Phagosomes Induced by Cytokines Function as anti-Listeria Vaccines

Carrasco-Marı́n, Eugenio; Río, Estela Rodríguez-Del; Frande-Cabanes, Elisabet; Tobes, Raquel; Pareja, Eduardo; Lecea-Cuello, M. Jesús; Ruiz-Sáez, Marta; Madrazo‐Toca, Fidel; Hölscher, Christoph; Álvarez-Domínguez, Carmen

doi:10.1074/jbc.m112.348615

Cited by 12 publications

(47 citation statements)

References 46 publications

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“…1D) and observed a characteristic exponential proliferation of 4 h duration that ended in a plateau phase of growth at 16 h postinfection, similar to LM WT kinetics in bone-marrow macrophages (BMDMs) (LM WT plots in Fig. 1D) (Alvarez-Dominguez and Stahl, 1999; Carrasco-Marin et al, 2009, 2011, 2012; Del Cerro-Vadillo et al, 2006; Prada-Delgado et al, 2001). We also used different LM mutant strains with known gene deletions relevant for specific LM intracellular stages: hly -deficient (LM ΔLLO ), actA -deficient (LM ΔActA ), or plcA and plcB -deficient mutants (LM ΔplcAΔplcB ) to analyze their role in LM growth in microglia.…”

Section: Resultssupporting

confidence: 60%

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Dissociation of innate immune responses in microglia infected with Listeria monocytogenes

Frande-Cabanes

Fernández-Prieto

Calderon-Gonzalez

et al. 2013

Glia

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Microglia, the innate immune cells of the brain, plays a central role in cerebral listeriosis. Here, we present evidence that microglia control Listeria infection differently than macrophages. Infection of primary microglial cultures and murine cell lines with Listeria resulted in a dual function of the two gene expression programmes involved in early and late immune responses in macrophages. Whereas the bacterial gene hly seems responsible for both transcriptional programmes in macrophages, Listeria induces in microglia only the tumor necrosis factor (TNF)‐regulated transcriptional programme. Listeria also represses in microglia the late immune response gathered in two clusters, microbial degradation, and interferon (IFN)‐inducible genes. The bacterial gene actA was required in microglia to induce TNF‐regulated responses and to repress the late response. Isolation of microglial phagosomes revealed a phagosomal environment unable to destroy Listeria. Microglial phagosomes were also defective in several signaling and trafficking components reported as relevant for Listeria innate immune responses. This transcriptional strategy in microglia induced high levels of TNF‐α and monocyte chemotactic protein‐1 and low production of other neurotoxic compounds such as nitric oxide, hydrogen peroxide, and Type I IFNs. These cytokines and toxic microglial products are also released by primary microglia, and this cytokine and chemokine cocktail display a low potential to trigger neuronal apoptosis. This overall bacterial strategy strongly suggests that microglia limit Listeria inflammation pattern exclusively through TNF‐mediated responses to preserve brain integrity. GLIA 2014;62:233–246

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Section: Resultssupporting

confidence: 60%

“…Replication indexes (RIs) were calculated as previously reported (Alvarez-Dominguez and Stahl, 1999; Alvarez-Dominguez et al, 2000; Carrasco-Marin et al, 2009, 2012; Del Cerro-Vadillo et al, 2006; Prada-Delgado et al, 2001). …”

Section: Methodsmentioning

confidence: 99%

Dissociation of innate immune responses in microglia infected with Listeria monocytogenes

Frande-Cabanes

Fernández-Prieto

Calderon-Gonzalez

et al. 2013

Glia

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“…Total membranes were pelleted from thawed PNSs after 35,000 × g ultracentrifugation, as previously described (Carrasco-Marín et al, 2012). To detect LLO bound to MHC class II molecules, total membranes from PNSs were immunoprecipitated with mouse anti-IA b antibody (Y3P).…”

Section: Methodsmentioning

confidence: 99%

Cellular vaccines in listeriosis: role of the Listeria antigen GAPDH

Calderon-Gonzalez

Frande-Cabanes

Bronchalo-Vicente

et al. 2014

Front. Cell. Infect. Microbiol.

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The use of live Listeria-based vaccines carries serious difficulties when administrated to immunocompromised individuals. However, cellular carriers have the advantage of inducing multivalent innate immunity as well as cell-mediated immune responses, constituting novel and secure vaccine strategies in listeriosis. Here, we compare the protective efficacy of dendritic cells (DCs) and macrophages and their safety. We examined the immune response of these vaccine vectors using two Listeria antigens, listeriolysin O (LLO) and glyceraldehyde-3-phosphate-dehydrogenase (GAPDH), and several epitopes such as the LLO peptides, LLO189−201 and LLO91−99 and the GAPDH peptide, GAPDH1−22. We discarded macrophages as safe vaccine vectors because they show anti-Listeria protection but also high cytotoxicity. DCs loaded with GAPDH1−22 peptide conferred higher protection and security against listeriosis than the widely explored LLO91−99 peptide. Anti-Listeria protection was related to the changes in DC maturation caused by these epitopes, with high production of interleukin-12 as well as significant levels of other Th1 cytokines such as monocyte chemotactic protein-1, tumor necrosis factor-α, and interferon-γ, and with the induction of GAPDH1−22-specific CD4+ and CD8+ immune responses. This is believed to be the first study to explore the use of a novel GAPDH antigen as a potential DC-based vaccine candidate for listeriosis, whose efficiency appears to highlight the relevance of vaccine designs containing multiple CD4+ and CD8+ epitopes.

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“…We previously reported this characteristic DC phenotype and cytokine pattern on a dendritic-based vaccine for listeriosis that triggers a pro-inflammatory CD8 + T cell based immune response [15]. LM WT infection of other APC such as J-774 macrophages does not cause transformation into DC-like phenotypes ( S1 Fig., panel C ), either production of the pro-inflammatory cytokines above-mentioned [15, 17]. In brief, LM WT infection transformed melanoma into matured DC with competent APC functions and potential for tumour therapies.…”

Section: Resultsmentioning

confidence: 94%

“…Phagosomes were isolated from an aliquot of PNS into a 20% sucrose gradient as described [16, 17]. An additional PNS was used to estimate the percentage of total internalized bacteria expressed as CFU.…”

Section: Methodsmentioning

confidence: 99%

A Novel Therapy for Melanoma Developed in Mice: Transformation of Melanoma into Dendritic Cells with Listeria monocytogenes

et al. 2015

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Listeria monocytogenes is a gram-positive bacteria and human pathogen widely used in cancer immunotherapy because of its capacity to induce a specific cytotoxic T cell response in tumours. This bacterial pathogen strongly induces innate and specific immunity with the potential to overcome tumour induced tolerance and weak immunogenicity. Here, we propose a Listeria based vaccination for melanoma based in its tropism for these tumour cells and its ability to transform in vitro and in vivo melanoma cells into matured and activated dendritic cells with competent microbicidal and antigen processing abilities. This Listeria based vaccination using low doses of the pathogen caused melanoma regression by apoptosis as well as bacterial clearance. Vaccination efficacy is LLO dependent and implies the reduction of LLO-specific CD4+ T cell responses, strong stimulation of innate pro-inflammatory immune cells and a prevalence of LLO-specific CD8+ T cells involved in tumour regression and Listeria elimination. These results support the use of low doses of pathogenic Listeria as safe melanoma therapeutic vaccines that do not require antibiotics for bacterial removal.

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Phagosomes Induced by Cytokines Function as anti-Listeria Vaccines

Cited by 12 publications

References 46 publications

Dissociation of innate immune responses in microglia infected with Listeria monocytogenes

Dissociation of innate immune responses in microglia infected with Listeria monocytogenes

Cellular vaccines in listeriosis: role of the Listeria antigen GAPDH

A Novel Therapy for Melanoma Developed in Mice: Transformation of Melanoma into Dendritic Cells with Listeria monocytogenes

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