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1.
Int J Mol Sci ; 22(16)2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34445098

RESUMO

Granulysin is an antimicrobial peptide (AMP) expressed by human T-lymphocytes and natural killer cells. Despite a remarkably broad antimicrobial spectrum, its implementation into clinical practice has been hampered by its large size and off-target effects. To circumvent these limitations, we synthesized a 29 amino acid fragment within the putative cytolytic site of Granulysin (termed "Gran1"). We evaluated the antimicrobial activity of Gran1 against the major human pathogen Mycobacterium tuberculosis (Mtb) and a panel of clinically relevant non-tuberculous mycobacteria which are notoriously difficult to treat. Gran1 efficiently inhibited the mycobacterial proliferation in the low micro molar range. Super-resolution fluorescence microscopy and scanning electron microscopy indicated that Gran1 interacts with the surface of Mtb, causing lethal distortions of the cell wall. Importantly, Gran1 showed no off-target effects (cytokine release, chemotaxis, cell death) in primary human cells or zebrafish embryos (cytotoxicity, developmental toxicity, neurotoxicity, cardiotoxicity). Gran1 was selectively internalized by macrophages, the major host cell of Mtb, and restricted the proliferation of the pathogen. Our results demonstrate that the hypothesis-driven design of AMPs is a powerful approach for the identification of small bioactive compounds with specific antimicrobial activity. Gran1 is a promising component for the design of AMP-containing nanoparticles with selective activity and favorable pharmacokinetics to be pushed forward into experimental in vivo models of infectious diseases, most notably tuberculosis.


Assuntos
Antígenos de Diferenciação de Linfócitos T/imunologia , Macrófagos/imunologia , Mycobacterium tuberculosis/imunologia , Tuberculose/imunologia , Animais , Antígenos de Diferenciação de Linfócitos T/química , Células Cultivadas , Interações Hospedeiro-Patógeno , Humanos , Macrófagos/microbiologia , Mycobacterium tuberculosis/fisiologia , Peptídeos/química , Peptídeos/imunologia , Tuberculose/microbiologia , Peixe-Zebra
2.
J Immunol ; 207(4): 1065-1077, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34321229

RESUMO

CNS tuberculosis (CNSTB) is the most severe manifestation of extrapulmonary tuberculosis infection, but the mechanism of how mycobacteria cross the blood-brain barrier (BBB) is not well understood. In this study, we report a novel murine in vitro BBB model combining primary brain endothelial cells, Mycobacterium bovis bacillus Calmette-Guérin-infected dendritic cells (DCs), PBMCs, and bacterial Ag-specific CD4+ T cells. We show that mycobacterial infection limits DC mobility and also induces cellular cluster formation that has a similar composition to pulmonary mycobacterial granulomas. Within the clusters, infection from DCs disseminates to the recruited monocytes, promoting bacterial expansion. Mycobacterium-induced in vitro granulomas have been described previously, but this report shows that they can form on brain endothelial cell monolayers. Cellular cluster formation leads to cluster-associated damage of the endothelial cell monolayer defined by mitochondrial stress, disorganization of the tight junction proteins ZO-1 and claudin-5, upregulation of the adhesion molecules VCAM-1 and ICAM-1, and increased transmigration of bacteria-infected cells across the BBB. TNF-α inhibition reduces cluster formation on brain endothelial cells and mitigates cluster-associated damage. These data describe a model of bacterial dissemination across the BBB shedding light on a mechanism that might contribute to CNS tuberculosis infection and facilitate treatments.


Assuntos
Barreira Hematoencefálica/imunologia , Células Dendríticas/imunologia , Mycobacterium bovis/imunologia , Tuberculose/imunologia , Fator de Necrose Tumoral alfa/imunologia , Animais , Encéfalo/imunologia , Linfócitos T CD4-Positivos/imunologia , Células Endoteliais/imunologia , Granuloma/imunologia , Molécula 1 de Adesão Intercelular/imunologia , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Molécula 1 de Adesão de Célula Vascular/imunologia
3.
Int J Mol Sci ; 22(14)2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34299161

RESUMO

Prostaglandin E2 (PGE2) is an important biological mediator involved in the defense against Mycobacterium tuberculosis (Mtb) infection. Currently, there are no reports on the mycobacterial components that regulate PGE2 production. Previously, we have reported that RpfE-treated dendritic cells (DCs) effectively expanded the Th1 and Th17 cell responses simultaneously; however, the mechanism underlying Th1 and Th17 cell differentiation is unclear. Here, we show that PGE2 produced by RpfE-activated DCs via the MAPK and cyclooxygenase 2 signaling pathways induces Th1 and Th17 cell responses mainly via the EP4 receptor. Furthermore, mice administered intranasally with PGE2 displayed RpfE-induced antigen-specific Th1 and Th17 responses with a significant reduction in bacterial load in the lungs. Furthermore, the addition of optimal PGE2 amount to IL-2-IL-6-IL-23p19-IL-1ß was essential for promoting differentiation into Th1/Th17 cells with strong bactericidal activity. These results suggest that RpfE-matured DCs produce PGE2 that induces Th1 and Th17 cell differentiation with potent anti-mycobacterial activity.


Assuntos
Proteínas de Bactérias/metabolismo , Diferenciação Celular , Células Dendríticas/metabolismo , Dinoprostona/metabolismo , Mycobacterium tuberculosis/fisiologia , Células Th1/citologia , Células Th17/citologia , Animais , Células Dendríticas/imunologia , Células Dendríticas/microbiologia , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais , Células Th1/imunologia , Células Th17/imunologia , Tuberculose/imunologia , Tuberculose/metabolismo , Tuberculose/microbiologia
4.
BMC Infect Dis ; 21(1): 651, 2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34225667

RESUMO

BACKGROUND: The differential diagnosis of active tuberculosis (ATB) and latent tuberculosis infection (LTBI) remains challenging in clinical practice. We aimed to evaluate the diagnostic accuracy of the IFN-γ/TNF-α FluoroSpot assay for differentiating ATB from LTBI. METHODS: We conducted a pilot study of case-control design, using the FluoroSpot assay to simultaneously detect IFN-γ and TNF-α secretion at the single-cell level. The frequencies of antigen-specific single TNF-α-, total TNF-α-, single IFN-γ-, total IFN-γ- and dual IFN-γ/TNF-α-secreting T cells were detected. The optimal cutoffs value of frequencies for differentiating ATB from LTBI were determined according to receiver operating characteristic curve analysis. The sensitivity, specificity, predictive values (PV) and likelihood ratios (LR) of the FluoroSpot assay were calculated. RESULTS: Thirty patients diagnosed microbiologically with ATB, 36 healthcare workers with LTBI and 36 healthy controls were enrolled. After stimulated by ESAT-6 or CFP-10 peptides, the median frequencies of single TNF-α-, total TNF-α-, single IFN-γ-, total IFN-γ- and dual IFN-γ/TNF-α-secreting T cells in ATB patients were all significantly higher than those in LTBI and HC groups (P < 0.01). The frequencies of total IFN-γ-secreting T cells detected by FluoroSpot assay correlated significantly with those of T-SPOT.TB (r = 0.910 for ESAT-6, P < 0.001, r = 0.845 for CFP-10, P < 0.001). After stimulated by ESAT-6 peptides, with total TNF-α-secreting T cells frequencies at a cut off value of 21 iSFCs/250,000 PBMCs, the sensitivity, specificity, PLR, NLR, PPV, NPV of IFN-γ/TNF-α FluoroSpot assay in differentiating ATB from LTBI were 96.7% (95%CI, 82.8-99.9%), 94.3% (95%CI, 80.8-99.3%), 16.92 (95%CI, 4.40-65.08), 0.04 (95%CI, 0.01-0.24), 93.6% (95%CI,78.6-99.2%) and 97.1% (95%CI, 84.7-99.9%), respectively. With the frequencies of total TNF-α- and total IFN-γ-secreting T cells stimulated by ESAT-6 peptides combined, the specificity was increased to 97.1%, and the positive likelihood ratio to 31.5. The combination with CFP-10 might not improve the diagnostic accuracy of the ESAT-6 for differentiating ATB from LTBI. CONCLUSIONS: IFN-γ/TNF-α FluoroSpot assay might have potential to help differentiate ATB from LTBI, but the findings need to be further verified by cross-sectional or prospective cohort studies.


Assuntos
Testes de Liberação de Interferon-gama , Tuberculose Latente/diagnóstico , Tuberculose/diagnóstico , Fator de Necrose Tumoral alfa/sangue , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Diagnóstico Diferencial , Humanos , Interferon gama/sangue , Tuberculose Latente/imunologia , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Tuberculose/imunologia , Adulto Jovem
5.
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
6.
Life Sci ; 282: 119806, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34252419

RESUMO

PURPOSE: Tuberculosis, a cost and life threatening disease, was being subjected for improving vaccine strategies beyond BCG. Thus, a novel particulate delivery system using alginate-coated chitosan nanoparticles including PPE17 protein and CpG were administered through intranasal (IN) and subcutaneous (SC) routes. METHODS: The encapsulated nanoparticles were first characterized for size, surface charge, encapsulation efficiency and in vitro release of PPE17 antigen. The nanoparticles were then administered intranasal and subcutaneously to evaluate the induction of systemic and/or mucosal immune responses in mice. RESULTS: According to our result, the mean size of nanoparticles was measured about 427 nm, and exhibited a negative zeta potential of -37 mV. Following subcutaneous and intranasal administration, the results from cytokines assay showed that an increasing in the level of IFN-γ, and adversely a decrease in the level of IL-4 (presumptive Th1 biased immune response) was happened and also a notable elicitation in IL-17 cytokine was observed. CONCLUSION: In conclusion, our study demonstrated that alginate-coated chitosan nanoparticles showed to be an effective way to improve BCG efficiency as booster strategy for subcutaneous vaccine, and also can induce strong immune responses as prime strategy through intranasal vaccination.


Assuntos
Antígenos de Bactérias , Portadores de Fármacos , Nanopartículas , Células Th1/imunologia , Vacinas contra a Tuberculose , Tuberculose/imunologia , Administração Intranasal , Alginatos/química , Alginatos/farmacologia , Animais , Antígenos de Bactérias/química , Antígenos de Bactérias/farmacologia , Quitosana/química , Quitosana/farmacologia , Portadores de Fármacos/química , Portadores de Fármacos/farmacologia , Injeções Subcutâneas , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/química , Nanopartículas/uso terapêutico , Células Th1/patologia , Tuberculose/prevenção & controle , Vacinas contra a Tuberculose/química , Vacinas contra a Tuberculose/farmacologia
7.
Front Immunol ; 12: 658843, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34276653

RESUMO

Background: Easily accessible tools that reliably stratify Mycobacterium tuberculosis (MTB) infection are needed to facilitate the improvement of clinical management. The current study attempts to reveal lymphocyte-related immune characteristics of active tuberculosis (ATB) patients and establish immunodiagnostic model for discriminating ATB from latent tuberculosis infection (LTBI) and healthy controls (HC). Methods: A total of 171 subjects consisted of 54 ATB, 57 LTBI, and 60 HC were consecutively recruited at Tongji hospital from January 2019 to January 2021. All participants were tested for lymphocyte subsets, phenotype, and function. Other examination including T-SPOT and microbiological detection for MTB were performed simultaneously. Results: Compared with LTBI and HC, ATB patients exhibited significantly lower number and function of lymphocytes including CD4+ T cells, CD8+ T cells and NK cells, and significantly higher T cell activation represented by HLA-DR and proportion of immunosuppressive cells represented by Treg. An immunodiagnostic model based on the combination of NK cell number, HLA-DR+CD3+ T cells, Treg, CD4+ T cell function, and NK cell function was built using logistic regression. Based on receiver operating characteristic curve analysis, the area under the curve (AUC) of the diagnostic model was 0.920 (95% CI, 0.867-0.973) in distinguishing ATB from LTBI, while the cut-off value of 0.676 produced a sensitivity of 81.48% (95% CI, 69.16%-89.62%) and specificity of 91.23% (95% CI, 81.06%-96.20%). Meanwhile, AUC analysis between ATB and HC according to the diagnostic model was 0.911 (95% CI, 0.855-0.967), with a sensitivity of 81.48% (95% CI, 69.16%-89.62%) and a specificity of 90.00% (95% CI, 79.85%-95.34%). Conclusions: Our study demonstrated that the immunodiagnostic model established by the combination of lymphocyte-related indicators could facilitate the status differentiation of MTB infection.


Assuntos
Interações Hospedeiro-Patógeno/imunologia , Linfócitos/imunologia , Mycobacterium tuberculosis/imunologia , Tuberculose/imunologia , Tuberculose/microbiologia , Biomarcadores , Humanos , Imunofenotipagem , Tuberculose Latente , Ativação Linfocitária/imunologia , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Linfócitos/metabolismo , Curva ROC , Tuberculose/diagnóstico
8.
Front Immunol ; 12: 661934, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34276654

RESUMO

Background: Neutrophils have been associated with lung tissue damage in many diseases, including tuberculosis (TB). Whether neutrophil count can serve as a predictor of adverse treatment outcomes is unknown. Methods: We prospectively assessed 936 patients (172 HIV-seropositive) with culture-confirmed pulmonary TB, enrolled in a multicenter prospective cohort study from different regions in Brazil, from June 2015 to June 2019, and were followed up to two years. TB patients had a baseline visit before treatment (month 0) and visits at month 2 and 6 (or at the end of TB treatment). Smear microscopy, and culture for Mycobacterium tuberculosis (MTB) were performed at TB diagnosis and during follow-up. Complete blood counts were measured at baseline. Treatment outcome was defined as either unfavorable (death, treatment failure or TB recurrence) or favorable (cure or treatment completion). We performed multivariable logistic regression, with propensity score regression adjustment, to estimate the association between neutrophil count with MTB culture result at month 2 and unfavorable treatment outcome. We used a propensity score adjustment instead of a fully adjusted regression model due to the relatively low number of outcomes. Results: Among 682 patients who had MTB culture results at month 2, 40 (5.9%) had a positive result. After regression with propensity score adjustment, no significant association between baseline neutrophil count (103/mm3) and positive MTB culture at month 2 was found among either HIV-seronegative (OR = 1.06, 95% CI = [0.95;1.19] or HIV-seropositive patients (OR = 0.77, 95% CI = [0.51; 1.20]). Of 691 TB patients followed up for at least 18 months and up to 24 months, 635 (91.9%) were either cured or completed treatment, and 56 (8.1%) had an unfavorable treatment outcome. A multivariable regression with propensity score adjustment found an association between higher neutrophil count (103/mm3) at baseline and unfavorable outcome among HIV-seronegative patients [OR= 1.17 (95% CI= [1.06;1.30]). In addition, adjusted Cox regression found that higher baseline neutrophil count (103/mm3) was associated with unfavorable treatment outcomes overall and among HIV-seronegative patients (HR= 1.16 (95% CI = [1.05;1.27]). Conclusion: Increased neutrophil count prior to anti-TB treatment initiation was associated with unfavorable treatment outcomes, particularly among HIV-seronegative patients. Further prospective studies evaluating neutrophil count in response to drug treatment and association with TB treatment outcomes are warranted.


Assuntos
Antituberculosos/uso terapêutico , Neutrófilos/imunologia , Tuberculose/tratamento farmacológico , Tuberculose/imunologia , Adulto , Antituberculosos/efeitos adversos , Brasil , Feminino , Humanos , Contagem de Leucócitos/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Escarro/microbiologia , Resultado do Tratamento , Tuberculose Pulmonar
9.
Front Immunol ; 12: 631696, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093524

RESUMO

In 2019 10 million people developed symptomatic tuberculosis (TB) disease and 1.2 million died. In active TB the inflammatory response causes tissue destruction, which leads to both acute morbidity and mortality. Tissue destruction in TB is driven by host innate immunity and mediated via enzymes, chiefly matrix metalloproteinases (MMPs) which are secreted by leukocytes and stromal cells and degrade the extracellular matrix. Here we review the growing evidence implicating platelets in TB immunopathology. TB patients typically have high platelet counts, which correlate with disease severity, and a hypercoagulable profile. Platelets are present in human TB granulomas and platelet-associated gene transcripts are increased in TB patients versus healthy controls. Platelets most likely drive TB immunopathology through their effect on other immune cells, particularly monocytes, to lead to upregulation of activation markers, increased MMP secretion, and enhanced phagocytosis. Finally, we consider current evidence supporting use of targeted anti-platelet agents in the treatment of TB due to growing interest in developing host-directed therapies to limit tissue damage and improve treatment outcomes. In summary, platelets are implicated in TB disease and contribute to MMP-mediated tissue damage via their cellular interactions with other leukocytes, and are potential targets for novel host-directed therapies.


Assuntos
Ativação Plaquetária/imunologia , Tuberculose/imunologia , Plaquetas/efeitos dos fármacos , Plaquetas/imunologia , Matriz Extracelular/imunologia , Humanos , Imunidade Inata/efeitos dos fármacos , Inflamação , Leucócitos/efeitos dos fármacos , Leucócitos/imunologia , Ativação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Tuberculose/tratamento farmacológico
10.
PLoS One ; 16(6): e0253169, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34143810

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has created a remarkable and varying impact in every country, inciting calls for broad attention. Recently, the Bacillus Calmette-Guérin (BCG) vaccination has been regarded as a potential candidate to explain this difference. Herein, we hypothesised that the past epidemic of Mycobacterium tuberculosis (M. tuberculosis) may act as a latent explanatory factor for the worldwide differences seen in COVID-19 impact on mortality and incidence. We compared two indicators of past epidemic of M. tuberculosis, specifically, incidence (90 countries in 1990) and mortality (28 countries in 1950), with the mortality and incidence of COVID-19. We determined that an inverse relationship existed between the past epidemic indicators of M. tuberculosis and current COVID-19 impact. The rate ratio of the cumulative COVID-19 mortality per 1 million was 2.70 (95% confidence interval [CI]: 1.09-6.68) per 1 unit decrease in the incidence rate of tuberculosis (per 100,000 people). The rate ratio of the cumulative COVID-19 incidence per 1 million was 2.07 (95% CI: 1.30-3.30). This association existed even after adjusting for potential confounders (rate of people aged 65 over, diabetes prevalence, the mortality rate from cardiovascular disease, and gross domestic product per capita), leading to an adjusted rate ratio of COVID-19 mortality of 2.44, (95% CI: 1.32-4.52) and a COVID-19 incidence of 1.31 (95% CI: 0.97-1.78). After latent infection, Mycobacterium survives in the human body and may continue to stimulate trained immunity. This study suggests a possible mechanism underlying the region-based variation in the COVID-19 impact.


Assuntos
Vacina BCG/imunologia , COVID-19/prevenção & controle , Mycobacterium tuberculosis/imunologia , SARS-CoV-2/isolamento & purificação , Tuberculose/imunologia , COVID-19/epidemiologia , COVID-19/virologia , Epidemias , Humanos , Incidência , Modelos Teóricos , Mycobacterium tuberculosis/fisiologia , Prevalência , SARS-CoV-2/fisiologia , Taxa de Sobrevida , Tuberculose/epidemiologia , Tuberculose/microbiologia , Vacinação
12.
Front Immunol ; 12: 653853, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093542

RESUMO

Early secreted antigenic target of 6 kDa (ESAT-6) has recently been identified as a biomarker for the rapid diagnosis of tuberculosis. We propose a stable and reusable immunosensor for the early diagnosis of tuberculosis based on the detection and quantification of ESAT-6 via cyclic voltammetry (CV). The immunosensor was synthesized by polymerizing aniline dispersed with the reduced graphene oxide (rGO) and Ni nanoparticles, followed by surface modification of the electroconductive polyaniline (PANI) film with anti-ESAT-6 antibody. Physicochemical characterization of the prepared materials was performed by several analytical techniques, including FE-SEM, EDX, XRD, FT-IR, Raman, TGA, TPR, and BET surface area analysis. The antibody-modified Ni-rGO-PANI electrode exhibited an approximately linear response (R2 = 0.988) towards ESAT-6 during CV measurements over the potential range of -1 to +1 V. The lower detection limit for ESAT-6 was approximately 1.0 ng mL-1. The novelty of this study includes the development of the reusable Ni-rGO-PANI-based electrochemical immunosensor for the early diagnosis of tuberculosis. Furthermore, this study successfully demonstrates that electro-conductive PANI may be used as a polymeric substrate for Ni nanoparticles and rGO.


Assuntos
Antígenos de Bactérias/imunologia , Proteínas de Bactérias/imunologia , Técnicas Biossensoriais , Imunoensaio/métodos , Mycobacterium tuberculosis/imunologia , Tuberculose/diagnóstico , Tuberculose/imunologia , Grafite , Nanopartículas Metálicas , Tuberculose/microbiologia
13.
Nat Med ; 27(9): 1646-1654, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34183838

RESUMO

The pathophysiology of adverse events following programmed cell death protein 1 (PD-1) blockade, including tuberculosis (TB) and autoimmunity, remains poorly characterized. We studied a patient with inherited PD-1 deficiency and TB who died of pulmonary autoimmunity. The patient's leukocytes did not express PD-1 or respond to PD-1-mediated suppression. The patient's lymphocytes produced only small amounts of interferon (IFN)-γ upon mycobacterial stimuli, similarly to patients with inborn errors of IFN-γ production who are vulnerable to TB. This phenotype resulted from a combined depletion of Vδ2+ γδ T, mucosal-associated invariant T and CD56bright natural killer lymphocytes and dysfunction of other T lymphocyte subsets. Moreover, the patient displayed hepatosplenomegaly and an expansion of total, activated and RORγT+ CD4-CD8- double-negative αß T cells, similar to patients with STAT3 gain-of-function mutations who display lymphoproliferative autoimmunity. This phenotype resulted from excessive amounts of STAT3-activating cytokines interleukin (IL)-6 and IL-23 produced by activated T lymphocytes and monocytes, and the STAT3-dependent expression of RORγT by activated T lymphocytes. Our work highlights the indispensable role of human PD-1 in governing both antimycobacterial immunity and self-tolerance, while identifying potentially actionable molecular targets for the diagnostic and therapeutic management of TB and autoimmunity in patients on PD-1 blockade.


Assuntos
Autoimunidade/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Receptor de Morte Celular Programada 1/genética , Fator de Transcrição STAT3/genética , Tuberculose/imunologia , Autoimunidade/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Antígeno CD56/genética , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Criança , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia/efeitos adversos , Interleucina-23/genética , Interleucina-6/genética , Linfócitos Intraepiteliais/imunologia , Linfócitos Intraepiteliais/patologia , Masculino , Mycobacterium tuberculosis/patogenicidade , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Neoplasias/mortalidade , Receptor de Morte Celular Programada 1/deficiência , Tuberculose/genética , Tuberculose/mortalidade
14.
Am J Trop Med Hyg ; 105(3): 564-572, 2021 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-34181579

RESUMO

Reports on tropical infections among kidney transplant (KT) recipients have increased in recent years, mainly because of the growing number of KT programs located in tropical and subtropical areas, and greater mobility or migration between different areas of the world. Endemic in emerging and developing regions, like most countries in Latin America, tropical infections are an important cause of morbidity and mortality in this population. Tropical infections in KT recipients may exhibit different pathways for acquisition compared with those in nonrecipients, such as transmission through a graft and reactivation of a latent infection triggered by immunosuppression. Clinical presentation may differ compared with that in immunocompetent patients, and there are also particularities in diagnostic aspects, treatment, and prognosis. KT patients must be screened for latent infections and immunized properly. Last, drug-drug interactions between immunosuppressive agents and drugs used to treat tropical infections are an additional challenge in KT patients. In this review, we summarize the management of tropical infections in KT patients.


Assuntos
Infecções por Arbovirus/diagnóstico , Doença de Chagas/diagnóstico , Transplante de Rim , Leishmaniose/diagnóstico , Estrongiloidíase/diagnóstico , Tuberculose/diagnóstico , Infecções por Arbovirus/imunologia , Infecções por Arbovirus/terapia , Doença de Chagas/imunologia , Doença de Chagas/terapia , Febre de Chikungunya/diagnóstico , Febre de Chikungunya/imunologia , Febre de Chikungunya/terapia , Dengue/diagnóstico , Dengue/imunologia , Dengue/terapia , Rejeição de Enxerto/prevenção & controle , Humanos , Hospedeiro Imunocomprometido , Imunossupressores/uso terapêutico , América Latina , Leishmaniose/imunologia , Leishmaniose/terapia , Estrongiloidíase/imunologia , Estrongiloidíase/terapia , Tuberculose/imunologia , Tuberculose/terapia , Febre Amarela/diagnóstico , Febre Amarela/imunologia , Febre Amarela/terapia , Infecção por Zika virus/diagnóstico , Infecção por Zika virus/imunologia , Infecção por Zika virus/terapia
15.
J Clin Invest ; 131(11)2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34060492

RESUMO

First administered to a human subject as a tuberculosis (TB) vaccine on July 18, 1921, Bacillus Calmette-Guérin (BCG) has a long history of use for the prevention of TB and later the immunotherapy of bladder cancer. For TB prevention, BCG is given to infants born globally across over 180 countries and has been in use since the late 1920s. With about 352 million BCG doses procured annually and tens of billions of doses having been administered over the past century, it is estimated to be the most widely used vaccine in human history. While its roles for TB prevention and bladder cancer immunotherapy are widely appreciated, over the past century, BCG has been also studied for nontraditional purposes, which include (a) prevention of viral infections and nontuberculous mycobacterial infections, (b) cancer immunotherapy aside from bladder cancer, and (c) immunologic diseases, including multiple sclerosis, type 1 diabetes, and atopic diseases. The basis for these heterologous effects lies in the ability of BCG to alter immunologic set points via heterologous T cell immunity, as well as epigenetic and metabolomic changes in innate immune cells, a process called "trained immunity." In this Review, we provide an overview of what is known regarding the trained immunity mechanism of heterologous protection, and we describe the current knowledge base for these nontraditional uses of BCG.


Assuntos
Diabetes Mellitus Tipo 1/terapia , Imunidade Celular , Esclerose Múltipla/terapia , Mycobacterium bovis/imunologia , Linfócitos T/imunologia , Neoplasias da Bexiga Urinária/terapia , Viroses/terapia , Animais , Diabetes Mellitus Tipo 1/história , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/patologia , História do Século XX , História do Século XXI , Humanos , Esclerose Múltipla/história , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia , Infecções por Mycobacterium não Tuberculosas/história , Infecções por Mycobacterium não Tuberculosas/imunologia , Infecções por Mycobacterium não Tuberculosas/patologia , Infecções por Mycobacterium não Tuberculosas/prevenção & controle , Tuberculose/história , Tuberculose/imunologia , Tuberculose/prevenção & controle , Neoplasias da Bexiga Urinária/história , Neoplasias da Bexiga Urinária/imunologia , Neoplasias da Bexiga Urinária/patologia , Viroses/história , Viroses/imunologia , Viroses/patologia
16.
Front Immunol ; 12: 641378, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33953714

RESUMO

Background: Inadequate tuberculosis (TB) diagnostics, especially for discrimination between active TB (ATB) and latent TB infection (LTBI), are major hurdle in the reduction of the disease burden. The present study aims to investigate the role of lymphocyte non-specific function detection for TB diagnosis in clinical practice. Methods: A total of 208 participants including 49 ATB patients, 64 LTBI individuals, and 95 healthy controls were recruited at Tongji hospital from January 2019 to October 2020. All subjects were tested with lymphocyte non-specific function detection and T-SPOT assay. Results: Significantly positive correlation existed between lymphocyte non-specific function and phytohemagglutinin (PHA) spot number. CD4+ T cell non-specific function showed the potential for differentiating patients with negative T-SPOT results from those with positive T-SPOT results with an area under the curve (AUC) of 0.732 (95% CI, 0.572-0.893). The non-specific function of CD4+ T cells, CD8+ T cells, and NK cells was found significantly lower in ATB patients than in LTBI individuals. The AUCs presented by CD4+ T cell non-specific function, CD8+ T cell non-specific function, and NK cell non-specific function for discriminating ATB patients from LTBI individuals were 0.845 (95% CI, 0.767-0.925), 0.770 (95% CI, 0.683-0.857), and 0.691 (95% CI, 0.593-0.789), respectively. Application of multivariable logistic regression resulted in the combination of CD4+ T cell non-specific function, NK cell non-specific function, and culture filtrate protein-10 (CFP-10) spot number as the optimally diagnostic model for differentiating ATB from LTBI. The AUC of the model in distinguishing between ATB and LTBI was 0.939 (95% CI, 0.898-0.981). The sensitivity and specificity were 83.67% (95% CI, 70.96%-91.49%) and 90.63% (95% CI, 81.02%-95.63%) with the threshold as 0.57. Our established model showed superior performance to TB-specific antigen (TBAg)/PHA ratio in stratifying TB infection status. Conclusions: Lymphocyte non-specific function detection offers an attractive alternative to facilitate TB diagnosis. The three-index diagnostic model was proved to be a potent tool for the identification of different events involved in TB infection, which is helpful for the treatment and management of patients.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Técnicas Imunológicas , Células Matadoras Naturais/imunologia , Tuberculose Latente/diagnóstico , Adulto , Antígenos de Bactérias/análise , Feminino , Humanos , Tuberculose Latente/imunologia , Masculino , Pessoa de Meia-Idade , Tuberculose/diagnóstico , Tuberculose/imunologia
17.
Sci Transl Med ; 13(592)2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-33952677

RESUMO

Host immune responses at the site of Mycobacterium tuberculosis infection can mediate pathogenesis of tuberculosis (TB) and onward transmission of infection. We hypothesized that pathological immune responses would be enriched at the site of host-pathogen interactions modeled by a standardized tuberculin skin test (TST) challenge in patients with active TB compared to those without disease, and interrogated immune responses by genome-wide transcriptional profiling. We show exaggerated interleukin-17A (IL-17A) and T helper 17 (TH17) responses among 48 individuals with active TB compared to 191 with latent TB infection, associated with increased neutrophil recruitment and matrix metalloproteinase-1 expression, both involved in TB pathogenesis. Curative antimicrobial treatment reversed these observed changes. Increased IL-1ß and IL-6 responses to mycobacterial stimulation were evident both in circulating monocytes and in molecular changes at the site of TST in individuals with active TB, supporting a model in which monocyte-derived IL-1ß and IL-6 promote TH17 differentiation within tissues. Modulation of these cytokine pathways may provide a rational strategy for host-directed therapy in active TB.


Assuntos
Interleucina-17/imunologia , Tuberculose Latente , Tuberculose , Humanos , Tuberculose Latente/diagnóstico , Tuberculose Latente/imunologia , Mycobacterium tuberculosis , Tuberculose/tratamento farmacológico , Tuberculose/imunologia
18.
Emerg Microbes Infect ; 10(1): 1217-1218, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34036874

RESUMO

A simple mRNA vaccine was shown to protect mice against tuberculosis more than 15 years ago. Like COVID-19, tuberculosis is a respiratory infection killing over a million people per year. It too presents a global emergency. Can the stunning success of RNA vaccination against COVID-19 be replicated for TB?


Assuntos
Vacinas contra a Tuberculose/imunologia , Tuberculose/prevenção & controle , Vacinas Sintéticas/imunologia , Humanos , Tuberculose/imunologia , Tuberculose/microbiologia
19.
Int J Mol Sci ; 22(9)2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33946542

RESUMO

Neutrophils readily infiltrate infection foci, phagocytose and usually destroy microbes. In tuberculosis (TB), a chronic pulmonary infection caused by Mycobacterium tuberculosis (Mtb), neutrophils harbor bacilli, are abundant in tissue lesions, and their abundances in blood correlate with poor disease outcomes in patients. The biology of these innate immune cells in TB is complex. Neutrophils have been assigned host-beneficial as well as deleterious roles. The short lifespan of neutrophils purified from blood poses challenges to cell biology studies, leaving intracellular biological processes and the precise consequences of Mtb-neutrophil interactions ill-defined. The phenotypic heterogeneity of neutrophils, and their propensity to engage in cellular cross-talk and to exert various functions during homeostasis and disease, have recently been reported, and such observations are newly emerging in TB. Here, we review the interactions of neutrophils with Mtb, including subcellular events and cell fate upon infection, and summarize the cross-talks between neutrophils and lung-residing and -recruited cells. We highlight the roles of neutrophils in TB pathophysiology, discussing recent findings from distinct models of pulmonary TB, and emphasize technical advances that could facilitate the discovery of novel neutrophil-related disease mechanisms and enrich our knowledge of TB pathogenesis.


Assuntos
Mycobacterium tuberculosis/imunologia , Neutrófilos/imunologia , Tuberculose/imunologia , Animais , Interações Hospedeiro-Patógeno , Humanos , Imunidade Inata , Mycobacterium tuberculosis/fisiologia , Neutrófilos/microbiologia , Neutrófilos/patologia , Fagocitose , Tuberculose/microbiologia , Tuberculose/patologia
20.
J Clin Invest ; 131(12)2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-33945513

RESUMO

T cells are involved in control of coronavirus disease 2019 (COVID-19), but limited knowledge is available on the relationship between antigen-specific T cell response and disease severity. Here, we used flow cytometry to assess the magnitude, function, and phenotype of SARS coronavirus 2-specific (SARS-CoV-2-specific) CD4+ T cells in 95 hospitalized COVID-19 patients, 38 of them being HIV-1 and/or tuberculosis (TB) coinfected, and 38 non-COVID-19 patients. We showed that SARS-CoV-2-specific CD4+ T cell attributes, rather than magnitude, were associated with disease severity, with severe disease being characterized by poor polyfunctional potential, reduced proliferation capacity, and enhanced HLA-DR expression. Moreover, HIV-1 and TB coinfection skewed the SARS-CoV-2 T cell response. HIV-1-mediated CD4+ T cell depletion associated with suboptimal T cell and humoral immune responses to SARS-CoV-2, and a decrease in the polyfunctional capacity of SARS-CoV-2-specific CD4+ T cells was observed in COVID-19 patients with active TB. Our results also revealed that COVID-19 patients displayed reduced frequency of Mycobacterium tuberculosis-specific CD4+ T cells, with possible implications for TB disease progression. These results corroborate the important role of SARS-CoV-2-specific T cells in COVID-19 pathogenesis and support the concept of altered T cell functions in patients with severe disease.


Assuntos
Linfócitos T CD4-Positivos/imunologia , COVID-19/imunologia , Coinfecção/imunologia , HIV-1/imunologia , Mycobacterium tuberculosis/imunologia , SARS-CoV-2/imunologia , Tuberculose/imunologia , Adulto , Idoso , Linfócitos T CD4-Positivos/patologia , COVID-19/patologia , Coinfecção/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Tuberculose/patologia
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