Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 18 de 18
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Immunology ; 2021 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-34775598

RESUMO

Tuberculosis (TB) and malaria remain serious threats to global health. Bacillus Calmette Guerin (BCG), the only licensed vaccine against TB protects against severe disseminated forms of TB in infants but shows poor efficacy against pulmonary TB in adults. Coinfections have been reported as one of the factors implicated in vaccine inefficacy. Given the geographical overlap of malaria and TB in areas where BCG vaccination is routinely administered, we hypothesised that virulence dependent co-infection with Plasmodium species could alter the BCG specific immune responses thus resulting in failure to protect against Mycobacterium tuberculosis. We compared virulent Plasmodium berghei and non-virulent Plasmodium chabaudi, their effects on B cells, effector and memory T cells, and the outcome on BCG induced efficacy against M. tuberculosis infection. We demonstrate that malaria co-infection modulates both B and T cell immune responses but does not significantly alter the ability of the BCG vaccine to inhibit the growth of M. tuberculosis irrespective of parasite virulence. This malaria-driven immune regulation may have serious consequences in the early clinical trials of novel vaccines which rely on vaccine-specific T cell responses to screen novel vaccines for progression to the more costly vaccine efficacy trials.

2.
Cell Host Microbe ; 29(11): 1611-1619.e5, 2021 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-34688376

RESUMO

The Johnson and Johnson Ad26.COV2.S single-dose vaccine represents an attractive option for coronavirus disease 2019 (COVID-19) vaccination in countries with limited resources. We examined the effect of prior infection with different SARS-CoV-2 variants on Ad26.COV2.S immunogenicity. We compared participants who were SARS-CoV-2 naive with those either infected with the ancestral D614G virus or infected in the second wave when Beta predominated. Prior infection significantly boosts spike-binding antibodies, antibody-dependent cellular cytotoxicity, and neutralizing antibodies against D614G, Beta, and Delta; however, neutralization cross-reactivity varied by wave. Robust CD4 and CD8 T cell responses are induced after vaccination, regardless of prior infection. T cell recognition of variants is largely preserved, apart from some reduction in CD8 recognition of Delta. Thus, Ad26.COV2.S vaccination after infection could result in enhanced protection against COVID-19. The impact of the infecting variant on neutralization breadth after vaccination has implications for the design of second-generation vaccines based on variants of concern.


Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/imunologia , SARS-CoV-2/imunologia , Vacinação , Adulto , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linfócitos T/imunologia
3.
J Immunol ; 207(5): 1239-1249, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34389623

RESUMO

HIV-1 infection substantially increases the risk of developing tuberculosis (TB). Mechanisms such as defects in the Th1 response to Mycobacterium tuberculosis in HIV-infected persons have been widely reported. However, Th1-independent mechanisms also contribute to protection against TB. To identify a broader spectrum of defects in TB immunity during HIV infection, we examined IL-17A and IL-22 production in response to mycobacterial Ags in peripheral blood of persons with latent TB infection and HIV coinfection. Upon stimulating with mycobacterial Ags, we observed a distinct CD4+ Th lineage producing IL-22 in the absence of IL-17A and IFN-γ. Mycobacteria-specific Th22 cells were present at high frequencies in blood and contributed up to 50% to the CD4+ T cell response to mycobacteria, comparable in magnitude to the IFN-γ Th1 response (median 0.91% and 0.55%, respectively). Phenotypic characterization of Th22 cells revealed that their memory differentiation was similar to M. tuberculosis-specific Th1 cells (i.e., predominantly early differentiated CD45RO+CD27+ phenotype). Moreover, CCR6 and CXCR3 expression profiles of Th22 cells were similar to Th17 cells, whereas their CCR4 and CCR10 expression patterns displayed an intermediate phenotype between Th1 and Th17 cells. Strikingly, mycobacterial IL-22 responses were 3-fold lower in HIV-infected persons compared with uninfected persons, and the magnitude of responses correlated inversely with HIV viral load. These data provide important insights into mycobacteria-specific Th subsets in humans and suggest a potential role for IL-22 in protection against TB during HIV infection. Further studies are needed to fully elucidate the role of IL-22 in protective TB immunity.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Infecções por HIV/imunologia , HIV-1/fisiologia , Interleucinas/metabolismo , Tuberculose Latente/imunologia , Mycobacterium tuberculosis/fisiologia , Subpopulações de Linfócitos T/imunologia , Adulto , Células Cultivadas , Coinfecção , Feminino , Soropositividade para HIV , Humanos , Interleucina-17/metabolismo , Masculino , África do Sul , Carga Viral , Adulto Jovem
4.
Front Immunol ; 12: 611673, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34220793

RESUMO

In tuberculosis, T cell-mediated immunity is extensively studied whilst B cells received limited attention in human and mice. Of interest, Mycobacterium tuberculosis (Mtb) does increase IL-4 Receptor-alpha (IL4Rα) expression in murine B cells. To better understand the role of IL4Rα signalling in B cells, we compared wild type mice with B cell-specific IL4Rα deficient mice (mb1creIL-4Rα-/lox mice). Chronic Mtb aerosol infection in mb1creIL-4Rα-/lox mice reduced lung and spleen bacterial burdens, compared to littermate (IL-4Rα-/lox) control animals. Consequently, lung pathology, inflammation and inducible nitric oxide synthase (iNOS) expression were reduced in the lungs of mb1creIL-4Rα-/lox mice, which was also accompanied by increased lung IgA and decreased IgG1 levels. Furthermore, intratracheal adoptive transfer of wild-type B cells into B cell-specific IL4Rα deficient mice reversed the protective phenotype. Moreover, constitutively mCherry expressing Mtb showed decreased association with B cells from mb1creIL-4Rα-/lox mice ex vivo. In addition, supernatants from Mtb-exposed B cells of mb1creIL-4Rα-/lox mice also increased the ability of macrophages to produce nitric oxide, IL-1ß, IL-6 and TNF. Together, this demonstrates that IL-4-responsive B cells are detrimental during the chronic phase of tuberculosis in mice with perturbed antibody profiles, inflammatory cytokines and tnf and stat1 levels in the lungs.


Assuntos
Linfócitos B/imunologia , Imunoglobulina A/metabolismo , Interleucina-4/metabolismo , Pulmão/metabolismo , Macrófagos/patologia , Mycobacterium tuberculosis/fisiologia , Tuberculose/imunologia , Animais , Doença Crônica , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Mediadores da Inflamação/metabolismo , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Receptores de Superfície Celular/genética , Transdução de Sinais
5.
Immunology ; 164(3): 524-540, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34129695

RESUMO

Tuberculosis presents a global health challenge, and tumour necrosis factor (TNF) signalling is required for host immunity against Mycobacterium tuberculosis (Mtb). TNF receptor shedding, however, compromises effective immunity by reducing bioactive TNF through the formation of inactive complexes. In this study, we first compared the effect of total soluble TNF receptors using a transgenic p55ΔNS /p75-/- murine strain on host protection during a low-dose aerosol Mtb H37Rv challenge. We report that the presence of membrane-bound TNFRp55 alone in the absence of TNFRp75 results in superior control of a primary Mtb infection where p55ΔNS /p75-/- hyperactive dendritic cells displayed an increased capacity to induce a hyperactive Mtb-specific CD4+ T-cell response. p55ΔNS /p75-/- dendritic cells expressed a higher frequency of MHCII and increased MFIs for both CD86 and MHCII, while CD4+ T cells had higher expression of CD44 and IFN-γ. Next, the relative contributions of soluble TNFRp55 and soluble TNFRp75 to host protection against either primary Mtb infection or during reactivation of latent tuberculosis were delineated by comparing the experimental outcomes of control C57BL/6 mice to transgenic p55ΔNS /p75-/- , p55ΔNS and p75-/- mouse strains. We found that soluble TNFRp55 is redundant for immune regulation during the chronic stages of a primary Mtb infection. However, TNFRp55 together with soluble TNFRp75 has a crucial role in immune regulation of reactivation of latent tuberculosis.


Assuntos
Células Dendríticas/imunologia , Mycobacterium tuberculosis/imunologia , Receptores Tipo II do Fator de Necrose Tumoral/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Tuberculose/imunologia , Animais , Células Dendríticas/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Receptores Tipo II do Fator de Necrose Tumoral/genética , Tuberculose/microbiologia
6.
Front Plant Sci ; 12: 589940, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33868324

RESUMO

Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has swept the world and poses a significant global threat to lives and livelihoods, with 115 million confirmed cases and at least 2.5 million deaths from Coronavirus disease 2019 (COVID-19) in the first year of the pandemic. Developing tools to measure seroprevalence and understand protective immunity to SARS-CoV-2 is a priority. We aimed to develop a serological assay using plant-derived recombinant viral proteins, which represent important tools in less-resourced settings. Methods: We established an indirect ELISA using the S1 and receptor-binding domain (RBD) portions of the spike protein from SARS-CoV-2, expressed in Nicotiana benthamiana. We measured antibody responses in sera from South African patients (n = 77) who had tested positive by PCR for SARS-CoV-2. Samples were taken a median of 6 weeks after the diagnosis, and the majority of participants had mild and moderate COVID-19 disease. In addition, we tested the reactivity of pre-pandemic plasma (n = 58) and compared the performance of our in-house ELISA with a commercial assay. We also determined whether our assay could detect SARS-CoV-2-specific IgG and IgA in saliva. Results: We demonstrate that SARS-CoV-2-specific immunoglobulins are readily detectable using recombinant plant-derived viral proteins, in patients who tested positive for SARS-CoV-2 by PCR. Reactivity to S1 and RBD was detected in 51 (66%) and 48 (62%) of participants, respectively. Notably, we detected 100% of samples identified as having S1-specific antibodies by a validated, high sensitivity commercial ELISA, and optical density (OD) values were strongly and significantly correlated between the two assays. For the pre-pandemic plasma, 1/58 (1.7%) of samples were positive, indicating a high specificity for SARS-CoV-2 in our ELISA. SARS-CoV-2-specific IgG correlated significantly with IgA and IgM responses. Endpoint titers of S1- and RBD-specific immunoglobulins ranged from 1:50 to 1:3,200. S1-specific IgG and IgA were found in saliva samples from convalescent volunteers. Conclusion: We demonstrate that recombinant SARS-CoV-2 proteins produced in plants enable robust detection of SARS-CoV-2 humoral responses. This assay can be used for seroepidemiological studies and to measure the strength and durability of antibody responses to SARS-CoV-2 in infected patients in our setting.

7.
Immunology ; 162(2): 220-234, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33020922

RESUMO

TNF signalling through TNFRp55 and TNFRp75, and receptor shedding is important for immune activation and regulation. TNFRp75 deficiency leads to improved control of Mycobacterium tuberculosis (M. tuberculosis) infection, but the effects of early innate immune events in this process are unclear. We investigated the role of TNFRp75 on cell activation and apoptosis of alveolar macrophages and neutrophils during M. tuberculosis and M. bovis BCG infection. We found increased microbicidal activity against M. tuberculosis occurred independently of IFNy and NO generation, and displayed an inverse correlation with alveolar macrophages (AMs) apoptosis. Both M. tuberculosis and M. bovis BCG induced higher expression of MHC-II in TNFRp75-/- AMs; however, M bovis BCG infection did not alter AM apoptosis in the absence of TNFRp75. Pulmonary concentrations of CCL2, CCL3 and IL-1ß were increased in TNFRp75-/- mice during M, bovis BCG infection, but had no effect on neutrophil responses. Thus, TNFRp75-dependent regulation of mycobacterial replication is virulence dependent and occurs independently of early alveolar macrophage apoptosis and neutrophil responses.


Assuntos
Vacina BCG/imunologia , Macrófagos Alveolares/imunologia , Neutrófilos/imunologia , Receptores Tipo II do Fator de Necrose Tumoral/imunologia , Tuberculose Bovina/imunologia , Tuberculose/imunologia , Animais , Apoptose/imunologia , Bovinos , Células Cultivadas , Feminino , Pulmão/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mycobacterium bovis/imunologia , Mycobacterium tuberculosis/imunologia , Receptores Tipo I de Fatores de Necrose Tumoral/imunologia , Transdução de Sinais/imunologia , Receptores Chamariz do Fator de Necrose Tumoral/imunologia , Virulência/imunologia
8.
Mediators Inflamm ; 2020: 4361043, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32410852

RESUMO

A hallmark of ulcerative colitis is the chronic colonic inflammation, which is the result of a dysregulated intestinal mucosal immune response. Epithelial barrier disruption which allows the entry of microorganisms eventually leads to more aggressive inflammation and potentially the removal of the colon. We have previously shown that the T helper- (Th-) type 2 cytokines, Interleukin- (IL-) 4 and IL-13, mediate CD4+ T cell- or B cell-driven inflammation in the oxazolone-induced mouse model of ulcerative colitis. In contrast, mice deficient in the shared receptor of IL-4 and IL-13, IL-4 receptor-alpha (IL-4Rα), on all cells develop an exacerbated disease phenotype. This suggests that a regulatory role of IL-4Rα is required to protect against severe colitis. However, the cell populations responsible for regulating the severity of disease onset through IL-4Rα in colitis are yet to be identified. By deleting IL-4Rα on specific cell subsets shown to play a role in mediating colitis, we determined their role in a loss of function approach. Our data demonstrated that the loss of IL-4Rα signalling on intestinal epithelial cells, smooth muscle cells, and macrophages/neutrophils had no effect on alleviating the pathology associated with colitis. These results suggest that IL-4/IL-13 signalling through IL-4Rα on nonhematopoietic intestinal epithelial or smooth muscle cells and hematopoietic macrophage/neutrophils has a redundant role in driving acute oxazolone colitis.


Assuntos
Colite/metabolismo , Células Epiteliais/metabolismo , Macrófagos/metabolismo , Miócitos de Músculo Liso/metabolismo , Receptores de Superfície Celular/metabolismo , Animais , Linfócitos T CD4-Positivos/citologia , Colite/induzido quimicamente , Colo/metabolismo , Deleção de Genes , Inflamação , Interleucina-13/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Oxazolona , Transdução de Sinais
9.
Front Immunol ; 8: 180, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28280495

RESUMO

Tuberculosis of the central nervous system (CNS-TB) is a devastating complication of tuberculosis, and tumor necrosis factor (TNF) is crucial for innate immunity and controlling the infection. TNF is produced by many cell types upon activation, in particularly the myeloid and T cells during neuroinflammation. Here we used mice with TNF ablation targeted to myeloid and T cell (MT-TNF-/-) to assess the contribution of myeloid and T cell-derived TNF in immune responses during CNS-TB. These mice exhibited impaired innate immunity and high susceptibility to cerebral Mycobacterium tuberculosis infection, a similar phenotype to complete TNF-deficient mice. Further, MT-TNF-/- mice were not able to control T cell responses and cytokine/chemokine production. Thus, our data suggested that collective TNF production by both myeloid and T cells are required to provide overall protective immunity against CNS-TB infection.

10.
Sci Rep ; 6: 39499, 2016 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-27995986

RESUMO

The pleiotropic activities of TNF are mediated by two structurally related but functionally distinct type I transmembrane receptors, p55TNFR and p75TNFR expressed in most cell types, that can be cleaved and act as TNF scavengers. Here, we investigated the effect of persistent p55TNFR cell surface expression during aerosol inhalation challenge with virulent M. tuberculosis H37Rv. We demonstrated that persistency of p55TNFR in macrophage cultures increased the synthesis of soluble TNF, p75TNFR and NO, however, had no effects on bacteria killing ability. Furthermore, it did not facilitate enhanced protection to primary acute M. tuberculosis infection in p55∆NS mice. Without exacerbated lung inflammation, we found a compensatory increase in p75TNFR shedding and decrease in bioactive TNF in BAL of p55∆NS mice after M. tuberculosis challenge. Defective expressions of CD44 and INFγ attributed to an impaired T cell response during persistent p55TNFR expression that caused marginal transient susceptibility during chronic infection. Moreover, persistent p55TNFR expression induced early reactivation during latent tuberculosis infection. These data indicate a prominent role of p55TNFR shedding in Th1 mediated protection against chronic and latent tuberculosis infection.


Assuntos
Tuberculose Latente/imunologia , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Linfócitos T/citologia , Animais , Doença Crônica , Citocinas/metabolismo , Ensaio de Imunoadsorção Enzimática , Receptores de Hialuronatos/metabolismo , Interferon gama/metabolismo , Pulmão/patologia , Macrófagos Peritoneais/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Mycobacterium tuberculosis , Óxido Nítrico/química , Linfócitos T/metabolismo
11.
J Neuroinflammation ; 12: 125, 2015 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-26112704

RESUMO

BACKGROUND: Tuberculosis (TB) affects one third of the global population, and TB of the central nervous system (CNS-TB) is the most severe form of tuberculosis which often associates with high mortality. The pro-inflammatory cytokine tumour necrosis factor (TNF) plays a critical role in the initial and long-term host immune protection against Mycobacterium tuberculosis (M. tuberculosis) which involves the activation of innate immune cells and structure maintenance of granulomas. However, the contribution of TNF, in particular neuron-derived TNF, in the control of cerebral M. tuberculosis infection and its protective immune responses in the CNS were not clear. METHODS: We generated neuron-specific TNF-deficient (NsTNF(-/-)) mice and compared outcomes of disease against TNF(f/f) control and global TNF(-/-) mice. Mycobacterial burden in brains, lungs and spleens were compared, and cerebral pathology and cellular contributions analysed by microscopy and flow cytometry after M. tuberculosis infection. Activation of innate immune cells was measured by flow cytometry and cell function assessed by cytokine and chemokine quantification using enzyme-linked immunosorbent assay (ELISA). RESULTS: Intracerebral M. tuberculosis infection of TNF(-/-) mice rendered animals highly susceptible, accompanied by uncontrolled bacilli replication and eventual mortality. In contrast, NsTNF(-/-) mice were resistant to infection and presented with a phenotype similar to that in TNF(f/f) control mice. Impaired immunity in TNF(-/-) mice was associated with altered cytokine and chemokine synthesis in the brain and characterised by a reduced number of activated innate immune cells. Brain pathology reflected enhanced inflammation dominated by neutrophil influx. CONCLUSION: Our data show that neuron-derived TNF has a limited role in immune responses, but overall TNF production is necessary for protective immunity against CNS-TB.


Assuntos
Interações Hospedeiro-Patógeno/fisiologia , Imunidade Inata/fisiologia , Mycobacterium tuberculosis/fisiologia , Neurônios/microbiologia , Neurônios/patologia , Tuberculose do Sistema Nervoso Central/imunologia , Fator de Necrose Tumoral alfa/fisiologia , Replicação Viral/fisiologia , Animais , Encéfalo/metabolismo , Encéfalo/microbiologia , Encéfalo/patologia , Proliferação de Células/fisiologia , Quimiocinas/metabolismo , Citocinas/metabolismo , Células Dendríticas/microbiologia , Células Dendríticas/patologia , Modelos Animais de Doenças , Resistência à Doença/imunologia , Interações Hospedeiro-Patógeno/imunologia , Imunidade Inata/imunologia , Macrófagos/microbiologia , Macrófagos/patologia , Camundongos , Camundongos Knockout , Microglia/microbiologia , Microglia/patologia , Tuberculose do Sistema Nervoso Central/patologia , Tuberculose do Sistema Nervoso Central/fisiopatologia , Fator de Necrose Tumoral alfa/deficiência , Fator de Necrose Tumoral alfa/genética
12.
PLoS Pathog ; 11(6): e1004964, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26070118

RESUMO

African trypanosomes are the causative agents of Human African Trypanosomosis (HAT/Sleeping Sickness) and Animal African Trypanosomosis (AAT/Nagana). A common hallmark of African trypanosome infections is inflammation. In murine trypanosomosis, the onset of inflammation occurs rapidly after infection and is manifested by an influx of myeloid cells in both liver and spleen, accompanied by a burst of serum pro-inflammatory cytokines. Within 48 hours after reaching peak parasitemia, acute anemia develops and the percentage of red blood cells drops by 50%. Using a newly developed in vivo erythrophagocytosis assay, we recently demonstrated that activated cells of the myeloid phagocytic system display enhanced erythrophagocytosis causing acute anemia. Here, we aimed to elucidate the mechanism and immune pathway behind this phenomenon in a murine model for trypanosomosis. Results indicate that IFNγ plays a crucial role in the recruitment and activation of erythrophagocytic myeloid cells, as mice lacking the IFNγ receptor were partially protected against trypanosomosis-associated inflammation and acute anemia. NK and NKT cells were the earliest source of IFNγ during T. b. brucei infection. Later in infection, CD8+ and to a lesser extent CD4+ T cells become the main IFNγ producers. Cell depletion and transfer experiments indicated that during infection the absence of NK, NKT and CD8+ T cells, but not CD4+ T cells, resulted in a reduced anemic phenotype similar to trypanosome infected IFNγR-/- mice. Collectively, this study shows that NK, NKT and CD8+ T cell-derived IFNγ is a critical mediator in trypanosomosis-associated pathology, driving enhanced erythrophagocytosis by myeloid phagocytic cells and the induction of acute inflammation-associated anemia.


Assuntos
Anemia/imunologia , Eritrócitos/patologia , Interferon gama/imunologia , Células Mieloides/imunologia , Fagocitose/imunologia , Tripanossomíase Africana/imunologia , Transferência Adotiva , Animais , Linfócitos T CD8-Positivos/imunologia , Separação Celular , Modelos Animais de Doenças , Feminino , Citometria de Fluxo , Células Matadoras Naturais/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células T Matadoras Naturais/imunologia , Tripanossomíase Africana/complicações
13.
Cell Host Microbe ; 17(2): 252-9, 2015 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-25674984

RESUMO

The interaction of microbes with pattern recognition receptors (PRRs) is essential for protective immunity. While many PRRs that recognize mycobacteria have been identified, none is essentially required for host defense in vivo. Here, we have identified the C-type lectin receptor CLECSF8 (CLEC4D, MCL) as a key molecule in anti-mycobacterial host defense. Clecsf8-/- mice exhibit higher bacterial burdens and increased mortality upon M. tuberculosis infection. Additionally, Clecsf8 deficiency is associated with exacerbated pulmonary inflammation, characterized by enhanced neutrophil recruitment. Clecsf8-/- mice show reduced mycobacterial uptake by pulmonary leukocytes, but infection with opsonized bacteria can restore this phagocytic defect as well as decrease bacterial burdens. Notably, a CLECSF8 polymorphism identified in humans is associated with an increased susceptibility to pulmonary tuberculosis. We conclude that CLECSF8 plays a non-redundant role in anti-mycobacterial immunity in mouse and in man.


Assuntos
Lectinas Tipo C/metabolismo , Proteínas de Membrana/metabolismo , Mycobacterium tuberculosis/imunologia , Animais , Carga Bacteriana , Modelos Animais de Doenças , Predisposição Genética para Doença , Humanos , Pulmão/patologia , Camundongos , Camundongos Knockout , Neutrófilos/imunologia , Fagocitose , Polimorfismo Genético , Receptores Imunológicos/metabolismo , Análise de Sobrevida , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/microbiologia , Tuberculose Pulmonar/patologia
14.
J Clin Invest ; 124(4): 1537-51, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24569452

RESUMO

Development of host protective immunity against Mycobacterium tuberculosis infection is critically dependent on the inflammatory cytokine TNF. TNF signals through 2 receptors, TNFRp55 and TNFRp75; however, the role of TNFRp75-dependent signaling in immune regulation is poorly defined. Here we found that mice lacking TNFRp75 exhibit greater control of M. tuberculosis infection compared with WT mice. TNFRp75-/- mice developed effective bactericidal granulomas and demonstrated increased pulmonary recruitment of activated DCs. Moreover, IL-12p40-dependent migration of DCs to lung draining LNs of infected TNFRp75-/- mice was substantially higher than that observed in WT M. tuberculosis-infected animals and was associated with enhanced frequencies of activated M. tuberculosis-specific IFN-γ-expressing CD4+ T cells. In WT mice, TNFRp75 shedding correlated with markedly reduced bioactive TNF levels and IL-12p40 expression. Neutralization of TNFRp75 in M. tuberculosis-infected WT BM-derived DCs (BMDCs) increased production of bioactive TNF and IL-12p40 to a level equivalent to that produced by TNFRp75-/- BMDCs. Addition of exogenous TNFRp75 to TNFRp75-/- BMDCs infected with M. tuberculosis decreased IL-12p40 synthesis, demonstrating that TNFRp75 shedding regulates DC activation. These data indicate that TNFRp75 shedding downmodulates protective immune function and reduces host resistance and survival; therefore, targeting TNFRp75 may be beneficial for improving disease outcome.


Assuntos
Mycobacterium tuberculosis/imunologia , Receptores Tipo II do Fator de Necrose Tumoral/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Células Dendríticas/imunologia , Feminino , Granuloma/patologia , Interações Hospedeiro-Patógeno/imunologia , Subunidade p40 da Interleucina-12/metabolismo , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mycobacterium tuberculosis/patogenicidade , Receptores Tipo I de Fatores de Necrose Tumoral/deficiência , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Receptores Tipo I de Fatores de Necrose Tumoral/imunologia , Receptores Tipo II do Fator de Necrose Tumoral/deficiência , Receptores Tipo II do Fator de Necrose Tumoral/genética , Transdução de Sinais/imunologia , Solubilidade , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/microbiologia , Tuberculose Pulmonar/patologia , Receptores Chamariz do Fator de Necrose Tumoral/deficiência , Receptores Chamariz do Fator de Necrose Tumoral/genética , Receptores Chamariz do Fator de Necrose Tumoral/imunologia , Fator de Necrose Tumoral alfa/metabolismo
15.
Infect Immun ; 82(5): 1880-90, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24566619

RESUMO

Mycobacterium tuberculosis infection of the central nervous system is thought to be initiated once the bacilli have breached the blood brain barrier and are phagocytosed, primarily by microglial cells. In this study, the interactions of M. tuberculosis with neurons in vitro and in vivo were investigated. The data obtained demonstrate that neurons can act as host cells for M. tuberculosis. M. tuberculosis bacilli were internalized by murine neuronal cultured cells in a time-dependent manner after exposure, with superior uptake by HT22 cells compared to Neuro-2a cells (17.7% versus 9.8%). Internalization of M. tuberculosis bacilli by human SK-N-SH cultured neurons suggested the clinical relevance of the findings. Moreover, primary murine hippocampus-derived neuronal cultures could similarly internalize M. tuberculosis. Internalized M. tuberculosis bacilli represented a productive infection with retention of bacterial viability and replicative potential, increasing 2- to 4-fold within 48 h. M. tuberculosis bacillus infection of neurons was confirmed in vivo in the brains of C57BL/6 mice after intracerebral challenge. This study, therefore, demonstrates neurons as potential new target cells for M. tuberculosis within the central nervous system.


Assuntos
Mycobacterium tuberculosis/fisiologia , Neurônios/microbiologia , Tuberculose do Sistema Nervoso Central/microbiologia , Animais , Linhagem Celular , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Tuberculose do Sistema Nervoso Central/imunologia
16.
Sci Rep ; 3: 1809, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23657146

RESUMO

Tumour Necrosis Factor (TNF) is critical for host control of M. tuberculosis, but the relative contribution of TNF from innate and adaptive immune responses during tuberculosis infection is unclear. Myeloid versus T-cell-derived TNF function in tuberculosis was investigated using cell type-specific TNF deletion. Mice deficient for TNF expression in macrophages/neutrophils displayed early, transient susceptibility to M. tuberculosis but recruited activated, TNF-producing CD4(+) and CD8(+) T-cells and controlled chronic infection. Strikingly, deficient TNF expression in T-cells resulted in early control but susceptibility and eventual mortality during chronic infection with increased pulmonary pathology. TNF inactivation in both myeloid and T-cells rendered mice critically susceptible to infection with a phenotype resembling complete TNF deficient mice, indicating that myeloid and T-cells are the primary TNF sources collaborating for host control of tuberculosis. Thus, while TNF from myeloid cells mediates early immune function, T-cell derived TNF is essential to sustain protection during chronic tuberculosis infection.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Pulmão/imunologia , Mycobacterium tuberculosis/imunologia , Células Mieloides/imunologia , Pneumonia/etiologia , Tuberculose/prevenção & controle , Fator de Necrose Tumoral alfa/fisiologia , Animais , Western Blotting , Linfócitos T CD8-Positivos/metabolismo , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Citometria de Fluxo , Integrases/metabolismo , Pulmão/citologia , Pulmão/microbiologia , Macrófagos/citologia , Macrófagos/imunologia , Macrófagos/microbiologia , Camundongos , Camundongos Knockout , Células Mieloides/citologia , Células Mieloides/microbiologia , Neutrófilos/citologia , Neutrófilos/imunologia , Neutrófilos/microbiologia , Pneumonia/metabolismo , Pneumonia/patologia , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Tuberculose/imunologia , Tuberculose/microbiologia
17.
PLoS One ; 6(11): e25121, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22132068

RESUMO

Of those individuals who are infected with M. tuberculosis, 90% do not develop active disease and represents a large reservoir of M. tuberculosis with the potential for reactivation of infection. Sustained TNF expression is required for containment of persistent infection and TNF neutralization leads to tuberculosis reactivation. In this study, we investigated the contribution of soluble TNF (solTNF) and transmembrane TNF (Tm-TNF) in immune responses generated against reactivating tuberculosis. In a chemotherapy induced tuberculosis reactivation model, mice were challenged by aerosol inhalation infection with low dose M. tuberculosis for three weeks to establish infection followed chemotherapeutic treatment for six weeks, after which therapy was terminated and tuberculosis reactivation investigated. We demonstrate that complete absence of TNF results in host susceptibility to M. tuberculosis reactivation in the presence of established mycobacteria-specific adaptive immunity with mice displaying unrestricted bacilli growth and diffused granuloma structures compared to WT control mice. Interestingly, bacterial re-emergence is contained in Tm-TNF mice during the initial phases of tuberculosis reactivation, indicating that Tm-TNF sustains immune pressure as in WT mice. However, Tm-TNF mice show susceptibility to long term M. tuberculosis reactivation associated with uncontrolled influx of leukocytes in the lungs and reduced IL-12p70, IFNγ and IL-10, enlarged granuloma structures, and failure to contain mycobacterial replication relative to WT mice. In conclusion, we demonstrate that both solTNF and Tm-TNF are required for maintaining immune pressure to contain reactivating M. tuberculosis bacilli even after mycobacteria-specific immunity has been established.


Assuntos
Membrana Celular/metabolismo , Mycobacterium tuberculosis/fisiologia , Tuberculose/microbiologia , Tuberculose/patologia , Fator de Necrose Tumoral alfa/metabolismo , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Granuloma/complicações , Granuloma/patologia , Inflamação/patologia , Pulmão/efeitos dos fármacos , Pulmão/enzimologia , Pulmão/microbiologia , Pulmão/patologia , Linfócitos/metabolismo , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Mycobacterium tuberculosis/crescimento & desenvolvimento , Óxido Nítrico Sintase Tipo II/metabolismo , Tuberculose/complicações , Tuberculose/prevenção & controle
18.
J Immunol ; 185(7): 4292-301, 2010 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-20817877

RESUMO

The contribution of lymphotoxin (LT)α in the host immune response to virulent Mycobacterium tuberculosis and Mycobacterium bovis bacillus Calmette-Guérin infections was investigated. Despite their ability to induce Th1 cytokine, IFN-γ, and IL-12 pulmonary response, "conventional" LTα(-/-) mice succumb rapidly to virulent M. tuberculosis aerosol infection, with uncontrolled bacilli growth, defective granuloma formation, necrosis, and reduced pulmonary inducible NO synthase expression, similar to TNF(-/-) mice. Contributions from developmental lymphoid abnormalities in LTα(-/-) mice were excluded because hematopoietic reconstitution with conventional LTα(-/-) bone marrow conferred enhanced susceptibility to wild-type mice, comparable to conventional LTα(-/-) control mice. However, conventional LTα(-/-) mice produced reduced levels of TNF after M. bovis bacillus Calmette-Guérin infection, and their lack of control of mycobacterial infection could be due to a defective contribution of either LTα or TNF, or both, to the host immune response. To address this point, the response of "neo-free" LTα(-/-) mice with unperturbed intrinsic TNF expression to M. tuberculosis infection was investigated in a direct comparative study with conventional LTα(-/-) mice. Strikingly, although conventional LTα(-/-) mice were highly sensitive, similar to TNF(-/-) mice, neo-free LTα(-/-) mice controlled acute M. tuberculosis infection essentially as wild-type mice. Pulmonary bacterial burden and inflammation was, however, slightly increased in neo-free LTα(-/-) mice 4-5 mo postinfection, but importantly, they did not succumb to infection. Our findings revise the notion that LTα might have a critical role in host defense to acute mycobacterial infection, independent of TNF, but suggest a contribution of LTα in the control of chronic M. tuberculosis infection.


Assuntos
Linfotoxina-alfa/imunologia , Tuberculose/imunologia , Animais , Citocinas/biossíntese , Citocinas/imunologia , Ensaio de Imunoadsorção Enzimática , Linfotoxina-alfa/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mycobacterium bovis/imunologia , Mycobacterium tuberculosis/imunologia , Óxido Nítrico Sintase Tipo II/biossíntese , Óxido Nítrico Sintase Tipo II/imunologia , Tuberculose/metabolismo , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/imunologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...