the down-modulation of MHC-I expression on human monocytes via TLR8 and the EGFR pathway

et al. 2017

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Despite eliciting a potent CD8+ T cell response, Brucella abortus is able to persist and establish a chronic infection inside its host. We have previously reported that the infection of human monocytes/macrophages with B. abortus inhibits the IFN-γ-induced MHC-I cell surface expression down-modulating cytotoxic CD8+ T cell responses. MHC-I down-modulation depends on bacterial viability and results from the capacity of B. abortus to retain the MHC-I molecules within the Golgi apparatus. Furthermore, we recently demonstrated that epidermal growth factor receptor (EGFR) pathway is involved in this phenomenon and that this is an early event during infection. However, the components and mechanisms whereby B. abortus is able to down-modulate MHC-I remained to be elucidated. In this study we demonstrated that the down-modulation of MHC-I expression is not mediated by well-known Brucella virulence factors but instead by B. abortus RNA, a PAMP associated to viability (vita-PAMP). Surprisingly, completely degraded RNA was also able to inhibit MHC-I expression to the same extent as intact RNA. Accordingly, B. abortus RNA and its degradation products were able to mimic the MHC-I intracellular retention within the Golgi apparatus observed upon infection. We further demonstrated that TLR8, a single-stranded RNA and RNA degradation products sensor, was involved in MHC-I inhibition. On the other hand, neutralization of the EGFR reversed the MHC-I inhibition, suggesting a connection between the TLR8 and EGFR pathways. Finally, B. abortus RNA-treated macrophages display diminished capacity of antigen presentation to CD8+ T cells. Overall, our results indicate that the vita-PAMP RNA as well as its degradation products constitute novel virulence factors whereby B. abortus, by a TLR8-dependent mechanism and through the EGFR pathway, inhibits the IFN-γ-induced MHC-I surface expression on human monocytes/macrophages. Thus, bacteria can hide within infected cells and avoid the immunological surveillance of cytotoxic CD8+ T cells.

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“…Viability of cells was >95% in all the experiments as measured by trypan blue exclusion test. Mouse bone marrow‐derived macrophages were generated by differentiation of bone marrow progenitors from C57BL/6 mice with recombinant macrophages colony‐stimulating factor (PeproTech), as previously described 50 …”

Section: Methodsmentioning

confidence: 99%

Inhibition of MHC‐I by Brucella abortus is an early event during infection and involves EGFR pathway

et al. 2016

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Brucella abortus is able to persist inside the host despite the development of potent CD8 T-cell responses. We have recently reported the ability of B. abortus to inhibit the interferon-γ-induced major histocompatibility complex (MHC)-I cell surface expression on human monocytes. This phenomenon was due to the B. abortus-mediated retention of MHC-I molecules within the Golgi apparatus and was dependent on bacterial viability. However, the implications of bacterial virulence or replicative capacity and the signaling pathways remained unknown. Here we demonstrated that the B. abortus mutant strains RB51 and virB10 are able to inhibit MHC-I expression in the same manner as wild-type B. abortus, even though they are unable to persist inside human monocytes for a long period of time. Consistent with this, the phenomenon was triggered early in time and could be observed at 8 h postinfection. At 24 and 48 h, it was even stronger. Regarding the signaling pathway, targeting epidermal growth factor (EGF) receptor (EGFR), ErbB2 (HER2) or inhibition of tumor necrosis factor-α-converting enzyme, one of the enzymes which generates soluble EGF-like ligands, resulted in partial recovery of MHC-I surface expression. Moreover, recombinant EGF and transforming growth factor-α as well as the combination of both were also able to reproduce the B. abortus-induced MHC-I downmodulation. Finally, when infection was performed in the presence of an extracellular signal-regulated kinase 1/2 (Erk1/2) inhibitor, MHC-I surface expression was significantly recovered. Overall, these results describe how B. abortus evades CD8 T-cell responses early during infection and exploits the EGFR-ERK signaling pathway to escape from the immune system and favor chronicity.

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A Brucella spp. Protease Inhibitor Limits Antigen Lysosomal Proteolysis, Increases Cross-Presentation, and Enhances CD8+ T Cell Responses

Cited by 28 publications

References 49 publications

U-Omp19 from Brucella abortus Is a Useful Adjuvant for Vaccine Formulations against Salmonella Infection in Mice

U-Omp19 from Brucella abortus Is a Useful Adjuvant for Vaccine Formulations against Salmonella Infection in Mice

B. abortus RNA is the component involved in the down-modulation of MHC-I expression on human monocytes via TLR8 and the EGFR pathway

Inhibition of MHC‐I by Brucella abortus is an early event during infection and involves EGFR pathway

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