ESAT-6 Targeting to DEC205+ Antigen Presenting Cells Induces Specific-T Cell Responses against ESAT-6 and Reduces Pulmonary Infection with Virulent Mycobacterium tuberculosis
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{"title"=>"ESAT-6 targeting to DEC205+ antigen presenting cells induces specific-T cell responses against ESAT-6 and reduces pulmonary infection with virulent Mycobacterium tuberculosis", "type"=>"journal", "authors"=>[{"first_name"=>"Aarón", "last_name"=>"Silva-Sánchez", "scopus_author_id"=>"55405630900"}, {"first_name"=>"Selene", "last_name"=>"Meza-Pérez", "scopus_author_id"=>"14520486700"}, {"first_name"=>"Adriana", "last_name"=>"Flores-Langarica", "scopus_author_id"=>"24172635500"}, {"first_name"=>"Luis", "last_name"=>"Donis-Maturano", "scopus_author_id"=>"26323079900"}, {"first_name"=>"Iris", "last_name"=>"Estrada-García", "scopus_author_id"=>"6701421668"}, {"first_name"=>"Juana", "last_name"=>"Calderón-Amador", "scopus_author_id"=>"56013566600"}, {"first_name"=>"Rogelio", "last_name"=>"Hernández-Pando", "scopus_author_id"=>"55989672100"}, {"first_name"=>"Juliana", "last_name"=>"Idoyaga", "scopus_author_id"=>"16743989300"}, {"first_name"=>"Ralph M.", "last_name"=>"Steinman", "scopus_author_id"=>"7202375022"}, {"first_name"=>"Leopoldo", "last_name"=>"Flores-Romo", "scopus_author_id"=>"56505046600"}], "year"=>2015, "source"=>"PLoS ONE", "identifiers"=>{"sgr"=>"84928717498", "doi"=>"10.1371/journal.pone.0124828", "pui"=>"604006432", "pmid"=>"25915045", "scopus"=>"2-s2.0-84928717498", "issn"=>"19326203", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)"}, "id"=>"cb23b8e3-8919-35ab-a0ca-4370376d614b", "abstract"=>"Airways infection with Mycobacterium tuberculosis (Mtb) is contained mostly by T cell re- sponses, however, Mtb has developed evasionmechanisms which affect antigen present- ing cell (APC) maturation/recruitment delaying the onset of Ag-specific T cell responses. Hypothetically, bypassing the natural infection routes by delivering antigens directly to APCs may overcome the pathogen’s naturally evolved evasion mechanisms, thus facilitat- ing the induction of protective immune responses. Wegenerated a murine monoclonal fu- sion antibody (α-DEC-ESAT) to deliver Early Secretory Antigen Target (ESAT)-6 directly to DEC205+ APCs and to assess its in vivo effects on protection associated responses (IFN-γ production, in vivo CTL killing, and pulmonarymycobacterial load). Treatment with α-DEC- ESAT alone induced ESAT-6-specific IFN-γ producing CD4+ T cells and prime-boost immu- nization prior to Mtb infection resulted in early influx (d14 post-infection) and increased IFN- γ+ production by specific T cells in the lungs, compared to scarce IFN-γ production in control mice. In vivo CTL killing was quantified in relevant tissues upon transferring target cells loaded with mycobacterial antigens. During infection, α-DEC-ESAT-treated mice showed increased target cell killing in the lungs, where histology revealed cellular infiltrate and considerably reduced bacterial burden. Targeting the mycobacterial antigen ESAT-6 to DEC205+ APCs before infection expands specific T cell clones responsible for early T cell responses (IFN-γ production and CTL activity) and substantially reduces lung bacterial bur- den. Deliveringmycobacterial antigens directly to APCs provides a unique approach to study in vivo the role of APCs and specific T cell responses to assess their potential anti- mycobacterial functions.", "link"=>"http://www.mendeley.com/research/esat6-targeting-dec205-antigen-presenting-cells-induces-specifict-cell-responses-against-esat6-reduc", "reader_count"=>17, "reader_count_by_academic_status"=>{"Researcher"=>4, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>6, "Student > Postgraduate"=>1, "Student > Master"=>3, "Professor"=>1}, "reader_count_by_user_role"=>{"Researcher"=>4, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>6, "Student > Postgraduate"=>1, "Student > Master"=>3, "Professor"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>1, "Biochemistry, Genetics and Molecular Biology"=>1, "Agricultural and Biological Sciences"=>11, "Chemistry"=>1, "Immunology and Microbiology"=>3}, "reader_count_by_subdiscipline"=>{"Chemistry"=>{"Chemistry"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>3}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>11}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>1}, "Unspecified"=>{"Unspecified"=>1}}, "reader_count_by_country"=>{"India"=>1}, "group_count"=>0}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/2041285"], "description"=>"<p>Pulmonary mycobacterial load (CFUs/lung) and cellular infiltrate (% pneumonic areas) were quantified at two time points during Mtb infection in the different experimental groups. Horizontally stripped bars indicate uninfected non-immunized mice (No-Inf). All other bars represent infected mice with different treatments. Black bars: untreated mice (Inf/No Tx); white bars: α-DEC-ESAT-treated mice (Inf/DE6-Tx); diagonally stripped bars: mice treated with isotype control antibody-ESAT (Inf/IsoE6-Tx). Quantification of the cellular infiltrate during the acute infection is shown in (A) while that of the chronic stage is shown in (C). The bacterial burden expressed as CFUs per lung is shown in (B) for the acute stage of the infection and in (D) for the chronic phase. (E) Representative picture of HE staining of lungs from infected mice which were α-DEC-ESAT-untreated (-) or α-DEC-ESAT-treated (+). Individual lungs were analyzed by duplicate and 3 mice were used per group. Data are presented as mean plus standard error. (*) Represents P<0.05.</p>", "links"=>[], "tags"=>["evasion mechanisms", "ifn", "apc", "Virulent Mycobacterium tuberculosis Airways infection", "ESAT", "Delivering mycobacterial antigens", "vivo CTL", "dec", "T cell responses", "T cell clones", "Secretory Antigen Target"], "article_id"=>1395560, "categories"=>["Biological Sciences"], "users"=>["Aaron Silva-Sanchez", "Selene Meza-Perez", "Adriana Flores-Langarica", "Luis Donis-Maturano", "Iris Estrada-García", "Juana Calderon-Amador", "Rogelio Hernández-Pando", "Juliana Idoyaga", "Ralph M. Steinman", "Leopoldo Flores-Romo"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0124828.g004", "stats"=>{"downloads"=>2, "page_views"=>38, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_945_DEC_ESAT_treated_mice_show_reduced_bacterial_burden_and_increased_cellular_infiltrate_in_the_lungs_/1395560", "title"=>"α-DEC-ESAT-treated mice show reduced bacterial burden and increased cellular infiltrate in the lungs.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-04-27 03:24:11"}
  • {"files"=>["https://ndownloader.figshare.com/files/2041278"], "description"=>"<p>The production of IFN-γ by CD4<sup>+</sup> and CD8<sup>+</sup> T cells was assessed in different tissues at two time-points during the experimental Mtb infection. α-DEC-ESAT treatment increased the percentages of IFN-γ<sup>+</sup> CD4<sup>+</sup> (A) and CD8<sup>+</sup> (B) T cells in the lungs, during the acute (day 14) but not during the chronic (day 60) phase of the disease. In the lymphoid organs analyzed such as mediastinal lymph nodes (MedLN; C-D), inguinal lymph nodes (IngLN; E-F), and spleen (G-H), we observed very low levels of IFN-γ production either by CD4<sup>+</sup> (left side panels) or CD8<sup>+</sup> (right side panels) T cells. Individual mice were analyzed and 3–5 mice were used per group. Data are presented as mean plus standard error. (*) indicates P < 0.05. All bars represent groups of infected mice with different treatments. Black bars: untreated mice (Inf/No-Tx); white bars: α-DEC-ESAT-treated mice (Inf/DE6-Tx); stripped bars: mice treated with isotype control antibody conjugated with ESAT-6 (Inf/IsoE6-Tx). Cell suspensions were cultured either with medium alone (M) or medium with ESAT-6 pool 1 of peptides (p1) as detailed in Materials and Methods. MedLN = Mediastinal lymph nodes, IngLN = Inguinal lymph nodes.</p>", "links"=>[], "tags"=>["evasion mechanisms", "ifn", "apc", "Virulent Mycobacterium tuberculosis Airways infection", "ESAT", "Delivering mycobacterial antigens", "vivo CTL", "dec", "T cell responses", "T cell clones", "Secretory Antigen Target"], "article_id"=>1395553, "categories"=>["Biological Sciences"], "users"=>["Aaron Silva-Sanchez", "Selene Meza-Perez", "Adriana Flores-Langarica", "Luis Donis-Maturano", "Iris Estrada-García", "Juana Calderon-Amador", "Rogelio Hernández-Pando", "Juliana Idoyaga", "Ralph M. Steinman", "Leopoldo Flores-Romo"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0124828.g002", "stats"=>{"downloads"=>1, "page_views"=>29, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_DEC_ESAT_treatment_increases_IFN_T_cells_in_the_lung_during_the_acute_phase_of_experimental_tuberculosis_/1395553", "title"=>"α-DEC-ESAT treatment increases IFN-γ<sup>+</sup> T cells in the lung during the acute phase of experimental tuberculosis.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-04-27 03:24:11"}
  • {"files"=>["https://ndownloader.figshare.com/files/2041288"], "description"=>"<div><p>Airways infection with <i>Mycobacterium tuberculosis</i> (Mtb) is contained mostly by T cell responses, however, Mtb has developed evasion mechanisms which affect antigen presenting cell (APC) maturation/recruitment delaying the onset of Ag-specific T cell responses. Hypothetically, bypassing the natural infection routes by delivering antigens directly to APCs may overcome the pathogen’s naturally evolved evasion mechanisms, thus facilitating the induction of protective immune responses. We generated a murine monoclonal fusion antibody (α-DEC-ESAT) to deliver Early Secretory Antigen Target (ESAT)-6 directly to DEC205<sup>+</sup> APCs and to assess its <i>in vivo</i> effects on protection associated responses (IFN-γ production, <i>in vivo</i> CTL killing, and pulmonary mycobacterial load). Treatment with α-DEC-ESAT alone induced ESAT-6-specific IFN-γ producing CD4<sup>+</sup> T cells and prime-boost immunization prior to Mtb infection resulted in early influx (d14 post-infection) and increased IFN-γ<sup>+</sup> production by specific T cells in the lungs, compared to scarce IFN-γ production in control mice. <i>In vivo</i> CTL killing was quantified in relevant tissues upon transferring target cells loaded with mycobacterial antigens. During infection, α-DEC-ESAT-treated mice showed increased target cell killing in the lungs, where histology revealed cellular infiltrate and considerably reduced bacterial burden. Targeting the mycobacterial antigen ESAT-6 to DEC205<sup>+</sup> APCs before infection expands specific T cell clones responsible for early T cell responses (IFN-γ production and CTL activity) and substantially reduces lung bacterial burden. Delivering mycobacterial antigens directly to APCs provides a unique approach to study <i>in vivo</i> the role of APCs and specific T cell responses to assess their potential anti-mycobacterial functions.</p></div>", "links"=>[], "tags"=>["evasion mechanisms", "ifn", "apc", "Virulent Mycobacterium tuberculosis Airways infection", "ESAT", "Delivering mycobacterial antigens", "vivo CTL", "dec", "T cell responses", "T cell clones", "Secretory Antigen Target"], "article_id"=>1395563, "categories"=>["Biological Sciences"], "users"=>["Aaron Silva-Sanchez", "Selene Meza-Perez", "Adriana Flores-Langarica", "Luis Donis-Maturano", "Iris Estrada-García", "Juana Calderon-Amador", "Rogelio Hernández-Pando", "Juliana Idoyaga", "Ralph M. Steinman", "Leopoldo Flores-Romo"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0124828", "stats"=>{"downloads"=>1, "page_views"=>28, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/ESAT_6_Targeting_to_DEC205_Antigen_Presenting_Cells_Induces_Specific_T_Cell_Responses_against_ESAT_6_and_Reduces_Pulmonary_Infection_with_Virulent_Mycobacterium_tuberculosis_/1395563", "title"=>"ESAT-6 Targeting to DEC205+ Antigen Presenting Cells Induces Specific-T Cell Responses against ESAT-6 and Reduces Pulmonary Infection with Virulent <i>Mycobacterium tuberculosis</i>", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-04-27 03:24:11"}
  • {"files"=>["https://ndownloader.figshare.com/files/2041280"], "description"=>"<p>The CTL activity was assessed <i>in vivo</i> at day 14 (left side panels: A, C, E, G) and day 60 (right side panels: B, D, F, H) after infection with virulent Mtb H37Rv. Two types of target cells were generated and stained differentially with CFSE alone or with CFSE plus PKH26. The target cells labeled with CFSE only were loaded with ESAT-6 pool 1 (p1) of peptides. Prior to transfer into different groups of Mtb-infected mice, both subsets of target cells were combined in equal proportions. The organs evaluated were the spleen, lungs, mediastinal and inguinal lymph nodes from mice treated with α-DEC-ESAT fusion antibody (Inf/DE6-Tx, white bars); and mice which received the isotype control antibody conjugated with ESAT-6 (Inf/IsoE6-Tx, stripped bars). Individual mice were analyzed and 3–5 mice were used per experimental group. Data are presented as mean plus standard error and percentage of cytotoxicity was calculated as indicated in Methods. (*) indicates P<0.05. All bars represent infected mice with different treatments for each group, as indicated.</p>", "links"=>[], "tags"=>["evasion mechanisms", "ifn", "apc", "Virulent Mycobacterium tuberculosis Airways infection", "ESAT", "Delivering mycobacterial antigens", "vivo CTL", "dec", "T cell responses", "T cell clones", "Secretory Antigen Target"], "article_id"=>1395555, "categories"=>["Biological Sciences"], "users"=>["Aaron Silva-Sanchez", "Selene Meza-Perez", "Adriana Flores-Langarica", "Luis Donis-Maturano", "Iris Estrada-García", "Juana Calderon-Amador", "Rogelio Hernández-Pando", "Juliana Idoyaga", "Ralph M. Steinman", "Leopoldo Flores-Romo"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0124828.g003", "stats"=>{"downloads"=>0, "page_views"=>28, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Lung_in_vivo_target_cell_killing_CTL_rate_in_DEC_ESAT_treated_mice_is_increased_against_ESAT_p1_pool_loaded_target_cells_/1395555", "title"=>"Lung <i>in vivo</i> target cell killing (CTL) rate in α-DEC-ESAT-treated mice is increased against ESAT p1 pool-loaded target cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-04-27 03:24:11"}
  • {"files"=>["https://ndownloader.figshare.com/files/2041269"], "description"=>"<p>A) A fusion antibody was generated to murine DEC205, genetically coupled to ESAT-6 and produced by transfected 293T cells. This Ab (α-DE6) presented an electrophoretic delay (left and middle figures), while binding to surface DEC205 on DEC205-transfected CHO cells was not affected (FACS histograms in the figure to the right). B) The ESAT-6 peptide library is depicted here to illustrate the distribution of the three pools of peptides that were used to stimulate cell suspensions from the different tissues examined, as indicated. Control unstimulated cell suspensions treated with culture medium alone are indicated with (M) while those treated with ESAT-6 pool 1 of peptides are indicated with (p1). C) and D) The IFN-γ production by ESAT-6-specific CD4<sup>+</sup> T cells is shown as dot plots in (C), and as integrated results of the experiments performed for the various tissues assessed in (D). Data are presented as mean plus standard error and percentage of IFN-γ producing T cells. (*) represents P<0.05; (**) indicates P<0.01; (***) represents P<0.001. All bars represent uninfected mice treated with α-DEC-ESAT (white bars) or untreated (gray bars). MedLN = Mediastinal lymph nodes, IngLN = Inguinal lymph nodes.</p>", "links"=>[], "tags"=>["evasion mechanisms", "ifn", "apc", "Virulent Mycobacterium tuberculosis Airways infection", "ESAT", "Delivering mycobacterial antigens", "vivo CTL", "dec", "T cell responses", "T cell clones", "Secretory Antigen Target"], "article_id"=>1395548, "categories"=>["Biological Sciences"], "users"=>["Aaron Silva-Sanchez", "Selene Meza-Perez", "Adriana Flores-Langarica", "Luis Donis-Maturano", "Iris Estrada-García", "Juana Calderon-Amador", "Rogelio Hernández-Pando", "Juliana Idoyaga", "Ralph M. Steinman", "Leopoldo Flores-Romo"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0124828.g001", "stats"=>{"downloads"=>1, "page_views"=>29, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Immunization_with_945_DEC_ESAT_hybrid_antibody_induces_Th1_responses_to_ESAT_6_in_the_lungs_and_mediastinal_lymph_nodes_of_non_infected_mice_/1395548", "title"=>"Immunization with α-DEC-ESAT hybrid antibody induces Th1 responses to ESAT-6 in the lungs and mediastinal lymph nodes of non-infected mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-04-27 03:24:11"}

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Relative Metric

{"start_date"=>"2015-01-01T00:00:00Z", "end_date"=>"2015-12-31T00:00:00Z", "subject_areas"=>[]}
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