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Nat Med ; 25(7): 1175, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31222179


In the version of this article originally published, there was an error in the abstract. The word disease should not have been included in the sentence "These individuals were highly exposed to Mtb but tested negative disease by IFN-γ release assay and tuberculin skin test, 'resisting' development of classic LTBI". The sentence should have been "These individuals were highly exposed to Mtb but tested negative by IFN-γ release assay and tuberculin skin test, 'resisting' development of classic LTBI." The error has been corrected in the HTML and PDF versions of this article.

Nat Med ; 25(6): 977-987, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31110348


Exposure to Mycobacterium tuberculosis (Mtb) results in heterogeneous clinical outcomes including primary progressive tuberculosis and latent Mtb infection (LTBI). Mtb infection is identified using the tuberculin skin test and interferon-γ (IFN-γ) release assay IGRA, and a positive result may prompt chemoprophylaxis to prevent progression to tuberculosis. In the present study, we report on a cohort of Ugandan individuals who were household contacts of patients with TB. These individuals were highly exposed to Mtb but tested negative disease by IFN-γ release assay and tuberculin skin test, 'resisting' development of classic LTBI. We show that 'resisters' possess IgM, class-switched IgG antibody responses and non-IFN-γ T cell responses to the Mtb-specific proteins ESAT6 and CFP10, immunologic evidence of exposure to Mtb. Compared to subjects with classic LTBI, 'resisters' display enhanced antibody avidity and distinct Mtb-specific IgG Fc profiles. These data reveal a distinctive adaptive immune profile among Mtb-exposed subjects, supporting an expanded definition of the host response to Mtb exposure, with implications for public health and the design of clinical trials.

Tuberculose Latente/imunologia , Mycobacterium tuberculosis/imunologia , Tuberculose/imunologia , Adulto , Anticorpos Antibacterianos/sangue , Antígenos de Bactérias/imunologia , Biomarcadores/metabolismo , Linfócitos T CD4-Positivos/imunologia , Criança , Estudos de Coortes , Feminino , Humanos , Interferon gama/imunologia , Testes de Liberação de Interferon-gama , Masculino , Teste Tuberculínico , Uganda , Adulto Jovem
Nat Microbiol ; 2: 16232, 2016 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-27918526


Mycobacterium tuberculosis (Mtb) establishes a persistent infection, despite inducing antigen-specific T-cell responses. Although T cells arrive at the site of infection, they do not provide sterilizing immunity. The molecular basis of how Mtb impairs T-cell function is not clear. Mtb has been reported to block major histocompatibility complex class II (MHC-II) antigen presentation; however, no bacterial effector or host-cell target mediating this effect has been identified. We recently found that Mtb EsxH, which is secreted by the Esx-3 type VII secretion system, directly inhibits the endosomal sorting complex required for transport (ESCRT) machinery. Here, we showed that ESCRT is required for optimal antigen processing; correspondingly, overexpression and loss-of-function studies demonstrated that EsxH inhibited the ability of macrophages and dendritic cells to activate Mtb antigen-specific CD4+ T cells. Compared with the wild-type strain, the esxH-deficient strain induced fivefold more antigen-specific CD4+ T-cell proliferation in the mediastinal lymph nodes of mice. We also found that EsxH undermined the ability of effector CD4+ T cells to recognize infected macrophages and clear Mtb. These results provide a molecular explanation for how Mtb impairs the adaptive immune response.

Proteínas de Bactérias/metabolismo , Linfócitos T CD4-Positivos/imunologia , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Interações Hospedeiro-Patógeno , Evasão da Resposta Imune , Ativação Linfocitária , Mycobacterium tuberculosis/imunologia , Animais , Proteínas de Bactérias/genética , Células Dendríticas/imunologia , Modelos Animais de Doenças , Expressão Gênica , Técnicas de Inativação de Genes , Macrófagos/imunologia , Camundongos Endogâmicos C57BL , Tuberculose/microbiologia , Tuberculose/patologia
Cell ; 167(2): 433-443.e14, 2016 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-27667685


While a third of the world carries the burden of tuberculosis, disease control has been hindered by a lack of tools, including a rapid, point-of-care diagnostic and a protective vaccine. In many infectious diseases, antibodies (Abs) are powerful biomarkers and important immune mediators. However, in Mycobacterium tuberculosis (Mtb) infection, a discriminatory or protective role for humoral immunity remains unclear. Using an unbiased antibody profiling approach, we show that individuals with latent tuberculosis infection (Ltb) and active tuberculosis disease (Atb) have distinct Mtb-specific humoral responses, such that Ltb infection is associated with unique Ab Fc functional profiles, selective binding to FcγRIII, and distinct Ab glycosylation patterns. Moreover, compared to Abs from Atb, Abs from Ltb drove enhanced phagolysosomal maturation, inflammasome activation, and, most importantly, macrophage killing of intracellular Mtb. Combined, these data point to a potential role for Fc-mediated Ab effector functions, tuned via differential glycosylation, in Mtb control.

Anticorpos Antibacterianos/imunologia , Interações Hospedeiro-Patógeno/imunologia , Imunidade Humoral , Tuberculose Latente/imunologia , Mycobacterium tuberculosis/imunologia , Adulto , Feminino , Glicosilação , Humanos , Fragmentos Fc das Imunoglobulinas/imunologia , Ativação de Macrófagos , Masculino , Pessoa de Meia-Idade , Polissacarídeos/imunologia , Análise Serial de Proteínas , Receptores de IgG/imunologia , Adulto Jovem
Cell Host Microbe ; 19(1): 44-54, 2016 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-26764596


Persistence of Mycobacterium tuberculosis results from bacterial strategies that manipulate host adaptive immune responses. Infected dendritic cells (DCs) transport M. tuberculosis to local lymph nodes but activate CD4 T cells poorly, suggesting bacterial manipulation of antigen presentation. However, M. tuberculosis antigens are also exported from infected DCs and taken up and presented by uninfected DCs, possibly overcoming this blockade of antigen presentation by infected cells. Here we show that the first stage of this antigen transfer, antigen export, benefits M. tuberculosis by diverting bacterial proteins from the antigen presentation pathway. Kinesin-2 is required for antigen export and depletion of this microtubule-based motor increases activation of antigen-specific CD4 T cells by infected cells and improves control of intracellular infection. Thus, although antigen transfer enables presentation by bystander cells, it does not compensate for reduced antigen presentation by infected cells and represents a bacterial strategy for CD4 T cell evasion.

Apresentação do Antígeno , Antígenos de Bactérias/imunologia , Linfócitos T CD4-Positivos/imunologia , Mycobacterium tuberculosis/imunologia , Tuberculose/imunologia , Animais , Antígenos de Bactérias/genética , Células Dendríticas/imunologia , Humanos , Camundongos , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/metabolismo , Transporte Proteico , Tuberculose/metabolismo , Tuberculose/microbiologia
J Immunol ; 196(1): 357-64, 2016 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-26573837


Mycobacterium tuberculosis commonly causes persistent or chronic infection, despite the development of Ag-specific CD4 T cell responses. We hypothesized that M. tuberculosis evades elimination by CD4 T cell responses by manipulating MHC class II Ag presentation and CD4 T cell activation and tested this hypothesis by comparing activation of Ag85B-specific CD4 T cell responses to M. tuberculosis and M. bovis bacillus Calmette-Guérin (BCG) Pasteur in vivo and in vitro. We found that, although M. tuberculosis persists in lungs of immunocompetent mice, M. bovis BCG is cleared, and clearance is T cell dependent. We further discovered that M. tuberculosis-infected macrophages and dendritic cells activate Ag85B-specific CD4 T cells less efficiently and less effectively than do BCG-infected cells, in vivo and in vitro, despite higher production and secretion of Ag85B by M. tuberculosis. During BCG infection, activation of Ag85B-specific CD4 T cells requires fewer infected dendritic cells and fewer Ag-producing bacteria than during M. tuberculosis infection. When dendritic cells containing equivalent numbers of M. tuberculosis or BCG were transferred to mice, BCG-infected cells activated proliferation of more Ag85B-specific CD4 T cells than did M. tuberculosis-infected cells. Differences in Ag85B-specific CD4 T cell activation were attributable to differential Ag presentation rather than differential expression of costimulatory or inhibitory molecules. These data indicate that suboptimal Ag presentation contributes to persistent infection and that limiting Ag presentation is a virulence property of M. tuberculosis.

Aciltransferases/imunologia , Apresentação do Antígeno/imunologia , Antígenos de Bactérias/imunologia , Proteínas de Bactérias/imunologia , Mycobacterium tuberculosis/imunologia , Mycobacterium tuberculosis/patogenicidade , Células Th1/imunologia , Animais , Proliferação de Células , Células Dendríticas/imunologia , Células Dendríticas/microbiologia , Células Dendríticas/transplante , Pulmão/imunologia , Pulmão/microbiologia , Ativação Linfocitária/imunologia , Macrófagos/imunologia , Macrófagos/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mycobacterium bovis/imunologia , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/microbiologia , Fatores de Virulência/imunologia